DNA双链断裂修复基因多态性与乳头状甲状腺癌基因重排的相关性分析
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摘要
目的
探索中国人乳头状甲状腺癌RET基因重排、BRAF突变、H4-PTEN基因重排的发生情况及其临床病理相关性,研究DNA双链断裂修复基因XRCC3的多态性与乳头状甲状腺癌的遗传易感性和基因重排发生的相关性。
材料与方法
第一部分
143例甲状腺肿瘤组织、瘤旁正常组织的RNA抽提及逆转录合成cDNA,其中包括6例结节性甲状腺肿,2例滤泡性腺瘤,7例甲状腺髓样癌和126例乳头状甲状腺癌。以cDNA为模板进行RET基因重排方式RET/PTC-1、RET/PTC-2、RET/PTC-3、ELKS/RET的PCR扩增和测序鉴定。对RET重排阳性和阴性的病人的临床病理特点进行分析。
第二部分
125例乳头状甲状腺癌组织、癌旁正常组织RNA和基因组DNA的抽提,以RNA为模板合成cDNA。以DNA为模板进行BRAF外显子PCR扩增及测序鉴定,比对癌及癌旁正常组织的序列,进行BRAF的突变分析。以cDNA为模板进行H4与PTEN基因重排产物的PCR扩增,测序鉴定,根据H4/PTEN的重排方式,设计PTEN/H4引物进行回复性重排的PCR扩增和测序鉴定。综合分析RET重排、H4-PTEN重排、BRAF突变在乳头状甲状腺癌的发生情况及其与临床病理之间的相关性和生物学意义。
第三部分
173例乳头状甲状腺癌病人以及120名正常对照群体血样基因组DNA的抽提,以DNA为模板进行DNA双链断裂修复基因XRCC3外显子的PCR扩增。运用DGGE(变性梯度凝胶电泳,Denatured Gradient Gel Electrophoresis)对PCR产物进行突变分析。根据DGGE结果,对阳性的外显子PCR产物进行测序鉴定。基于病人和正常人的XRCC3多态性的病例-正常对照分析,进行XRCC3多态性与乳头状甲状腺癌的遗传易感性的相关性研究。基于基因重排阳性病人和基因重排阴性病人的XRCC3基因多态性差异的病例之间对照分析,进行DNA双链断裂修复基因与基因重排的相关性分析。
结果
第一部分
在126例乳头状甲状腺癌组织中,发现了18例(14.3%)RET基因重排,包括12例RET/PTC-1和6例RET/PTC-3,癌旁正常甲状腺组织、非乳头状甲状腺癌肿瘤组织未发现RET重排,所有组织没有发现RET/PTC-2、ELKS/RET重排。RET重排在年龄＜20岁、20-40岁和≥40岁三组中的概率分别为:50%、14.6%和11.1%,年龄＜20岁的群体的RET重排的概率最高(P=0.033)。RET/PTC-1阳性的病例更容易在良性甲状腺疾病的基础上伴随乳头状甲状腺癌(P=0.021),尤其是甲状腺炎的基础上;RET/PTC-3阳性的病例具有高的甲状腺外侵犯的特点(P=0.005),同时其分期也相对较晚(P=0.007)。通过多因素的回归分析,RET重排(OR=8.703,95%CI 1.690-44.818),男性(OR=3.875,95%CI 1.405-10.685),年龄(OR=0.964,95%CI 0.933-0.996),多灶性(OR=3.543,95%CI 1.333-9.416)和晚期的T分类(OR=7.318,95%CI2.910-18.400)是乳头状甲状腺癌颈侧区(Ⅱ-Ⅴ区)淋巴结转移的高危因素。
第二部分
在125例乳头状甲状腺癌中,58例发现了BRAF突变V600E(46.4%),12例为RET/PTC-1(9.6%),6例为RET/PTC-3(4.8%),6例H4/PTEN重排(4.8%),7例发现了PTEN/H4重排(5.6%)。在BRAF突变阳性的病人中,11例(19.0%)同时检测出了一种或者多种的重排,同时在RET/PTC和H4-PTEN阳性的样本中,发生另外一种突变的概率分别为38.9%(7/18)和75%(9/12),多重分子改变群体比单种分子病理改变和没有分子病理改变的病人发病年龄要轻(P=0.019)。在发生重排的四种基因里,H4基因(CCDC4),也就是形成RET/PTC-1和H4-PTEN的基因,是最常见的涉及重排的基因(17.6%,22/125)。基因重排阳性的乳头状甲状腺癌的病人的发病年龄比那些没有基因重排的病人要年轻(36.81±12.416 VS 43.53±13.890,P=0.025),在年龄小于20岁的病人中,拥有最高的基因重排的发生率(50%),在年龄≥60岁的病人中,BRAF突变是唯一一个检测出的分子改变(81.8%)。基因重排的发生率随着年龄的增大而减少,而BRAF突变的发生率随着年龄的增大而增大。重排阳性的病人比阴性的病人具有更高的淋巴结转移的可能(92.6%VS 70.4%,P=0.018)。
第三部分
根据XRCC3(AF037222)的序列,共发现了6种多态性位点6390G＞T(位于5'-UTR)、6410A＞G(dSNP登录号:rs56377012)、14242G＞A(Val165Ile)、14304C＞T、14362T＞C、18440C＞T,6410A＞G和14304C＞T的杂合度(Heterozygosity)相对较高,在正常人群均为2.5%,正常人群中野生型等位基因的基因频率均为98.8%,其它4种多态性均为少见突变。6410A＞G和14304C＞T所显示的基因频率和基因型频率符合Hardy-Weinburg Equilibrium(P＞0.05)。6410A＞G的G等位基因与乳头状甲状腺癌的发病相关(基因频率在病例和对照分别为4.3%和1.3%),P值为0.033,OR值为3.580(95%CI,1.025-12.505)。由6410A＞G和14304C＞T两个多态性位点构成的单倍型(haplotype) A~(6410)C~(14304)为常见单倍型,在对照和病例中的发生率为97.5%与93.1%,与少见单倍型(A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304))相比,A~(6410)C~(14304)单倍型对乳头状甲状腺癌的发生具有明显的保护性作用,P值为0.017(OR 2.907,95%CI 1.170-7.224)。XRCC3 6410A＞G的A/G和GG型个体所患甲状腺癌组织的RET重排率高于AA型个体的RET重排发生率(25%V.S.14%),但差异没有统计学意义(P=0.335)。
结论
第一部分
本研究中中国人乳头状甲状腺癌仅存在RET/PTC-1和RET/PTC-3两种重排方式,在年龄＜20岁的病人群体,RET重排的概率是50%,明显高于其它的年龄群体;RET重排同乳头状甲状腺癌Ⅱ-Ⅴ区淋巴结密切相关,RET/PTC、男性、发病年龄早、多发病灶、晚期的T分类被证实为乳头状甲状腺癌侧颈部淋巴结转移的高危险因素,应当对RET/PTC阳性乳头状甲状腺癌的病人的侧颈部进行更详细的术前评估和术后随访。我们推测RET/PTC-1和RET/PTC-3在甲状腺癌的演进方面具有不同的作用,RET/PTC-1可能在乳头状甲状腺癌与甲状腺炎的相关性方面具有一定的作用。
第二部分
基因重排的发生率随着年龄的增大而减少,而BRAF突变的发生率随着年龄的增大而增大,是年龄≥60岁的病人中唯一被检测出的分子改变(81.8%)。RET重排,BRAF突变和H4-PTEN重排可以发生在同一个乳头状甲状腺癌的标本,这种多重分子病理改变容易在年轻的病人中发生。联合检测RET/PTC、BRAF突变、H4-PTEN和其他的涉及乳头状甲状腺癌分子改变的危险因素,将会提高分子标记作为一种诊断指标和靶向治疗指标的预测意义。
第三部分
XRCC3基因6410A＞G(rs56377012)G等位基因与乳头状甲状腺癌的发病相关,与另外一个SNP 14304C＞T进行的单倍型分析,发现常见单倍型A~(6410)C~(14304)与其他少见单倍型相比,对乳头状甲状腺癌的发生具有明显的保护性作用。6410A＞G的A/G和GG型个体发生RET基因重排的概率高于AA型个体的重排发生率。这些基因多态性对乳头状甲状腺癌发病的影响机制,可能是由于多态性自身作为致病因素,或者可能是由于该多态性位点与另外一个致病性多态性位点处于连锁不平衡的结果,尚需进一步实验来证实。
Objectives
To investigate the prevalance and clinicopathological significance of RET rearrangement,BRAF mutation,H4-PTEN gene rearrangement in papillary thyroid carcinoma,the association of XRCC3 gene(one of DNA double strand break repair genes) polymorphism and predisposition to papillary thyroid carcinoma or with gene rearrangement.
Subjects and Methods
PARTⅠ
One hundred and fourty three thyroid tumors were enrolled in this study which included 6 nodular goiter,2 folicular tumor,7 medullary thyroid carcinoma and 126 papillary thyroid carcinoma.Total RNA were isolated from the tumor tissues and para-tumor tissues and reversely transcribed to cDNA.RET/PTC-1,RET/PTC-2,RET/PTC-3 and ELKS/RET fusion genes were amplified by PCR and confirmed by sequencing.The clinicopathological significance of RET rearrangement was analyzed.
PARTⅡ
Total RNA and DNA of tumor and para-tumor tissues of 125 papillary thyroid carcinoma were isolated.BRAF gene coding sequence were amplified by PCR with DNA as template and sequenced.H4 and PTEN rearrangement,H4/PTEN,was amplified by PCR with cDNA as template and sequenced.According to the sequencing results of H4/PTEN,new primers were designed to amplify PTEN/H4,the reciprocal rearrangement of H4/PTEN,and the PCR products were sequenced to confirm the rearrangement style.The interaction,exclusivity and clinicopathological significance of RET rearrangement,BRAF mutation and H4-PTEN rearrangement were analyzed.
PARTⅢ
The genomic DNA of 173 papillary thyroid carcinoma patients and 120 normal controls were isolated and used as the template to amplify the DNA double strand break repair gene XRCC3 exons.The PCR products were electrophoresed on DGGE(Denatured Gradient Gel Electrophoresis) system to detect the mutaions.The mutation positive exons were reamplified and sequenced from both the cases and controls to get the mutation allele. Association study of XRCC3 polymorphism and papillary thyroid carcinoma predisposition were analyzed by case-control study including the patients and normal controls.The XRCC3 polymorphisms were compared between the gene rearrangement positive patients and negative patients to get the relationship of DNA double strand break repair gene polymorphisms and gene rearrangement.
Results
PARTⅠ
RET rearrangement,which included 12 RET/PTC-1 and 6 RET/PTC-3,was only detected in 14.3%(18 of 126) of PTC and was not observed in non-PTC thyroid tumor and para-tumor normal tissues.No RET/PTC-2 and ELKS/RET were detected in this serial study.The patient group of age＜20 years had the highest frequency(50%) of RET rearrangement among the groups of age＜20 years,20-40 years and≥40 years(P = 0.033).RET/PTC-1 positive patients were more easily to suffer from another benign thyroid disease simultaneously(P=0.021),especially thyroiditis.RET/PTC-3 positive patients had a higher frequency of extrathyroidal extension(P =0.005) and advanced T classification(P = 0.007).RET rearrangement (OR = 8.703,95%CI 1.690-44.818),male(OR = 3.875,95%CI 1.405-10.685), age(OR = 0.964,95%CI 0.933-0.996),multifocality(OR = 3.543,95%CI 1.333-9.416) and advanced T classification(OR = 7.318,95%CI 2.910-18.400) were all identified as risk factors of levelⅡ-Ⅴlymph node involvement in the multivariate analysis.
PARTⅡ
Among 125 cases of papillary thyroid carcinoma,58 cases of BRAF mutation(46.4%),12 cases of RET/PTC-1(9.6%),6 cases of RET/PTC-3(4.8%),6 cases of H4/PTEN(4.8%) and 7 cases of PTEN/H4(5.6%) were dectected.Eleven cases(19.0%) of BRAF mutation positive patients were found with another genetic aberration and the frequency of multi-genetic aberrantions of RET rearrangement and H4-PTEN rearrangement were 38.9%(7/18)and 75%(9/12),respectively.H4 gene (CCDC4),the fusion parter of RET/PTC-1 and H4-PTEN,is the most frequently involved gene in rearrangement(17.6%,22/125).The age of gene rearrangement positive patients was younger than that of the negative patients(36.81±12.416 VS 43.53±13.890,P= 0.025),and the highest frequency of gene rearrangement were detected in patients with age＜20 years(50%).BRAF was the only genetic aberration in patients of age≥60 years(81.8%).The frequency of gene rearrangement was decreasing with the age while the trendency of BRAF mutation was reverse.Rearrangment positive patients had a higher lymph node involvement than negative patients(92.6%VS 70.4%,P=0.018).
PARTⅢ
According to the sequence of XRCC3(AF037222),6 SNPs were detected,which included 6390G＞T(located at 5' -UTR),6410A＞G(dSNP number:rs56377012),14242G＞A(Val165Ile),14304C＞T,14362T＞C and 18440C＞T.The heterozygosity of both 6410A＞G and 14304C＞T of normal controls were 2.5%,and their wild type allele frequcncy were 98.8%, while other four polymorphisms were incidental mutation with lower heterozygosity.The allelic and genotypic frequency of 6410A＞G and 14304C＞T were tested with Hardy-Weinburg Equilibrium(P＞0.05).6410A＞G allele G was associated with papillary thyroid carcinoma(the allele frequency of case and control were 4.3%and 1.3%,respectively),P =0.033(OR 3.580,95%CI 1.025-12.505).Haplotylpe analysis of 6410A＞G and 14304C＞T showed that the frequency of haplotype A~(6410)C~(14304) at case and control were 97.5%and 93.1%,and haplotype A~(6410)C~(14304) had a protective effect on papillary thyroid carcinoma genetic predisposition(P=0.017,OR 2.907,95%CI 1.170-7.224) when compared with the less frequent haplotypes (A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304)).The frequency of RET rearrangement of tumor samples of XRCC3 6410A＞G A/G and GG cases were higer than the XRCC3 6410A＞G AA cases(25%V.S.14%,P=0.335).
Conclusion
PARTⅠ
Only two RET rearrangements,RET/PTC-1 and RET/PTC-3,were detected in Chinese patients with papillary thyroid carcinoma in the present study.The patients with age＜20 years have the highest frequency of RET rearrangement among the four age groups(50%).RET rearrangement is associated with LevelⅡ-Ⅴlymph node metastasis.Male,young age, multifocality,advanced T classification and RET rearrangement were indentified as the risk factors of lateral neck lymph node metastasis. Serious pre-operative scanning and intensive post-operative followup should be performed to the patients with the risk factors.RET/PTC-1 and RET/PTC-3 have different role in the progression of throid cancer,and RET/PTC-1 may be associated with thyroiditis.
PARTⅡ
The frequency of gene rearrangement was decreasing with the increasing age.While BRAF mutation was the only genetic aberration of papillary thyroid carcinoma in patients of age≥60 years(81.8%) and have a reverse trendency.RET rearrangement,BRAF mutation and H4-PTEN rearrangement can be detected in one tumor sample simultaneously, especially in patients with young age.The predictive value of molecular changes as a diagnostic and target therapeutic markers will be improved by screening RET rearrangement,BRAF mutation,H4-PTEN rearrangement and other possibly involved genes together.
PARTⅢ
XRCC3 gene 6410A＞G(rs56377012)G allele is associated with papillary thyroid carcinoma risk.Haplotylpe analysis of 6410A＞G and 14304C＞T shows that haplotype A~(6410)C~(14304) has a protective effect on papillary thyroid carcinoma genetic predisposition compared with the less frequent haplotype(A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304)).The frequency of RET rearrangement of tumor samples of XRCC3 6410A＞G A/G and GG cases is higer than that of XRCC3 6410A＞G AA cases.These SNPs may affect the papillary thyroid carcinoma risk as a potential etiological factor or just becase of linkage disequilibrium with another etiological SNP.Futher experiments need to be carried out to confirm these associations.
探索中国人乳头状甲状腺癌RET基因重排、BRAF突变、H4-PTEN基因重排的发生情况及其临床病理相关性,研究DNA双链断裂修复基因XRCC3的多态性与乳头状甲状腺癌的遗传易感性和基因重排发生的相关性。
材料与方法
第一部分
143例甲状腺肿瘤组织、瘤旁正常组织的RNA抽提及逆转录合成cDNA,其中包括6例结节性甲状腺肿,2例滤泡性腺瘤,7例甲状腺髓样癌和126例乳头状甲状腺癌。以cDNA为模板进行RET基因重排方式RET/PTC-1、RET/PTC-2、RET/PTC-3、ELKS/RET的PCR扩增和测序鉴定。对RET重排阳性和阴性的病人的临床病理特点进行分析。
第二部分
125例乳头状甲状腺癌组织、癌旁正常组织RNA和基因组DNA的抽提,以RNA为模板合成cDNA。以DNA为模板进行BRAF外显子PCR扩增及测序鉴定,比对癌及癌旁正常组织的序列,进行BRAF的突变分析。以cDNA为模板进行H4与PTEN基因重排产物的PCR扩增,测序鉴定,根据H4/PTEN的重排方式,设计PTEN/H4引物进行回复性重排的PCR扩增和测序鉴定。综合分析RET重排、H4-PTEN重排、BRAF突变在乳头状甲状腺癌的发生情况及其与临床病理之间的相关性和生物学意义。
第三部分
173例乳头状甲状腺癌病人以及120名正常对照群体血样基因组DNA的抽提,以DNA为模板进行DNA双链断裂修复基因XRCC3外显子的PCR扩增。运用DGGE(变性梯度凝胶电泳,Denatured Gradient Gel Electrophoresis)对PCR产物进行突变分析。根据DGGE结果,对阳性的外显子PCR产物进行测序鉴定。基于病人和正常人的XRCC3多态性的病例-正常对照分析,进行XRCC3多态性与乳头状甲状腺癌的遗传易感性的相关性研究。基于基因重排阳性病人和基因重排阴性病人的XRCC3基因多态性差异的病例之间对照分析,进行DNA双链断裂修复基因与基因重排的相关性分析。
结果
第一部分
在126例乳头状甲状腺癌组织中,发现了18例(14.3%)RET基因重排,包括12例RET/PTC-1和6例RET/PTC-3,癌旁正常甲状腺组织、非乳头状甲状腺癌肿瘤组织未发现RET重排,所有组织没有发现RET/PTC-2、ELKS/RET重排。RET重排在年龄＜20岁、20-40岁和≥40岁三组中的概率分别为:50%、14.6%和11.1%,年龄＜20岁的群体的RET重排的概率最高(P=0.033)。RET/PTC-1阳性的病例更容易在良性甲状腺疾病的基础上伴随乳头状甲状腺癌(P=0.021),尤其是甲状腺炎的基础上;RET/PTC-3阳性的病例具有高的甲状腺外侵犯的特点(P=0.005),同时其分期也相对较晚(P=0.007)。通过多因素的回归分析,RET重排(OR=8.703,95%CI 1.690-44.818),男性(OR=3.875,95%CI 1.405-10.685),年龄(OR=0.964,95%CI 0.933-0.996),多灶性(OR=3.543,95%CI 1.333-9.416)和晚期的T分类(OR=7.318,95%CI2.910-18.400)是乳头状甲状腺癌颈侧区(Ⅱ-Ⅴ区)淋巴结转移的高危因素。
第二部分
在125例乳头状甲状腺癌中,58例发现了BRAF突变V600E(46.4%),12例为RET/PTC-1(9.6%),6例为RET/PTC-3(4.8%),6例H4/PTEN重排(4.8%),7例发现了PTEN/H4重排(5.6%)。在BRAF突变阳性的病人中,11例(19.0%)同时检测出了一种或者多种的重排,同时在RET/PTC和H4-PTEN阳性的样本中,发生另外一种突变的概率分别为38.9%(7/18)和75%(9/12),多重分子改变群体比单种分子病理改变和没有分子病理改变的病人发病年龄要轻(P=0.019)。在发生重排的四种基因里,H4基因(CCDC4),也就是形成RET/PTC-1和H4-PTEN的基因,是最常见的涉及重排的基因(17.6%,22/125)。基因重排阳性的乳头状甲状腺癌的病人的发病年龄比那些没有基因重排的病人要年轻(36.81±12.416 VS 43.53±13.890,P=0.025),在年龄小于20岁的病人中,拥有最高的基因重排的发生率(50%),在年龄≥60岁的病人中,BRAF突变是唯一一个检测出的分子改变(81.8%)。基因重排的发生率随着年龄的增大而减少,而BRAF突变的发生率随着年龄的增大而增大。重排阳性的病人比阴性的病人具有更高的淋巴结转移的可能(92.6%VS 70.4%,P=0.018)。
第三部分
根据XRCC3(AF037222)的序列,共发现了6种多态性位点6390G＞T(位于5'-UTR)、6410A＞G(dSNP登录号:rs56377012)、14242G＞A(Val165Ile)、14304C＞T、14362T＞C、18440C＞T,6410A＞G和14304C＞T的杂合度(Heterozygosity)相对较高,在正常人群均为2.5%,正常人群中野生型等位基因的基因频率均为98.8%,其它4种多态性均为少见突变。6410A＞G和14304C＞T所显示的基因频率和基因型频率符合Hardy-Weinburg Equilibrium(P＞0.05)。6410A＞G的G等位基因与乳头状甲状腺癌的发病相关(基因频率在病例和对照分别为4.3%和1.3%),P值为0.033,OR值为3.580(95%CI,1.025-12.505)。由6410A＞G和14304C＞T两个多态性位点构成的单倍型(haplotype) A~(6410)C~(14304)为常见单倍型,在对照和病例中的发生率为97.5%与93.1%,与少见单倍型(A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304))相比,A~(6410)C~(14304)单倍型对乳头状甲状腺癌的发生具有明显的保护性作用,P值为0.017(OR 2.907,95%CI 1.170-7.224)。XRCC3 6410A＞G的A/G和GG型个体所患甲状腺癌组织的RET重排率高于AA型个体的RET重排发生率(25%V.S.14%),但差异没有统计学意义(P=0.335)。
结论
第一部分
本研究中中国人乳头状甲状腺癌仅存在RET/PTC-1和RET/PTC-3两种重排方式,在年龄＜20岁的病人群体,RET重排的概率是50%,明显高于其它的年龄群体;RET重排同乳头状甲状腺癌Ⅱ-Ⅴ区淋巴结密切相关,RET/PTC、男性、发病年龄早、多发病灶、晚期的T分类被证实为乳头状甲状腺癌侧颈部淋巴结转移的高危险因素,应当对RET/PTC阳性乳头状甲状腺癌的病人的侧颈部进行更详细的术前评估和术后随访。我们推测RET/PTC-1和RET/PTC-3在甲状腺癌的演进方面具有不同的作用,RET/PTC-1可能在乳头状甲状腺癌与甲状腺炎的相关性方面具有一定的作用。
第二部分
基因重排的发生率随着年龄的增大而减少,而BRAF突变的发生率随着年龄的增大而增大,是年龄≥60岁的病人中唯一被检测出的分子改变(81.8%)。RET重排,BRAF突变和H4-PTEN重排可以发生在同一个乳头状甲状腺癌的标本,这种多重分子病理改变容易在年轻的病人中发生。联合检测RET/PTC、BRAF突变、H4-PTEN和其他的涉及乳头状甲状腺癌分子改变的危险因素,将会提高分子标记作为一种诊断指标和靶向治疗指标的预测意义。
第三部分
XRCC3基因6410A＞G(rs56377012)G等位基因与乳头状甲状腺癌的发病相关,与另外一个SNP 14304C＞T进行的单倍型分析,发现常见单倍型A~(6410)C~(14304)与其他少见单倍型相比,对乳头状甲状腺癌的发生具有明显的保护性作用。6410A＞G的A/G和GG型个体发生RET基因重排的概率高于AA型个体的重排发生率。这些基因多态性对乳头状甲状腺癌发病的影响机制,可能是由于多态性自身作为致病因素,或者可能是由于该多态性位点与另外一个致病性多态性位点处于连锁不平衡的结果,尚需进一步实验来证实。
Objectives
To investigate the prevalance and clinicopathological significance of RET rearrangement,BRAF mutation,H4-PTEN gene rearrangement in papillary thyroid carcinoma,the association of XRCC3 gene(one of DNA double strand break repair genes) polymorphism and predisposition to papillary thyroid carcinoma or with gene rearrangement.
Subjects and Methods
PARTⅠ
One hundred and fourty three thyroid tumors were enrolled in this study which included 6 nodular goiter,2 folicular tumor,7 medullary thyroid carcinoma and 126 papillary thyroid carcinoma.Total RNA were isolated from the tumor tissues and para-tumor tissues and reversely transcribed to cDNA.RET/PTC-1,RET/PTC-2,RET/PTC-3 and ELKS/RET fusion genes were amplified by PCR and confirmed by sequencing.The clinicopathological significance of RET rearrangement was analyzed.
PARTⅡ
Total RNA and DNA of tumor and para-tumor tissues of 125 papillary thyroid carcinoma were isolated.BRAF gene coding sequence were amplified by PCR with DNA as template and sequenced.H4 and PTEN rearrangement,H4/PTEN,was amplified by PCR with cDNA as template and sequenced.According to the sequencing results of H4/PTEN,new primers were designed to amplify PTEN/H4,the reciprocal rearrangement of H4/PTEN,and the PCR products were sequenced to confirm the rearrangement style.The interaction,exclusivity and clinicopathological significance of RET rearrangement,BRAF mutation and H4-PTEN rearrangement were analyzed.
PARTⅢ
The genomic DNA of 173 papillary thyroid carcinoma patients and 120 normal controls were isolated and used as the template to amplify the DNA double strand break repair gene XRCC3 exons.The PCR products were electrophoresed on DGGE(Denatured Gradient Gel Electrophoresis) system to detect the mutaions.The mutation positive exons were reamplified and sequenced from both the cases and controls to get the mutation allele. Association study of XRCC3 polymorphism and papillary thyroid carcinoma predisposition were analyzed by case-control study including the patients and normal controls.The XRCC3 polymorphisms were compared between the gene rearrangement positive patients and negative patients to get the relationship of DNA double strand break repair gene polymorphisms and gene rearrangement.
Results
PARTⅠ
RET rearrangement,which included 12 RET/PTC-1 and 6 RET/PTC-3,was only detected in 14.3%(18 of 126) of PTC and was not observed in non-PTC thyroid tumor and para-tumor normal tissues.No RET/PTC-2 and ELKS/RET were detected in this serial study.The patient group of age＜20 years had the highest frequency(50%) of RET rearrangement among the groups of age＜20 years,20-40 years and≥40 years(P = 0.033).RET/PTC-1 positive patients were more easily to suffer from another benign thyroid disease simultaneously(P=0.021),especially thyroiditis.RET/PTC-3 positive patients had a higher frequency of extrathyroidal extension(P =0.005) and advanced T classification(P = 0.007).RET rearrangement (OR = 8.703,95%CI 1.690-44.818),male(OR = 3.875,95%CI 1.405-10.685), age(OR = 0.964,95%CI 0.933-0.996),multifocality(OR = 3.543,95%CI 1.333-9.416) and advanced T classification(OR = 7.318,95%CI 2.910-18.400) were all identified as risk factors of levelⅡ-Ⅴlymph node involvement in the multivariate analysis.
PARTⅡ
Among 125 cases of papillary thyroid carcinoma,58 cases of BRAF mutation(46.4%),12 cases of RET/PTC-1(9.6%),6 cases of RET/PTC-3(4.8%),6 cases of H4/PTEN(4.8%) and 7 cases of PTEN/H4(5.6%) were dectected.Eleven cases(19.0%) of BRAF mutation positive patients were found with another genetic aberration and the frequency of multi-genetic aberrantions of RET rearrangement and H4-PTEN rearrangement were 38.9%(7/18)and 75%(9/12),respectively.H4 gene (CCDC4),the fusion parter of RET/PTC-1 and H4-PTEN,is the most frequently involved gene in rearrangement(17.6%,22/125).The age of gene rearrangement positive patients was younger than that of the negative patients(36.81±12.416 VS 43.53±13.890,P= 0.025),and the highest frequency of gene rearrangement were detected in patients with age＜20 years(50%).BRAF was the only genetic aberration in patients of age≥60 years(81.8%).The frequency of gene rearrangement was decreasing with the age while the trendency of BRAF mutation was reverse.Rearrangment positive patients had a higher lymph node involvement than negative patients(92.6%VS 70.4%,P=0.018).
PARTⅢ
According to the sequence of XRCC3(AF037222),6 SNPs were detected,which included 6390G＞T(located at 5' -UTR),6410A＞G(dSNP number:rs56377012),14242G＞A(Val165Ile),14304C＞T,14362T＞C and 18440C＞T.The heterozygosity of both 6410A＞G and 14304C＞T of normal controls were 2.5%,and their wild type allele frequcncy were 98.8%, while other four polymorphisms were incidental mutation with lower heterozygosity.The allelic and genotypic frequency of 6410A＞G and 14304C＞T were tested with Hardy-Weinburg Equilibrium(P＞0.05).6410A＞G allele G was associated with papillary thyroid carcinoma(the allele frequency of case and control were 4.3%and 1.3%,respectively),P =0.033(OR 3.580,95%CI 1.025-12.505).Haplotylpe analysis of 6410A＞G and 14304C＞T showed that the frequency of haplotype A~(6410)C~(14304) at case and control were 97.5%and 93.1%,and haplotype A~(6410)C~(14304) had a protective effect on papillary thyroid carcinoma genetic predisposition(P=0.017,OR 2.907,95%CI 1.170-7.224) when compared with the less frequent haplotypes (A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304)).The frequency of RET rearrangement of tumor samples of XRCC3 6410A＞G A/G and GG cases were higer than the XRCC3 6410A＞G AA cases(25%V.S.14%,P=0.335).
Conclusion
PARTⅠ
Only two RET rearrangements,RET/PTC-1 and RET/PTC-3,were detected in Chinese patients with papillary thyroid carcinoma in the present study.The patients with age＜20 years have the highest frequency of RET rearrangement among the four age groups(50%).RET rearrangement is associated with LevelⅡ-Ⅴlymph node metastasis.Male,young age, multifocality,advanced T classification and RET rearrangement were indentified as the risk factors of lateral neck lymph node metastasis. Serious pre-operative scanning and intensive post-operative followup should be performed to the patients with the risk factors.RET/PTC-1 and RET/PTC-3 have different role in the progression of throid cancer,and RET/PTC-1 may be associated with thyroiditis.
PARTⅡ
The frequency of gene rearrangement was decreasing with the increasing age.While BRAF mutation was the only genetic aberration of papillary thyroid carcinoma in patients of age≥60 years(81.8%) and have a reverse trendency.RET rearrangement,BRAF mutation and H4-PTEN rearrangement can be detected in one tumor sample simultaneously, especially in patients with young age.The predictive value of molecular changes as a diagnostic and target therapeutic markers will be improved by screening RET rearrangement,BRAF mutation,H4-PTEN rearrangement and other possibly involved genes together.
PARTⅢ
XRCC3 gene 6410A＞G(rs56377012)G allele is associated with papillary thyroid carcinoma risk.Haplotylpe analysis of 6410A＞G and 14304C＞T shows that haplotype A~(6410)C~(14304) has a protective effect on papillary thyroid carcinoma genetic predisposition compared with the less frequent haplotype(A~(6410)T~(14304),G~(6410)C~(14304),G~(6410)T~(14304)).The frequency of RET rearrangement of tumor samples of XRCC3 6410A＞G A/G and GG cases is higer than that of XRCC3 6410A＞G AA cases.These SNPs may affect the papillary thyroid carcinoma risk as a potential etiological factor or just becase of linkage disequilibrium with another etiological SNP.Futher experiments need to be carried out to confirm these associations.
引文
[1] Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas.Prevalence by palpation and ultrasonography [J]. Arch Intern Med,1994,154(16): 1838-1840.
[2] 上海市疾病预防控制中心.2005年上海市市区恶性肿瘤发病病率[J],肿瘤,2008,28(8):726.
[3] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008 [J]. CA Cancer J Clin, 2008, 58(2):71-96.
[4] Merino MJ, Middleton LP. Pathology of the Thyroid. Pilch BZ, editor.Philadelphia: Lippincott Williams & Wilkins; 2001. 350 p.
[5] Roman S, Mehta P, Sosa JA. Medullary thyroid cancer: early detection and novel treatments [J]. Curr Opin Oncol, 2009, 21 (1): 5-10.
[6] Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma [J]. World J Surg,2007, 31(5):957-968.
[7] Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ,Roeher HD, Wah1 RA, Lamesch P, Raue F, Conte-Devolx B and others. Early malignant progression of hereditary medullary thyroid cancer [J]. N Engl J Med, 2003, 349 (16):1517-1525.
[8] Cardon LR, Bell JI. Association study designs for complex diseases [J].Nat Rev Genet, 2001, 2(2):91-99.
[9] Prazeres HJ, Rodrigues F, Soares P, Naidenov P, Figueiredo P, Campos B,Lacerda M, Martins TC. Loss of heterozygosity at 19pl3. 2 and 2q21 in tumours from familial clusters of non-medullary thyroid carcinoma [J].Fam Cancer, 2008, 7(2):141-149.
[10] He H, Nagy R, Liyanarachchi S, Jiao H, Li W, Suster S, Kere J, de la Chapelle A. A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24 [J]. Cancer Res, 2009, 69(2):625-631.
[11] Cavaco BM, Batista PF, Sobrinho LG, Leite V. Mapping a new familial thyroid epithelial neoplasia susceptibility locus to chromosome 8p23. l-p22 by high-density single-nucleotide polymorphism genome-wide linkage analysis [J]. J Clin Endocrinol Metab, 2008,93(11):4426-4430.
[12] Baida A, Akdi M, Gonzalez-Flores E, Galofre P, Marcos R, Velazquez A. Strong association of chromosome lpl2 loci with thyroid cancer susceptibility[J].Cancer Epidemiol Biomarkers Prey,2008,17(6):1499-1504.
[13]Gudmundsson J,Sulem P,Gudbjartsson DF,Jonasson JG,Sigurdsson A,Bergthorsson JT,He H,Blondal T,Geller F,Jakobsdottir M and others.Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations[J].Nat Genet,2009.
[14]Tabor HK,Risch NJ,Myers RM.Candidate-gene approaches for studying complex genetic traits:practical considerations[J].Nat Rev Genet,2002,3(5):391-397.
[15]张荣梅.TPO与TSHR基因序列多态性与遗传性甲状腺疾病的连锁与关联研究[D].上海:复旦大学:2002.
[16]Kawabata M,Kawabata T,Nishibori M.Role of recA/RAD51 family proteins in mammals[J].Acta Med Okayama,2005,59(1):1-9.
[17]Gorbunova MP.[Cells with unusual mitochondria in the thyroid gland of an old rat][J].Tsitologiia,1979,21(7):786-792.
[18]Wang H,Boecker W,Wang H,Wang X,Guan J,Thompson LH,Nickoloff JA,Iliakis G.Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks[J].Oncogene,2004,23(3):824-834.
[19]Longhese MP,Mantiero D,Clerici M.The cellular response to chromosome breakage[J].Mol Microbiol,2006,60(5):1099-1108.
[20]Knauf JA,Ward LS,Nikiforov YE,Nikiforova M,Puxeddu E,Medvedovic M,Liron T,Mochly-Rosen D,Fagin JA.Isozyme-specific abnormalities of PKC in thyroid cancer:evidence for post-transcriptional changes in PKC epsilon[J].J Clin Endocrinol Metab,2002,87(5):2150-2159.
[21]Nakazawa T,Kondo T,Kobayashi Y,Takamura N,Murata S,Kameyama K,Muramatsu A,Ito K,Kobayashi M,Katoh R.RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country(Japan)[J].Cancer,2005,104(5):943-951.
[22]Tallini G,Asa SL.RET oncogene activation in papillary thyroid carcinoma [J].Adv Anat Pathol,2001,8(6):345-354.
[23]Sansal I,Sellers WR.The biology and clinical relevance of the PTEN tumor suppressor pathway[J].J Clin Oncol,2004,22(14):2954-2963.
[24]Frame S,Balmain A.Integration of positive and negative growth signals during ras pathway activation in vivo [J]. Curr Opin Genet Dev,2000,10(1):106-113.
[25] Zbuk KM, Patocs A, Shealy A, Sylvester H, Miesfeldt S, Eng C. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma [J]. Nat Clin Pract Oncol, 2007,4(10):608-612.
[26] Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer [J]. Cytokine Growth Factor Rev,2005,16(4-5): 441-467.
[27] Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma [J]. Cancer Res, 2003, 63(7): 1454-1457.
[28] Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, Caiazzo F, Basolo F, Giannini R, Kruhoffer M and others. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells [J]. J Clin Invest,2005,115(4): 1068-1081.
[29] Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C, Jr., Knauf JA,Zhang L, Taira K, Fagin JA. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis [J]. Endocrinology, 2006,147(2): 1014-1019.
[30] Carta C, Moretti S, Passeri L, Barbi F, Avenia N, Cavaliere A, Monacelli M, Macchiarulo A, Santeusanio F, Tartaglia M and others. Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V5991ns)) [J]. Clin Endocrinol (Oxf), 2006,64(1):105-109.
[31] Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM,Fagin JA, Nikiforov YE. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer [J]. J Clin Invest,2005, 115(1):94-101.
[32] Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC,Hong SJ and others. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma [J]. Clin Endocrinol (Oxf), 2006, 65(3):364-368.
[33] Lam KY, Lo CY, Leung PS. High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas [J]. Eur J Endocrinol,2002,147(6):741-745.
[34] Lee CH, Hsu LS, Chi CW, Chen GD, Yang AH, Chen JY. High frequency of rearrangement of the RET protooncogene (RET/PTC) in Chinese papillary thyroid carcinomas [J]. J Clin Endocrinol Metab, 1998, 83(5):1629-1632.
[35] Liu RT, Chou FF, Wang CH, Lin CL, Chao FP, Chung JC, Huang CC, Wang PW,Cheng JT. Low prevalence of RET rearrangements (RET/PTC1, RET/PTC2,RET/PTC3, and ELKS-RET) in sporadic papillary thyroid carcinomas in Taiwan Chinese [J]. Thyroid, 2005,15(4):326-335.
[36] Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ,Biddinger PW, Nikiforov YE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas [J]. Am J Surg Pathol,2006, 30(2):216-222.
[37] Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA.RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features [J].Clin Cancer Res, 1998,4(1):223-228.
[38] Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident [J]. Oncogene, 1995,11(12):2459-2467.
[39] Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological,phenotypic, and clinical implications [J]. Clin Cancer Res,2000,6(3):1093-1103.
[40] Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. ret/PTC-1, -2,and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? [J]. J Clin Endocrinol Metab,1996, 81(9): 3360-3365.
[41] Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G and others. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant [J]. J Clin Endocrinol Metab, 1999,84 (11):4232-4238.
[42] Xing M. BRAF mutation in thyroid cancer [J]. Endocr Relat Cancer,2005,12(2): 245-262.
[43] Fugazzola L, Mannavola D, Cirello V, Vannucchi G, Muzza M, Vicentini L,Beck-Peccoz P. BRAF mutations in an Italian cohort of thyroid cancers [J]. Clin Endocrinol (Oxf), 2004, 61 (2): 239-243.
[44] Sapio MR, Posca D, Troncone G, Pettinato G, Palombini L, Rossi G, Fenzi G, Vitale M. Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA) [J]. Eur J Endocrinol,2006,154(2): 341-348.
[45] Lee S, Hong SW, Moon WC, Oh MR, Lee JK, Ahn CW, Cha BS, Kim KR, Lee HC,Lim SK. High prevalence of c-RET expression in papillary thyroid carcinomas from the Korean population [J]. Thyroid, 2005,15(3):259-266.
[46] Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy [J]. J Clin Oncol, 2007, 25(7): 884-896.
[47] RhodenKJ, Unger K, Salvatore G, Yilmaz Y, Vovk V, Chiappetta G, Qumsiyeh MB, Rothstein JL, Fusco A, Santoro M and others. RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma [J]. J Clin Endocrinol Metab,2006, 91(6): 2414-2423.
[48] Milano A, Chiofalo MG, BasileM, Salzano de Luna A, Pezzullo L, Caponigro F. New molecular targeted therapies in thyroid cancer [J]. Anticancer Drugs, 2006, 17(8):869-879.
[49] Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006 [J]. CA Cancer J Clin, 2006, 56(2):106-130.
[50] Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53, 856 cases of thyroid carcinoma treated in the U. S., 1985-1995[see commetns] [J]. Cancer, 1998, 83(12):2638-2648.
[51] Holzer S, Reiners C, Mann K, Bamberg M, Rothmund M, Dudeck J, Stewart AK, Hundahl SA. Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U. S. and German Thyroid Cancer Group [J]. Cancer, 2000, 89(1): 192-201.
[52] Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, McKee RF, Rosai J, Shah JP, Fremgen AM, Stewart AK, Holzer S. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study[J]. Cancer, 2000, 89(1): 202-217.
[53] Fagin JA. Challenging dogma in thyroid cancer molecular genetics—role of RET/PTC and BRAF in tumor initiation [J]. J Clin Endocrinol Metab,2004,89(9):4264-4266.
[54] Di Cristofaro J, Vasko V, Savchenko V, Cherenko S, Larin A, Ringel MD,Saji M, Marcy M, Henry JF, Carayon P and others. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients [J]. Endocr Relat Cancer,2005,12(1):173-183.
[55] Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E,Basolo F, Demidchik EP, Miccoli P, Pinchera A and others. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults [J]. J Clin Endocrinol Metab, 2001,86(7) :3211-3216.
[56] Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, Suarez HG. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation [J]. Oncogene, 1997,15(11):1263-1273.
[57] Collins BJ, Chiappetta G, Schneider AB, Santoro M, Pentimalli F,Fogelfeld L, Gierlowski T, Shore-Freedman E, Jaffe G, Fusco A. RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions [J]. J Clin Endocrinol Metab,2002, 87(8):3941-3946.
[58] Santoro M, Papotti M, Chiappetta G, Garcia-Rostan G, Volante M, Johnson C, Camp RL, Pentimalli F, Monaco C, Herrero A and others. RET activation and clinicopathologic features in poorly differentiated thyroid tumors [J]. J Clin Endocrinol Metab, 2002, 87(1):370-379.
[59] Corvi R, Martinez-Alfaro M, Harach HR, Zini M, Papotti M, Romeo G.Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization [J]. Lab Invest,2001,81(12):1639-1645.
[60] Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? [J]. J Pathol,1998,185(1):71-78.
[61] Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia [J]. J Clin Endocrinol Metab, 1998, 83(11):4116-4122.
[62] Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G,Carcangiu ML, Fusco A. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes [J]. Clin Cancer Res, 1998, 4(2): 287-294.
[63] Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M.AJCC Cancer Staging Manual New York: Springer-Verlag; 2002.
[64] Frasoldati A, Pesenti M, Gallo M, Caroggio A, Salvo D, Valcavi R.Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma [J]. Cancer, 2003,97(1):90-96.
[65] Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality [J]. Cancer, 2003, 98(1):31-40.
[66] BritishThyroidAssociationandRoyalCollegeofPhysicians. Guidelines for the management of thyroid cancer in adults. London: Royal College of Physicians 2002.
[67] Mann B, Buhr HJ. Lymph node dissection in patients with differentiatedthyroid carcinoma—who benefits? [J]. Langenbecks Arch Surg,1998, 383(5):355-358.
[68] Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer [J]. Thyroid,
?2006,16(2):109-142.
[69] HedingerC, Williams ED, SobinLH. Histological typing of thyroid tumours. World Health Organization International Histological Classification of Tumours [M]. 2nd ed. Volume 11. Berlin: Springer-Verlag; 1988. p 3-18.
[70] Caron NR, Tan YY, Ogilvie JB, Triponez F, Reiff ES, Kebebew E, Duh QY,Clark OH. Selective Modified Radical Neck Dissection for Papillary Thyroid Cancer-Is Level I, II and V Dissection Always Necessary? [J].World J Surg, 2006, 30(5):833-840.
[71] Palazzo FF, Gosnell J, Savio R, Reeve TS, Sidhu SB, Sywak MS, Robinson B, Delbridge LW. Lymphadenectomy for papillary thyroid cancer: changes in practice over four decades [J]. Eur J Surg Oncol, 2006, 32(3): 340-344.
[72] Watkinson JC, Franklyn JA, Olliff JF. Detection and surgical treatment of cervical lymph nodes in differentiated thyroid cancer [J]. Thyroid,2006,16(2):187-194.
[73] Machens A, Holzhausen HJ, Lautenschlager C, Thanh PN, Dralle H.Enhancement of lymph node metastasis and distant metastasis of thyroid carcinoma [J]. Cancer, 2003, 98(4):712-719.
[74] Mayr B, Brabant G, Goretzki P, Ruschoff J, Dietmaier W, Dralle H.ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas:implications for metastatic potential? [J]. J Clin Endocrinol Metab,1997, 82(4):1306-1307.
[75] Cady B. Comparative analysis of thyroid carcinoma in Germany and the U. S [J]. Cancer, 2000, 89(1): 1-4.
[76] Domingues R, Mendonca E, Sobrinho L, Bugalho MJ. Searching for RET/PTC rearrangements and BRAF V600E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma [J]. Cytopathology, 2005,16(1): 27-31.
[77] Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA,Nikiforov YE, Troncone G, Palombini L, Basolo F and others. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma [J]. J Clin Endocrinol Metab, 2004,89(10):5175-5180.
[78] Cheung CC, Carydis B, Ezzat S, Bedard YC, Asa SL. Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer [J]. J Clin Endocrinol Metab, 2001, 86(5):2187-2190.
[79] Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study [J]. Cancer,2006,106(3):524-531.
[80] Noguchi S, Murakami N, YamashitaH, Toda M, Kawamoto H. Papillary thyroid carcinoma: modified radical neck dissection improves prognosis [J]. Arch Surg, 1998,133(3):276-280.
[81] Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F,Kuma K, Miyauchi A. Ultrasonographically and anatomopathologically detectable node metastases in the lateral compartment as indicators of worse relapse-free survival in patients with papillary thyroid carcinoma [J]. World J Surg, 2005, 29(7):917-920.
[82] Tronko MD, Bogdanova TI, Komissarenko IV, Epstein OV, Oliynyk V,Kovalenko A, Likhtarev IA, Kairo I, Peters SB, LiVolsi VA. Thyroid carcinoma in children and adolescents in Ukraine after the Chernobyl nuclear accident: statistical data and clinicomorphologic characteristics [J]. Cancer, 1999, 86(1):149-156.
[83] Chung JH, Hahm JR, Min YK, Lee MS, Lee MK, Kim KW, Nam SJ, Yang JH, Ree HJ. Detection of RET/PTC oncogene rearrangements in Korean papillary thyroid carcinomas [J]. Thyroid, 1999,9(12):1237-1243.
[84] Sadetzki S, Calderon-Margalit R, Modan B, Srivastava S, Tuttle RM.Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose externA1-beam irradiation in childhood [J]. J Clin Endocrinol Metab, 2004,89(5):2281-2289.
[85] Cetta F, Gori M, Montalto G, Zuckermann M, Toti P. Different significance of ret/PTC(1) and ret/PTC(3) rearrangements in thyroid carcinogenesis:lesson from two subgroups of patients with papillary thyroid carcinomas showing the highest incidence of ret/PTC activation [J]. J Clin Endocrinol Metab, 2001, 86(3):1429.
[86] Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M,Salvatore G, Chiappetta G, Pacini F, Elisei R and others. Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma [J]. Am J Pathol, 2002,160(1): 247-254.
[87] Borrello MG, Alberti L, Fischer A, Degl' innocenti D, Ferrario C,Gariboldi M, Marchesi F, Allavena P, Greco A, Collini P and others.Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC 1 oncogene [J]. Proc Natl Acad Sci U S A,2005,102(41):14825-14830.
[88] Okayasu I, Fujiwara M, Hara Y, Tanaka Y, Rose NR. Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma. A study of surgical cases among Japanese, and white and African Americans [J].Cancer, 1995, 76(11):2312-2318.
[89] Davies TF. T-cell receptor gene expression in autoimmune thyroid disease: some observations and possible mechanisms [J]. Ann N Y Acad Sci,1995,756:331-344.
[90] Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM,Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems [J]. Proc Natl Acad Sci U S A, 1999, 96(4):1563-1568.
[91] Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V,Botelho T, Seruca R, Sobrinho-Simoes M. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC [J]. Oncogene, 2003, 22(29):4578-4580.
[92] Finn SP, Smyth P, O'Regan E, Cahill S, Flavin R, O'Leary J, Sheils O. Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes [J]. Virchows Arch, 2004, 445(4):396-404.
[93] Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, Sidransky D. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis [J]. Cancer Res,2004, 64(5):1664-1668.
[94] Ciampi R, Nikiforov YE. Ret/Ptc Rearrangements and Braf Mutations in Thyroid Tumorigenesis [J]. Endocrinology, 2007, 148(3):936-941.
[95] Ouyang B, Knauf JA, Smith EP, Zhang L, Ramsey T, Yusuff N, Batt D, Fagin JA. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo [J]. Clin Cancer Res, 2006,12(6):1785-1793.
[96] Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity[J]. J Clin Endocrinol Metab,2006, 91(9):3603-3610.
[97] Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations [J]. Cancer, 2005,103(11):2261-2268.
[98] Oler G, Ebina KN, Michaluart P, Jr., Kimura ET, Cerutti J. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis reveals a new mutation in metastasis [J].Clin Endocrinol (Oxf), 2005,62(4):509-511.
[99] Lima J, Trovisco V, Soares P, Maximo V, Magalhaes J, Salvatore G, Santoro M, Bogdanova T, Tronko M, Abrosimov A and others. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas [J]. J Clin Endocrinol Metab, 2004, 89(9):4267-4271.
[100] Chung KW, Yang SK, Lee GK, Kim EY, Kwon S, Lee SH, Park do J, Lee HS,Cho BY, Lee ES and others. Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis,especially in BRAF600E mutation-prevalent area [J]. Clin Endocrinol (Oxf), 2006,65(5):660-666.
[101] Vitagliano D, Carlomagno F, Motti ML, Viglietto G, Nikiforov YE,Nikiforova MN, Hershman JM, Ryan AJ, Fusco A, Melillo RM and others.Regulation of p27Kipl protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells [J]. Cancer Res,2004, 64(11):3823-3829.
[102] UngerK, Zitzelsberger H, Salvatore G, Santoro M, Bogdanova T, Braselmann H, Kastner P, Zurnadzhy L, Tronko N, Hutzler P and others. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas [J]. J Clin Endocrinol Metab,2004,89(9):4272-4279.
[103] Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells [J]. Science, 2000, 290(5489):138-141.
[104] Roccato E, Bressan P, Sabatella G, Rumio C, Vizzotto L, Pierotti MA, Greco A. Proximity of TPR and NTRKl rearranging loci in human thyrocytes [J]. Cancer Res, 2005, 65(7):2572-2576.
[105] Schwaller J, Anastasiadou E, Cain D, Kutok J, Wojiski S, Williams IR,LaStarza R, Crescenzi B, Sternberg DW, Andreasson P and others.H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma,is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t (5; 10) (q33;q22) [J]. Blood,2001,97(12):3910-3918.
[106] Celetti A, Cerrato A, Merolla F, Vitagliano D, Vecchio G, Grieco M.H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization [J]. Oncogene,2004,23(1):109-121.
[107] Vieland VJ, Huang Y, Bartlett C, Davies TF, Tomer Y. A multilocus model of the genetic architecture of autoimmune thyroid disorder, with clinical implications [J]. Am J Hum Genet, 2008, 82(6):1349-1356.
[108] Tolone C, Cirillo G, Papparella A, Tolone S, Santoro N, Grandone A,Perrone L, Del Giudice EM. A common CTLA4 polymorphism confers susceptibility to Autoimmune Thyroid Disease in celiac children [J].Dig Liver Dis, 2008.
[109] Inoue N, Watanabe M, Nanba T, Wada M, Akamizu T, Iwatani Y. Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody [J]. Clin Exp Immunol, 2009.
[110] Ban Y, Tozaki T, Tobe T, Ban Y, Jacobson EM, Concepcion ES, Tomer Y.The regulatory T cell gene F0XP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts [J]. J Autoimmun, 2007,28(4):201-207.
[111] Hernandez A, Xamena N, Surralles J, Galofre P, Velazquez A, Creus A,Marcos R. Role of GST and NAT2 polymorphisms in thyroid cancer [J]. J Endocrinol Invest, 2008, 31(11):1025-1031.
[112] Siraj AK, A1-Rasheed M, Ibrahim M, Siddiqui K, A1-Dayel F, A1-Sanea 0,Uddin S, A1-Kuraya K. RAD52 polymorphisms contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population [J]. J Endocrinol Invest, 2008, 31 (10):893-899.
[113] Chiang FY, Wu CW, Hsiao PJ, Kuo WR, Lee KW, Lin JC, Liao YC, Juo SH.Association between polymorphisms in DNA base excision repair genes XRCC1,APE1, and ADPRT and differentiated thyroid carcinoma [J]. Clin Cancer Res, 2008,14(18):5919-5924.
[114] Lonn S, Bhatti P, Alexander BH, Pineda MA, Doody MM, Struewing JP,Sigurdson AJ. Papillary thyroid cancer and polymorphic variants in TSHR-and RET-related genes: a nested case-control study within a cohort of U. S.radiologic technologists [J]. Cancer Epidemiol Biomarkers Prev,2007,16(1):174-177.
[115] SirajAK, Ibrahim M, A1-Rasheed M, Abubaker J, Bu R, Siddiqui SU, A1-Dayel F, A1-Sanea O, A1-Nuaim A, Uddin S and others. Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population [J]. BMC Med Genet,2008,9:61.
[116] Lemos MC, Carrilho F, Rodrigues F, Coutinho E, Gomes L, Carvalheiro M,Regateiro FJ. Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer [J]. Clin Endocrinol (Oxf),2007,67(2):180-183.
[117] Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma [J]. Proc Natl Acad Sci U S A, 2008,10520):7269-7274.
[118] Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, TroviscoV, Vieira de Castro I, Cardoso-de-01iveira M, Fonseca E, Soares P and others.PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma [J]. J Clin Endocrinol Metab,2006,91(1):213-220.
[119] Fischer SG, Lerman LS. DNA fragments differing by single base-pair substitutions are separated in denaturing gradient gels: correspondence with melting theory [J]. Proc Natl Acad Sci US A, 1983,80(6):1579-1583.
[120] Lerman LS, Fischer SG, Hurley I, Silverstein K, Lumelsky N.Sequence-determined DNA separations [J]. Annu Rev Biophys Bioeng,1984,13:399-423.
[121] Myers RM, Fischer SG, Lerman LS, Maniatis T. Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresis [J]. Nucleic Acids Res,1985,13(9):3131-3145.
[122] Myers RM, Fischer SG, ManiatisT, Lerman LS. Modification of the melting properties of duplex DNA by attachment of a GC-rich DNA sequence as determined by denaturing gradient gel electrophoresis [J]. Nucleic Acids Res, 1985,13(9):3111-3129.
[123] Ardlie KG, Kruglyak L, Seielstad M. Patterns of linkage disequilibrium in the human genome [J]. Nat Rev Genet, 2002, 3(4):299-309.
[124] Shifman S, Kuypers J, Kokoris M, Yakir B, Darvasi A. Linkage disequilibrium patterns of the human genome across populations [J]. Hum Mol Genet, 2003,12(7):771-776.
[125] Ngan ES, Lang BH, Liu T, Shum CK, So MT, Lau DK, Leon TY, Cherny SS,Tsai SY, Lo CY and others. A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma [J]. J Natl Cancer Inst,2009,101(3):162-175.
[126] Adjadj E, Schlumberger M, de Vathaire F. Germ-line DNA polymorphisms and susceptibility to differentiated thyroid cancer [J]. Lancet Oncol,2009,10(2):181-190.
[127] Shi WP, Bian JC, Jiang F, Ni HX, Zhu QX, Tang HW, Shen Q, Wu Y. [Association of genetic polymorphisms and haplotypes in hMLHl and hMSH3 gene with the risk of papillary thyroid carcinoma] [J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2008, 25(4):390-395.
[128] Sturgis EM, Zhao C, Zheng R, Wei Q. Radiation response genotype and risk of differentiated thyroid cancer: a case-control analysis [J].Laryngoscope, 2005, 115(6):938-945.
[129] Tang H. Confronting ethnicity-specific disease risk [J]. Nat Genet,2006,38(1):13-15.
[130] Improta G, Sgambato A, Bianchino G, Zupa A, Grieco V, La Torre G,Traficante A, Cittadini A. Polymorphisms of the DNA repair genes XRCC1 and XRCC3 and risk of lung and colorectal cancer: a case-control study in a Southern Italian population [J]. Anticancer Res,2008, 28(5B):2941-2946.
[131] Sangrajrang S, Schmezer P, Burkholder I, Boffetta P, Brennan P,Woelfelschneider A, Bartsch H, Wiangnon S, Cheisilpa A, Popanda O. The XRCC3 Thr241Met polymorphism and breast cancer risk: a case-control study in a Thai population [J]. Biomarkers, 2007,12(5):523-532.
[132] Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P,Matullo G. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review [J]. Am J Epidemiol, 2006,164(4):297-302.
[133] Long XD, Ma Y, Qu de Y, Liu YG, Huang ZQ, Huang YZ, Lin ZH, Wei NB, Zhou SC. The polymorphism of XRCC3 codon 241 and AFBl-related hepatocellular carcinoma in Guangxi population, China [J]. Ann Epidemiol,2008,18(7):572-578.
[134] Wen SX, Zhang XM, Tang PZ, Zhao D, Guo YL, Tan W, Lin DX. [Association between genetic polymorphism in DNA repair genes XRCC3 and risks of laryngeal and hypopharyngeal carcinomas] [J]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2007, 42(11):856-859.
[135] Mateuca RA, Roelants M, Iarmarcovai G, Aka PV, Godderis L, Tremp A,Bonassi S, Fenech M, Berge-Lefranc JL, Kirsch-Volders M. hOGG1(326),XRCCK399) and XRCC3(241) polymorphisms influence micronucleus frequencies in human lymphocytes in vivo [J]. Mutagenesis,2008,23(1):35-41.
[136] LoignonM, Amrein L, Dunn M, Aloyz R. XRCC3 Depletion Induces Spontaneous DNA Breaks and p53-Dependent Cell Death [J]. Cell Cycle, 2007,6(5).
[137] AlsbeihG, E1-Sebaie M, A1-Harbi N, A1-Buhairi M, A1-Hadyan K, A1-Rajhi N. Radiosensitivity of human fibroblasts is associated with amino acid substitution variants in susceptible genes and correlates with the number of risk alleles [J]. Int J Radiat Oncol Biol Phys, 2007.
[138] Zijno A, Verdina A, Galati R, Leopardi P, Marcon F, Andreoli C, Rossi S, Crebelli R. Influence of DNA repair polymorphisms on biomarkers of genotoxic damage in peripheral lymphocytes of healthy subjects[J]. Mutat Res, 2006, 600(1-2):184-192.
[139] Halasova E, Matakova T, Musak L, Polakova V, Vodicka P. Chromosomal damage and polymorphisms of DNA repair genes XRCC1 and XRCC3 in workers exposed to chromium [J]. Neuro Endocrinol Lett, 2008, 29(5):658-662.
[140] Font A, Salazar R, Maurel J, Taron M, Ramirez JL, Tabernero J, Gallego R, Casado E, Manzano JL, Carcereny E and others. Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms [J].Cancer Chemother Pharmacol, 2008,62(6):1075-1083.
[141] Burri RJ, Stock RG, Cesaretti JA, Atencio DP, Peters S, Peters CA, Fan G, Stone NN, Ostrer H, Rosenstein BS. Association of single nucleotide polymorphisms in S0D2, XRCC1 and XRCC3 with susceptibility for the development of adverse effects resulting from radiotherapy for prostate cancer [J]. Radiat Res, 2008, 170(1):49-59.
[142] Vangsted A, GimsingP, Klausen TW, Nexo BA, WallinH, Andersen P, Hokland P, Lillevang ST, Vogel U. Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation [J]. Int J Cancer,2007,120(5):1036-1045.
[143] Dardano A, Falzoni S, Caraccio N, Polini A, Tognini S, Solini A, Berti P, Di Virgilio F, Monzani F. 1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters [J]. J Clin Endocrinol Metab, 2009, 94(2):695-698.
[144] Lemos MC, Coutinho E, Gomes L, Carrilho F, Rodrigues F, Regateiro FJ,Carvalheiro M. Combined GSTMl and GSTTl null genotypes are associated with a lower risk of papillary thyroid cancer [J]. J Endocrinol Invest,2008, 31(6):542-545.
[145] Guirouilh-Barbat J, Huck S, Bertrand P, Pirzio L, Desmaze C, Sabatier L, Lopez BS. Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells [J]. Mol Cell, 2004, 14(5):611-623.
[146] Thacker J, Zdzienicka MZ. The mammalian XRCC genes: their roles in DNA repair and genetic stability [J]. DNA Repair (Amst), 2003,2(6) :655-672.
[147] Auranen A, Song H, Waterfall C, DicioccioRA, Kuschel B, Kjaer SK, Hogdall E, Hogdall C, Stratton J, Whittemore AS and others. Polymorphisms in DNA repair genes and epithelial ovarian cancer risk [J]. Int J Cancer,2005, 117(4):611-618.
[148] Loizidou MA, Michael T, Neuhausen SL, Newbold RF, Marcou Y, Kakouri E,Daniel M, Papadopoulos P, Malas S, Kyriacou K and others. Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus [J]. Breast Cancer Res Treat,2008,112(3):575-579.
[149] Brooks J, Shore RE, Zeleniuch-Jacquotte A, Currie D, AfanasyevaY, Koenig KL, Arslan AA, Toniolo P, Wirgin I. Polymorphisms in RAD51, XRCC2, and XRCC3 are not related to breast cancer risk [J]. Cancer Epidemiol Biomarkers Prev, 2008,17(4):1016-1019.
[150] Lee SA, Lee KM, Park SK, Choi JY, Kim B, Nam J, Yoo KY, Noh DY, Ahn SH,Kang D. Genetic polymorphism of XRCC3 Thr241Met and breast cancer risk:case-control study in Korean women and meta-analysis of 12 studies [J].Breast Cancer Res Treat, 2007,103(1):71-76.
[151] Kiuru A, Lindholm C, Heinavaara S, Ilus T, Jokinen P, Haapasalo H,Salminen T, Christensen HC, Feychting M, Johansen C and others. XRCC1 and XRCC3 variants and risk of glioma and meningioma [J]. J Neurooncol,2008, 88(2): 135-142.
[152] Jiao L, Hassan MM, Bondy ML, Wolff RA, Evans DB, Abbruzzese JL, Li D.XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer [J].Am J Gastroenterol, 2008,103(2):360-367.
[153] He X, Ye F, Zhang J, Cheng Q, Shen J, Chen H. Susceptibility of XRCC3,XPD, and XPG genetic variants to cervical carcinoma [J]. Pathobiology,2008, 75(6):356-363.
[154] Fontana L, Bosviel R, Delort L, Guy L, Chalabi N, Kwiatkowski F, Satih S, Rabiau N, Boiteux JP, Chamoux A and others. DNA repair gene ERCC2, XPC,XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort [J]. Anticancer Res, 2008, 28(3B):1853-1856.
[155] Covolo L, Placidi D, Gelatti U, Carta A, Scotto Di Carlo A, Lodetti P,Picciche A, Orizio G, CampagnaM, Arici C and others. Bladder cancer, GSTs,NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case-control study [J]. Eur J Epidemiol,2008, 23(5):355-362.
[156] Lopez-Cima MF, Gonzalez-Arriaga P, Garcia-Castro L, Pascual T, Marron MG, Puente XS, Tardon A. Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain [J].BMC Cancer, 2007,7:162.
[157] Zienolddiny S, CampaD, LindH, RybergD, Skaug V, Stangeland L, Phillips DH, Canzian F, Haugen A. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer [J]. Carcinogenesis, 2006,27(3): 560-567.
[158] Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A, Becker N, de Sanjose S, ForetovaL, Maynadie M and others. Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma [J]. Hum Mol Genet, 2007,16(24):3117-312.7.
[159] Yeh CC, Sung FC, Tang R, Chang-Chieh CR, Hsieh LL. Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan [J]. J Biomed Sci, 2006.
[160] Ye W, Kumar R, Bacova G, Lagergren J, Hemminki K, Nyren 0. The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma:a population-based case-control study in Sweden [J]. Carcinogenesis,2006, 27(9):1835-1841.
[161] Abaji C, Cousineau I, Belmaaza A. BRCA2 regulates homologous recombination in response to DNA damage: implications for genome stability and carcinogenesis [J]. Cancer Res, 2005,65(10) :4117—4125.
[162] Grabsch H, Dattani M, Barker L, Maughan N, Maude K, Hansen O, Gabbert HE, Quirke P, Mueller W. Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer [J]. Clin Cancer Res, 2006,12(5):1494-1500.
[163] Kimura ET, Vanvooren V, van Sande J, Nikiforov YE, Fagin JA. Autonomously functioning thyroid nodules are not associated with BRAF mutations [J].Clin Endocrinol (Oxf), 2004, 60(3):394-396.
[164] Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Delia Porta G. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas [J]. Oncogene, 1992, 7(2):237-242.
[165] Caudill CM, Zhu Z, Ciampi R, Stringer JR, Nikiforov YE. Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation [J]. J Clin Endocrinol Metab,2005, 90(4):2364-2369.
[166] Wu G, Mambo E, Guo Z, Hu S, Huang X, Gollin SM, Trink B, Ladenson PW,Sidransky D, Xing M. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors [J]. J Clin Endocrinol Metab,2005,90(8): 4688-4693.
[167] Silva SN, Gil OM, Oliveira VC, Cabral MN, Azevedo AP, Faber A, Manita I, Ferreira TC, Limbert E, Pina JE and others. Association of polymorphisms in ERCC2 gene with non-familial thyroid cancer risk [J].Cancer Epidemiol Biomarkers Prev, 2005, 14(10):2407-2412.
[168] Ho T, Li G, Lu J, Zhao C, Wei Q, Sturgis EM. Association of XRCC1 polymorphisms and risk of differentiated thyroid carcinoma: a case-control analysis [J]. Thyroid, 2009,19(2): 129-135.
[169] Sigurdson AJ, Land CE, Bhatti P, Pineda M, Brenner A, Carr Z, Gusev BI,Zhumadilov Z, Simon SL, Bouville A and others. Thyroid nodules,polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan [J].Radiat Res, 2009,171(1):77-88.
[170] Coelho SM, Carvalho DP, Vaisman M. New perspectives on the treatment of differentiated thyroid cancer [J]. Arq Bras Endocrinol Metabol,2007, 51(4): 612-624.
[171] Riesco-Eizaguirre G, Santisteban P. New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy [J]. Endocr Relat Cancer, 2007,14(4): 957-977.
[172] McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE,Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB and others. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance [J]. Adv Enzyme Regul, 2006,46:249-279.
[173] Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, E1-Naggar AK, Xing M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers [J]. J Clin Endocrinol Metab, 2008, 93(8):3106-3116.
[174] Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R,Hermsem MJ, Herrero A, Fusco A, Cameselle-Tei jeiro J, Santoro M. Mutation of the PIK3CA gene in anaplastic thyroid cancer [J]. Cancer Res,2005, 65(22): 10199-10207.
[175] Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S and others. Somatic mutation and gain of copy number of PIK3CA in human breast cancer [J]. Breast Cancer Res,2005, 7(5) :R609-616.
[176] Zhang H, Liu G, Dziubinski M, Yang Z, Ethier SP, Wu G. Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells [J]. Breast Cancer Res Treat, 2008,112(2) :217-227.
[177] Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA, Wu X. Genetic variations in the PI3K/PTEN/AKT/mT0R pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy [J]. J Clin Oncol, 2009,27(6):857-871.
[178] Santoro M, Fusco A. New drugs in thyroid cancer [J]. Arq Bras Endocrinol Metabol, 2007, 51(5):857-861.
[179] deGroot JW, Links TP, Plukker JT, Lips CJ, HofstraRM. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors [J].Endocr Rev, 2006, 27(5):535-560.
[180] Akeno-Stuart N, CroyleM, Knauf JA, Malaguarnera R, VitaglianoD, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R and others. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells [J]. Cancer Res,2007, 67(14):6956-6964.
[181] Fagin JA. How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy [J]. J Endocrinol,2004,183(2): 249-256.
[182] Mandal M, Kim S, Younes MN, Jasser SA, E1-Naggar AK, Mills GB, Myers JN. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells [J]. Br J Cancer, 2005, 92(10):1899-1905.
[183] Durante C, Puxeddu E, Ferretti E, Morisi R, Moretti S, Bruno R, Barbi F, Avenia N, Scipioni A, Verrienti A and others. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism [J]. J Clin Endocrinol Metab, 2007,92(7): 2840-2843.
[184] Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G,Carlomagno F, Melillo RM, Wilhelm SM, Santoro M. BRAF is a therapeutic target in aggressive thyroid carcinoma [J]. Clin Cancer Res, 2006,12(5): 1623-1629.
[185] Mitsiades CS, Negri J, McMullanC, McMillinDW, Sozopoulos E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Poulaki V, Batt D and others.Targeting BRAFV600E in thyroid carcinoma: therapeutic implications [J].Mol Cancer Ther, 2007, 6(3):1070-1078.
[186] Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, Nelkin BD.Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 [J]. J Clin Endocrinol Metab, 2007, 92(12):4712-4718.
[187] Mitsiades CS, Kotoula V, Poulaki V, Sozopoulos E, Negri J, Charalambous E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Mitsiades N. Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma:mutational and functional analysis [J]. J Clin Endocrinol Metab,2006,91(9): 3662-3666.
[188] Chattopadhyay C, E1-Naggar AK, Williams MD, dayman GL. Small molecule c-MET inhibitor PHA665752: effect on cell growth andmotility in papillary thyroid carcinoma [J]. Head Neck, 2008, 30(8):991-1000.
[189] Robinson-White AJ, Hsiao HP, Leitner WW, Greene E, Bauer A, Krett NL,Nesterova M, Stratakis CA. Protein kinase A-independent inhibition of proliferation and induction of apoptosis in human thyroid cancer cells by 8-C1-adenosine [J]. J Clin Endocrinol Metab, 2008, 93(3): 1020-1029.
[190] Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P,Monia BP, Nguyen NT and others. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients [J]. Cancer Cell, 2004, 6(2):117-127.
[191] Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha [J]. Cancer Cell, 2008,14(2):180-192.
[192] Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M,Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L and others. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies [J]. Cancer Res, 2009, 69(5): 1851-1857.
[193] Libertini S, Iacuzzo I, Perruolo G, Scala S, Ierano C, Franco R, Hallden G, Portella G. Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922-947 [J]. Clin Cancer Res,2008,14(20): 6505-6514.
[194] Kurebayashi J, Okubo S, Yamamoto Y, Ikeda M, Tanaka K, Otsuki T, Sonoo H. Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells [J]. Cancer Chemother Pharmacol,2006, 58(4): 460-470.
[195] Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors [J]. Cancer Control, 2007,14(3): 285-294.
[196] Sherman SI. Early clinical studies of novel therapies for thyroid cancers [J]. Endocrinol Metab Clin North Am, 2008, 37(2): 511-524, xi.
[2] 上海市疾病预防控制中心.2005年上海市市区恶性肿瘤发病病率[J],肿瘤,2008,28(8):726.
[3] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008 [J]. CA Cancer J Clin, 2008, 58(2):71-96.
[4] Merino MJ, Middleton LP. Pathology of the Thyroid. Pilch BZ, editor.Philadelphia: Lippincott Williams & Wilkins; 2001. 350 p.
[5] Roman S, Mehta P, Sosa JA. Medullary thyroid cancer: early detection and novel treatments [J]. Curr Opin Oncol, 2009, 21 (1): 5-10.
[6] Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma [J]. World J Surg,2007, 31(5):957-968.
[7] Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ,Roeher HD, Wah1 RA, Lamesch P, Raue F, Conte-Devolx B and others. Early malignant progression of hereditary medullary thyroid cancer [J]. N Engl J Med, 2003, 349 (16):1517-1525.
[8] Cardon LR, Bell JI. Association study designs for complex diseases [J].Nat Rev Genet, 2001, 2(2):91-99.
[9] Prazeres HJ, Rodrigues F, Soares P, Naidenov P, Figueiredo P, Campos B,Lacerda M, Martins TC. Loss of heterozygosity at 19pl3. 2 and 2q21 in tumours from familial clusters of non-medullary thyroid carcinoma [J].Fam Cancer, 2008, 7(2):141-149.
[10] He H, Nagy R, Liyanarachchi S, Jiao H, Li W, Suster S, Kere J, de la Chapelle A. A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24 [J]. Cancer Res, 2009, 69(2):625-631.
[11] Cavaco BM, Batista PF, Sobrinho LG, Leite V. Mapping a new familial thyroid epithelial neoplasia susceptibility locus to chromosome 8p23. l-p22 by high-density single-nucleotide polymorphism genome-wide linkage analysis [J]. J Clin Endocrinol Metab, 2008,93(11):4426-4430.
[12] Baida A, Akdi M, Gonzalez-Flores E, Galofre P, Marcos R, Velazquez A. Strong association of chromosome lpl2 loci with thyroid cancer susceptibility[J].Cancer Epidemiol Biomarkers Prey,2008,17(6):1499-1504.
[13]Gudmundsson J,Sulem P,Gudbjartsson DF,Jonasson JG,Sigurdsson A,Bergthorsson JT,He H,Blondal T,Geller F,Jakobsdottir M and others.Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations[J].Nat Genet,2009.
[14]Tabor HK,Risch NJ,Myers RM.Candidate-gene approaches for studying complex genetic traits:practical considerations[J].Nat Rev Genet,2002,3(5):391-397.
[15]张荣梅.TPO与TSHR基因序列多态性与遗传性甲状腺疾病的连锁与关联研究[D].上海:复旦大学:2002.
[16]Kawabata M,Kawabata T,Nishibori M.Role of recA/RAD51 family proteins in mammals[J].Acta Med Okayama,2005,59(1):1-9.
[17]Gorbunova MP.[Cells with unusual mitochondria in the thyroid gland of an old rat][J].Tsitologiia,1979,21(7):786-792.
[18]Wang H,Boecker W,Wang H,Wang X,Guan J,Thompson LH,Nickoloff JA,Iliakis G.Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks[J].Oncogene,2004,23(3):824-834.
[19]Longhese MP,Mantiero D,Clerici M.The cellular response to chromosome breakage[J].Mol Microbiol,2006,60(5):1099-1108.
[20]Knauf JA,Ward LS,Nikiforov YE,Nikiforova M,Puxeddu E,Medvedovic M,Liron T,Mochly-Rosen D,Fagin JA.Isozyme-specific abnormalities of PKC in thyroid cancer:evidence for post-transcriptional changes in PKC epsilon[J].J Clin Endocrinol Metab,2002,87(5):2150-2159.
[21]Nakazawa T,Kondo T,Kobayashi Y,Takamura N,Murata S,Kameyama K,Muramatsu A,Ito K,Kobayashi M,Katoh R.RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country(Japan)[J].Cancer,2005,104(5):943-951.
[22]Tallini G,Asa SL.RET oncogene activation in papillary thyroid carcinoma [J].Adv Anat Pathol,2001,8(6):345-354.
[23]Sansal I,Sellers WR.The biology and clinical relevance of the PTEN tumor suppressor pathway[J].J Clin Oncol,2004,22(14):2954-2963.
[24]Frame S,Balmain A.Integration of positive and negative growth signals during ras pathway activation in vivo [J]. Curr Opin Genet Dev,2000,10(1):106-113.
[25] Zbuk KM, Patocs A, Shealy A, Sylvester H, Miesfeldt S, Eng C. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma [J]. Nat Clin Pract Oncol, 2007,4(10):608-612.
[26] Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer [J]. Cytokine Growth Factor Rev,2005,16(4-5): 441-467.
[27] Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma [J]. Cancer Res, 2003, 63(7): 1454-1457.
[28] Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, Caiazzo F, Basolo F, Giannini R, Kruhoffer M and others. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells [J]. J Clin Invest,2005,115(4): 1068-1081.
[29] Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C, Jr., Knauf JA,Zhang L, Taira K, Fagin JA. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis [J]. Endocrinology, 2006,147(2): 1014-1019.
[30] Carta C, Moretti S, Passeri L, Barbi F, Avenia N, Cavaliere A, Monacelli M, Macchiarulo A, Santeusanio F, Tartaglia M and others. Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V5991ns)) [J]. Clin Endocrinol (Oxf), 2006,64(1):105-109.
[31] Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM,Fagin JA, Nikiforov YE. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer [J]. J Clin Invest,2005, 115(1):94-101.
[32] Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC,Hong SJ and others. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma [J]. Clin Endocrinol (Oxf), 2006, 65(3):364-368.
[33] Lam KY, Lo CY, Leung PS. High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas [J]. Eur J Endocrinol,2002,147(6):741-745.
[34] Lee CH, Hsu LS, Chi CW, Chen GD, Yang AH, Chen JY. High frequency of rearrangement of the RET protooncogene (RET/PTC) in Chinese papillary thyroid carcinomas [J]. J Clin Endocrinol Metab, 1998, 83(5):1629-1632.
[35] Liu RT, Chou FF, Wang CH, Lin CL, Chao FP, Chung JC, Huang CC, Wang PW,Cheng JT. Low prevalence of RET rearrangements (RET/PTC1, RET/PTC2,RET/PTC3, and ELKS-RET) in sporadic papillary thyroid carcinomas in Taiwan Chinese [J]. Thyroid, 2005,15(4):326-335.
[36] Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ,Biddinger PW, Nikiforov YE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas [J]. Am J Surg Pathol,2006, 30(2):216-222.
[37] Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA.RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features [J].Clin Cancer Res, 1998,4(1):223-228.
[38] Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident [J]. Oncogene, 1995,11(12):2459-2467.
[39] Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological,phenotypic, and clinical implications [J]. Clin Cancer Res,2000,6(3):1093-1103.
[40] Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. ret/PTC-1, -2,and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? [J]. J Clin Endocrinol Metab,1996, 81(9): 3360-3365.
[41] Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G and others. High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant [J]. J Clin Endocrinol Metab, 1999,84 (11):4232-4238.
[42] Xing M. BRAF mutation in thyroid cancer [J]. Endocr Relat Cancer,2005,12(2): 245-262.
[43] Fugazzola L, Mannavola D, Cirello V, Vannucchi G, Muzza M, Vicentini L,Beck-Peccoz P. BRAF mutations in an Italian cohort of thyroid cancers [J]. Clin Endocrinol (Oxf), 2004, 61 (2): 239-243.
[44] Sapio MR, Posca D, Troncone G, Pettinato G, Palombini L, Rossi G, Fenzi G, Vitale M. Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA) [J]. Eur J Endocrinol,2006,154(2): 341-348.
[45] Lee S, Hong SW, Moon WC, Oh MR, Lee JK, Ahn CW, Cha BS, Kim KR, Lee HC,Lim SK. High prevalence of c-RET expression in papillary thyroid carcinomas from the Korean population [J]. Thyroid, 2005,15(3):259-266.
[46] Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy [J]. J Clin Oncol, 2007, 25(7): 884-896.
[47] RhodenKJ, Unger K, Salvatore G, Yilmaz Y, Vovk V, Chiappetta G, Qumsiyeh MB, Rothstein JL, Fusco A, Santoro M and others. RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma [J]. J Clin Endocrinol Metab,2006, 91(6): 2414-2423.
[48] Milano A, Chiofalo MG, BasileM, Salzano de Luna A, Pezzullo L, Caponigro F. New molecular targeted therapies in thyroid cancer [J]. Anticancer Drugs, 2006, 17(8):869-879.
[49] Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006 [J]. CA Cancer J Clin, 2006, 56(2):106-130.
[50] Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53, 856 cases of thyroid carcinoma treated in the U. S., 1985-1995[see commetns] [J]. Cancer, 1998, 83(12):2638-2648.
[51] Holzer S, Reiners C, Mann K, Bamberg M, Rothmund M, Dudeck J, Stewart AK, Hundahl SA. Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U. S. and German Thyroid Cancer Group [J]. Cancer, 2000, 89(1): 192-201.
[52] Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, McKee RF, Rosai J, Shah JP, Fremgen AM, Stewart AK, Holzer S. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study[J]. Cancer, 2000, 89(1): 202-217.
[53] Fagin JA. Challenging dogma in thyroid cancer molecular genetics—role of RET/PTC and BRAF in tumor initiation [J]. J Clin Endocrinol Metab,2004,89(9):4264-4266.
[54] Di Cristofaro J, Vasko V, Savchenko V, Cherenko S, Larin A, Ringel MD,Saji M, Marcy M, Henry JF, Carayon P and others. ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients [J]. Endocr Relat Cancer,2005,12(1):173-183.
[55] Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E,Basolo F, Demidchik EP, Miccoli P, Pinchera A and others. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults [J]. J Clin Endocrinol Metab, 2001,86(7) :3211-3216.
[56] Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, Suarez HG. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation [J]. Oncogene, 1997,15(11):1263-1273.
[57] Collins BJ, Chiappetta G, Schneider AB, Santoro M, Pentimalli F,Fogelfeld L, Gierlowski T, Shore-Freedman E, Jaffe G, Fusco A. RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions [J]. J Clin Endocrinol Metab,2002, 87(8):3941-3946.
[58] Santoro M, Papotti M, Chiappetta G, Garcia-Rostan G, Volante M, Johnson C, Camp RL, Pentimalli F, Monaco C, Herrero A and others. RET activation and clinicopathologic features in poorly differentiated thyroid tumors [J]. J Clin Endocrinol Metab, 2002, 87(1):370-379.
[59] Corvi R, Martinez-Alfaro M, Harach HR, Zini M, Papotti M, Romeo G.Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization [J]. Lab Invest,2001,81(12):1639-1645.
[60] Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? [J]. J Pathol,1998,185(1):71-78.
[61] Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia [J]. J Clin Endocrinol Metab, 1998, 83(11):4116-4122.
[62] Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G,Carcangiu ML, Fusco A. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes [J]. Clin Cancer Res, 1998, 4(2): 287-294.
[63] Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M.AJCC Cancer Staging Manual New York: Springer-Verlag; 2002.
[64] Frasoldati A, Pesenti M, Gallo M, Caroggio A, Salvo D, Valcavi R.Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma [J]. Cancer, 2003,97(1):90-96.
[65] Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality [J]. Cancer, 2003, 98(1):31-40.
[66] BritishThyroidAssociationandRoyalCollegeofPhysicians. Guidelines for the management of thyroid cancer in adults. London: Royal College of Physicians 2002.
[67] Mann B, Buhr HJ. Lymph node dissection in patients with differentiatedthyroid carcinoma—who benefits? [J]. Langenbecks Arch Surg,1998, 383(5):355-358.
[68] Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer [J]. Thyroid,
?2006,16(2):109-142.
[69] HedingerC, Williams ED, SobinLH. Histological typing of thyroid tumours. World Health Organization International Histological Classification of Tumours [M]. 2nd ed. Volume 11. Berlin: Springer-Verlag; 1988. p 3-18.
[70] Caron NR, Tan YY, Ogilvie JB, Triponez F, Reiff ES, Kebebew E, Duh QY,Clark OH. Selective Modified Radical Neck Dissection for Papillary Thyroid Cancer-Is Level I, II and V Dissection Always Necessary? [J].World J Surg, 2006, 30(5):833-840.
[71] Palazzo FF, Gosnell J, Savio R, Reeve TS, Sidhu SB, Sywak MS, Robinson B, Delbridge LW. Lymphadenectomy for papillary thyroid cancer: changes in practice over four decades [J]. Eur J Surg Oncol, 2006, 32(3): 340-344.
[72] Watkinson JC, Franklyn JA, Olliff JF. Detection and surgical treatment of cervical lymph nodes in differentiated thyroid cancer [J]. Thyroid,2006,16(2):187-194.
[73] Machens A, Holzhausen HJ, Lautenschlager C, Thanh PN, Dralle H.Enhancement of lymph node metastasis and distant metastasis of thyroid carcinoma [J]. Cancer, 2003, 98(4):712-719.
[74] Mayr B, Brabant G, Goretzki P, Ruschoff J, Dietmaier W, Dralle H.ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas:implications for metastatic potential? [J]. J Clin Endocrinol Metab,1997, 82(4):1306-1307.
[75] Cady B. Comparative analysis of thyroid carcinoma in Germany and the U. S [J]. Cancer, 2000, 89(1): 1-4.
[76] Domingues R, Mendonca E, Sobrinho L, Bugalho MJ. Searching for RET/PTC rearrangements and BRAF V600E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma [J]. Cytopathology, 2005,16(1): 27-31.
[77] Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA,Nikiforov YE, Troncone G, Palombini L, Basolo F and others. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma [J]. J Clin Endocrinol Metab, 2004,89(10):5175-5180.
[78] Cheung CC, Carydis B, Ezzat S, Bedard YC, Asa SL. Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer [J]. J Clin Endocrinol Metab, 2001, 86(5):2187-2190.
[79] Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study [J]. Cancer,2006,106(3):524-531.
[80] Noguchi S, Murakami N, YamashitaH, Toda M, Kawamoto H. Papillary thyroid carcinoma: modified radical neck dissection improves prognosis [J]. Arch Surg, 1998,133(3):276-280.
[81] Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F,Kuma K, Miyauchi A. Ultrasonographically and anatomopathologically detectable node metastases in the lateral compartment as indicators of worse relapse-free survival in patients with papillary thyroid carcinoma [J]. World J Surg, 2005, 29(7):917-920.
[82] Tronko MD, Bogdanova TI, Komissarenko IV, Epstein OV, Oliynyk V,Kovalenko A, Likhtarev IA, Kairo I, Peters SB, LiVolsi VA. Thyroid carcinoma in children and adolescents in Ukraine after the Chernobyl nuclear accident: statistical data and clinicomorphologic characteristics [J]. Cancer, 1999, 86(1):149-156.
[83] Chung JH, Hahm JR, Min YK, Lee MS, Lee MK, Kim KW, Nam SJ, Yang JH, Ree HJ. Detection of RET/PTC oncogene rearrangements in Korean papillary thyroid carcinomas [J]. Thyroid, 1999,9(12):1237-1243.
[84] Sadetzki S, Calderon-Margalit R, Modan B, Srivastava S, Tuttle RM.Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose externA1-beam irradiation in childhood [J]. J Clin Endocrinol Metab, 2004,89(5):2281-2289.
[85] Cetta F, Gori M, Montalto G, Zuckermann M, Toti P. Different significance of ret/PTC(1) and ret/PTC(3) rearrangements in thyroid carcinogenesis:lesson from two subgroups of patients with papillary thyroid carcinomas showing the highest incidence of ret/PTC activation [J]. J Clin Endocrinol Metab, 2001, 86(3):1429.
[86] Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M,Salvatore G, Chiappetta G, Pacini F, Elisei R and others. Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma [J]. Am J Pathol, 2002,160(1): 247-254.
[87] Borrello MG, Alberti L, Fischer A, Degl' innocenti D, Ferrario C,Gariboldi M, Marchesi F, Allavena P, Greco A, Collini P and others.Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC 1 oncogene [J]. Proc Natl Acad Sci U S A,2005,102(41):14825-14830.
[88] Okayasu I, Fujiwara M, Hara Y, Tanaka Y, Rose NR. Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma. A study of surgical cases among Japanese, and white and African Americans [J].Cancer, 1995, 76(11):2312-2318.
[89] Davies TF. T-cell receptor gene expression in autoimmune thyroid disease: some observations and possible mechanisms [J]. Ann N Y Acad Sci,1995,756:331-344.
[90] Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM,Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems [J]. Proc Natl Acad Sci U S A, 1999, 96(4):1563-1568.
[91] Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V,Botelho T, Seruca R, Sobrinho-Simoes M. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC [J]. Oncogene, 2003, 22(29):4578-4580.
[92] Finn SP, Smyth P, O'Regan E, Cahill S, Flavin R, O'Leary J, Sheils O. Array comparative genomic hybridisation analysis of gamma-irradiated human thyrocytes [J]. Virchows Arch, 2004, 445(4):396-404.
[93] Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, Sidransky D. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis [J]. Cancer Res,2004, 64(5):1664-1668.
[94] Ciampi R, Nikiforov YE. Ret/Ptc Rearrangements and Braf Mutations in Thyroid Tumorigenesis [J]. Endocrinology, 2007, 148(3):936-941.
[95] Ouyang B, Knauf JA, Smith EP, Zhang L, Ramsey T, Yusuff N, Batt D, Fagin JA. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo [J]. Clin Cancer Res, 2006,12(6):1785-1793.
[96] Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity[J]. J Clin Endocrinol Metab,2006, 91(9):3603-3610.
[97] Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations [J]. Cancer, 2005,103(11):2261-2268.
[98] Oler G, Ebina KN, Michaluart P, Jr., Kimura ET, Cerutti J. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis reveals a new mutation in metastasis [J].Clin Endocrinol (Oxf), 2005,62(4):509-511.
[99] Lima J, Trovisco V, Soares P, Maximo V, Magalhaes J, Salvatore G, Santoro M, Bogdanova T, Tronko M, Abrosimov A and others. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas [J]. J Clin Endocrinol Metab, 2004, 89(9):4267-4271.
[100] Chung KW, Yang SK, Lee GK, Kim EY, Kwon S, Lee SH, Park do J, Lee HS,Cho BY, Lee ES and others. Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis,especially in BRAF600E mutation-prevalent area [J]. Clin Endocrinol (Oxf), 2006,65(5):660-666.
[101] Vitagliano D, Carlomagno F, Motti ML, Viglietto G, Nikiforov YE,Nikiforova MN, Hershman JM, Ryan AJ, Fusco A, Melillo RM and others.Regulation of p27Kipl protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells [J]. Cancer Res,2004, 64(11):3823-3829.
[102] UngerK, Zitzelsberger H, Salvatore G, Santoro M, Bogdanova T, Braselmann H, Kastner P, Zurnadzhy L, Tronko N, Hutzler P and others. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas [J]. J Clin Endocrinol Metab,2004,89(9):4272-4279.
[103] Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells [J]. Science, 2000, 290(5489):138-141.
[104] Roccato E, Bressan P, Sabatella G, Rumio C, Vizzotto L, Pierotti MA, Greco A. Proximity of TPR and NTRKl rearranging loci in human thyrocytes [J]. Cancer Res, 2005, 65(7):2572-2576.
[105] Schwaller J, Anastasiadou E, Cain D, Kutok J, Wojiski S, Williams IR,LaStarza R, Crescenzi B, Sternberg DW, Andreasson P and others.H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma,is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t (5; 10) (q33;q22) [J]. Blood,2001,97(12):3910-3918.
[106] Celetti A, Cerrato A, Merolla F, Vitagliano D, Vecchio G, Grieco M.H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization [J]. Oncogene,2004,23(1):109-121.
[107] Vieland VJ, Huang Y, Bartlett C, Davies TF, Tomer Y. A multilocus model of the genetic architecture of autoimmune thyroid disorder, with clinical implications [J]. Am J Hum Genet, 2008, 82(6):1349-1356.
[108] Tolone C, Cirillo G, Papparella A, Tolone S, Santoro N, Grandone A,Perrone L, Del Giudice EM. A common CTLA4 polymorphism confers susceptibility to Autoimmune Thyroid Disease in celiac children [J].Dig Liver Dis, 2008.
[109] Inoue N, Watanabe M, Nanba T, Wada M, Akamizu T, Iwatani Y. Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody [J]. Clin Exp Immunol, 2009.
[110] Ban Y, Tozaki T, Tobe T, Ban Y, Jacobson EM, Concepcion ES, Tomer Y.The regulatory T cell gene F0XP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts [J]. J Autoimmun, 2007,28(4):201-207.
[111] Hernandez A, Xamena N, Surralles J, Galofre P, Velazquez A, Creus A,Marcos R. Role of GST and NAT2 polymorphisms in thyroid cancer [J]. J Endocrinol Invest, 2008, 31(11):1025-1031.
[112] Siraj AK, A1-Rasheed M, Ibrahim M, Siddiqui K, A1-Dayel F, A1-Sanea 0,Uddin S, A1-Kuraya K. RAD52 polymorphisms contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population [J]. J Endocrinol Invest, 2008, 31 (10):893-899.
[113] Chiang FY, Wu CW, Hsiao PJ, Kuo WR, Lee KW, Lin JC, Liao YC, Juo SH.Association between polymorphisms in DNA base excision repair genes XRCC1,APE1, and ADPRT and differentiated thyroid carcinoma [J]. Clin Cancer Res, 2008,14(18):5919-5924.
[114] Lonn S, Bhatti P, Alexander BH, Pineda MA, Doody MM, Struewing JP,Sigurdson AJ. Papillary thyroid cancer and polymorphic variants in TSHR-and RET-related genes: a nested case-control study within a cohort of U. S.radiologic technologists [J]. Cancer Epidemiol Biomarkers Prev,2007,16(1):174-177.
[115] SirajAK, Ibrahim M, A1-Rasheed M, Abubaker J, Bu R, Siddiqui SU, A1-Dayel F, A1-Sanea O, A1-Nuaim A, Uddin S and others. Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population [J]. BMC Med Genet,2008,9:61.
[116] Lemos MC, Carrilho F, Rodrigues F, Coutinho E, Gomes L, Carvalheiro M,Regateiro FJ. Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer [J]. Clin Endocrinol (Oxf),2007,67(2):180-183.
[117] Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma [J]. Proc Natl Acad Sci U S A, 2008,10520):7269-7274.
[118] Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, TroviscoV, Vieira de Castro I, Cardoso-de-01iveira M, Fonseca E, Soares P and others.PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma [J]. J Clin Endocrinol Metab,2006,91(1):213-220.
[119] Fischer SG, Lerman LS. DNA fragments differing by single base-pair substitutions are separated in denaturing gradient gels: correspondence with melting theory [J]. Proc Natl Acad Sci US A, 1983,80(6):1579-1583.
[120] Lerman LS, Fischer SG, Hurley I, Silverstein K, Lumelsky N.Sequence-determined DNA separations [J]. Annu Rev Biophys Bioeng,1984,13:399-423.
[121] Myers RM, Fischer SG, Lerman LS, Maniatis T. Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresis [J]. Nucleic Acids Res,1985,13(9):3131-3145.
[122] Myers RM, Fischer SG, ManiatisT, Lerman LS. Modification of the melting properties of duplex DNA by attachment of a GC-rich DNA sequence as determined by denaturing gradient gel electrophoresis [J]. Nucleic Acids Res, 1985,13(9):3111-3129.
[123] Ardlie KG, Kruglyak L, Seielstad M. Patterns of linkage disequilibrium in the human genome [J]. Nat Rev Genet, 2002, 3(4):299-309.
[124] Shifman S, Kuypers J, Kokoris M, Yakir B, Darvasi A. Linkage disequilibrium patterns of the human genome across populations [J]. Hum Mol Genet, 2003,12(7):771-776.
[125] Ngan ES, Lang BH, Liu T, Shum CK, So MT, Lau DK, Leon TY, Cherny SS,Tsai SY, Lo CY and others. A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma [J]. J Natl Cancer Inst,2009,101(3):162-175.
[126] Adjadj E, Schlumberger M, de Vathaire F. Germ-line DNA polymorphisms and susceptibility to differentiated thyroid cancer [J]. Lancet Oncol,2009,10(2):181-190.
[127] Shi WP, Bian JC, Jiang F, Ni HX, Zhu QX, Tang HW, Shen Q, Wu Y. [Association of genetic polymorphisms and haplotypes in hMLHl and hMSH3 gene with the risk of papillary thyroid carcinoma] [J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2008, 25(4):390-395.
[128] Sturgis EM, Zhao C, Zheng R, Wei Q. Radiation response genotype and risk of differentiated thyroid cancer: a case-control analysis [J].Laryngoscope, 2005, 115(6):938-945.
[129] Tang H. Confronting ethnicity-specific disease risk [J]. Nat Genet,2006,38(1):13-15.
[130] Improta G, Sgambato A, Bianchino G, Zupa A, Grieco V, La Torre G,Traficante A, Cittadini A. Polymorphisms of the DNA repair genes XRCC1 and XRCC3 and risk of lung and colorectal cancer: a case-control study in a Southern Italian population [J]. Anticancer Res,2008, 28(5B):2941-2946.
[131] Sangrajrang S, Schmezer P, Burkholder I, Boffetta P, Brennan P,Woelfelschneider A, Bartsch H, Wiangnon S, Cheisilpa A, Popanda O. The XRCC3 Thr241Met polymorphism and breast cancer risk: a case-control study in a Thai population [J]. Biomarkers, 2007,12(5):523-532.
[132] Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P,Matullo G. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review [J]. Am J Epidemiol, 2006,164(4):297-302.
[133] Long XD, Ma Y, Qu de Y, Liu YG, Huang ZQ, Huang YZ, Lin ZH, Wei NB, Zhou SC. The polymorphism of XRCC3 codon 241 and AFBl-related hepatocellular carcinoma in Guangxi population, China [J]. Ann Epidemiol,2008,18(7):572-578.
[134] Wen SX, Zhang XM, Tang PZ, Zhao D, Guo YL, Tan W, Lin DX. [Association between genetic polymorphism in DNA repair genes XRCC3 and risks of laryngeal and hypopharyngeal carcinomas] [J]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2007, 42(11):856-859.
[135] Mateuca RA, Roelants M, Iarmarcovai G, Aka PV, Godderis L, Tremp A,Bonassi S, Fenech M, Berge-Lefranc JL, Kirsch-Volders M. hOGG1(326),XRCCK399) and XRCC3(241) polymorphisms influence micronucleus frequencies in human lymphocytes in vivo [J]. Mutagenesis,2008,23(1):35-41.
[136] LoignonM, Amrein L, Dunn M, Aloyz R. XRCC3 Depletion Induces Spontaneous DNA Breaks and p53-Dependent Cell Death [J]. Cell Cycle, 2007,6(5).
[137] AlsbeihG, E1-Sebaie M, A1-Harbi N, A1-Buhairi M, A1-Hadyan K, A1-Rajhi N. Radiosensitivity of human fibroblasts is associated with amino acid substitution variants in susceptible genes and correlates with the number of risk alleles [J]. Int J Radiat Oncol Biol Phys, 2007.
[138] Zijno A, Verdina A, Galati R, Leopardi P, Marcon F, Andreoli C, Rossi S, Crebelli R. Influence of DNA repair polymorphisms on biomarkers of genotoxic damage in peripheral lymphocytes of healthy subjects[J]. Mutat Res, 2006, 600(1-2):184-192.
[139] Halasova E, Matakova T, Musak L, Polakova V, Vodicka P. Chromosomal damage and polymorphisms of DNA repair genes XRCC1 and XRCC3 in workers exposed to chromium [J]. Neuro Endocrinol Lett, 2008, 29(5):658-662.
[140] Font A, Salazar R, Maurel J, Taron M, Ramirez JL, Tabernero J, Gallego R, Casado E, Manzano JL, Carcereny E and others. Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms [J].Cancer Chemother Pharmacol, 2008,62(6):1075-1083.
[141] Burri RJ, Stock RG, Cesaretti JA, Atencio DP, Peters S, Peters CA, Fan G, Stone NN, Ostrer H, Rosenstein BS. Association of single nucleotide polymorphisms in S0D2, XRCC1 and XRCC3 with susceptibility for the development of adverse effects resulting from radiotherapy for prostate cancer [J]. Radiat Res, 2008, 170(1):49-59.
[142] Vangsted A, GimsingP, Klausen TW, Nexo BA, WallinH, Andersen P, Hokland P, Lillevang ST, Vogel U. Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation [J]. Int J Cancer,2007,120(5):1036-1045.
[143] Dardano A, Falzoni S, Caraccio N, Polini A, Tognini S, Solini A, Berti P, Di Virgilio F, Monzani F. 1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters [J]. J Clin Endocrinol Metab, 2009, 94(2):695-698.
[144] Lemos MC, Coutinho E, Gomes L, Carrilho F, Rodrigues F, Regateiro FJ,Carvalheiro M. Combined GSTMl and GSTTl null genotypes are associated with a lower risk of papillary thyroid cancer [J]. J Endocrinol Invest,2008, 31(6):542-545.
[145] Guirouilh-Barbat J, Huck S, Bertrand P, Pirzio L, Desmaze C, Sabatier L, Lopez BS. Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells [J]. Mol Cell, 2004, 14(5):611-623.
[146] Thacker J, Zdzienicka MZ. The mammalian XRCC genes: their roles in DNA repair and genetic stability [J]. DNA Repair (Amst), 2003,2(6) :655-672.
[147] Auranen A, Song H, Waterfall C, DicioccioRA, Kuschel B, Kjaer SK, Hogdall E, Hogdall C, Stratton J, Whittemore AS and others. Polymorphisms in DNA repair genes and epithelial ovarian cancer risk [J]. Int J Cancer,2005, 117(4):611-618.
[148] Loizidou MA, Michael T, Neuhausen SL, Newbold RF, Marcou Y, Kakouri E,Daniel M, Papadopoulos P, Malas S, Kyriacou K and others. Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus [J]. Breast Cancer Res Treat,2008,112(3):575-579.
[149] Brooks J, Shore RE, Zeleniuch-Jacquotte A, Currie D, AfanasyevaY, Koenig KL, Arslan AA, Toniolo P, Wirgin I. Polymorphisms in RAD51, XRCC2, and XRCC3 are not related to breast cancer risk [J]. Cancer Epidemiol Biomarkers Prev, 2008,17(4):1016-1019.
[150] Lee SA, Lee KM, Park SK, Choi JY, Kim B, Nam J, Yoo KY, Noh DY, Ahn SH,Kang D. Genetic polymorphism of XRCC3 Thr241Met and breast cancer risk:case-control study in Korean women and meta-analysis of 12 studies [J].Breast Cancer Res Treat, 2007,103(1):71-76.
[151] Kiuru A, Lindholm C, Heinavaara S, Ilus T, Jokinen P, Haapasalo H,Salminen T, Christensen HC, Feychting M, Johansen C and others. XRCC1 and XRCC3 variants and risk of glioma and meningioma [J]. J Neurooncol,2008, 88(2): 135-142.
[152] Jiao L, Hassan MM, Bondy ML, Wolff RA, Evans DB, Abbruzzese JL, Li D.XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer [J].Am J Gastroenterol, 2008,103(2):360-367.
[153] He X, Ye F, Zhang J, Cheng Q, Shen J, Chen H. Susceptibility of XRCC3,XPD, and XPG genetic variants to cervical carcinoma [J]. Pathobiology,2008, 75(6):356-363.
[154] Fontana L, Bosviel R, Delort L, Guy L, Chalabi N, Kwiatkowski F, Satih S, Rabiau N, Boiteux JP, Chamoux A and others. DNA repair gene ERCC2, XPC,XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort [J]. Anticancer Res, 2008, 28(3B):1853-1856.
[155] Covolo L, Placidi D, Gelatti U, Carta A, Scotto Di Carlo A, Lodetti P,Picciche A, Orizio G, CampagnaM, Arici C and others. Bladder cancer, GSTs,NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case-control study [J]. Eur J Epidemiol,2008, 23(5):355-362.
[156] Lopez-Cima MF, Gonzalez-Arriaga P, Garcia-Castro L, Pascual T, Marron MG, Puente XS, Tardon A. Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain [J].BMC Cancer, 2007,7:162.
[157] Zienolddiny S, CampaD, LindH, RybergD, Skaug V, Stangeland L, Phillips DH, Canzian F, Haugen A. Polymorphisms of DNA repair genes and risk of non-small cell lung cancer [J]. Carcinogenesis, 2006,27(3): 560-567.
[158] Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A, Becker N, de Sanjose S, ForetovaL, Maynadie M and others. Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma [J]. Hum Mol Genet, 2007,16(24):3117-312.7.
[159] Yeh CC, Sung FC, Tang R, Chang-Chieh CR, Hsieh LL. Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan [J]. J Biomed Sci, 2006.
[160] Ye W, Kumar R, Bacova G, Lagergren J, Hemminki K, Nyren 0. The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma:a population-based case-control study in Sweden [J]. Carcinogenesis,2006, 27(9):1835-1841.
[161] Abaji C, Cousineau I, Belmaaza A. BRCA2 regulates homologous recombination in response to DNA damage: implications for genome stability and carcinogenesis [J]. Cancer Res, 2005,65(10) :4117—4125.
[162] Grabsch H, Dattani M, Barker L, Maughan N, Maude K, Hansen O, Gabbert HE, Quirke P, Mueller W. Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer [J]. Clin Cancer Res, 2006,12(5):1494-1500.
[163] Kimura ET, Vanvooren V, van Sande J, Nikiforov YE, Fagin JA. Autonomously functioning thyroid nodules are not associated with BRAF mutations [J].Clin Endocrinol (Oxf), 2004, 60(3):394-396.
[164] Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Delia Porta G. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas [J]. Oncogene, 1992, 7(2):237-242.
[165] Caudill CM, Zhu Z, Ciampi R, Stringer JR, Nikiforov YE. Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation [J]. J Clin Endocrinol Metab,2005, 90(4):2364-2369.
[166] Wu G, Mambo E, Guo Z, Hu S, Huang X, Gollin SM, Trink B, Ladenson PW,Sidransky D, Xing M. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors [J]. J Clin Endocrinol Metab,2005,90(8): 4688-4693.
[167] Silva SN, Gil OM, Oliveira VC, Cabral MN, Azevedo AP, Faber A, Manita I, Ferreira TC, Limbert E, Pina JE and others. Association of polymorphisms in ERCC2 gene with non-familial thyroid cancer risk [J].Cancer Epidemiol Biomarkers Prev, 2005, 14(10):2407-2412.
[168] Ho T, Li G, Lu J, Zhao C, Wei Q, Sturgis EM. Association of XRCC1 polymorphisms and risk of differentiated thyroid carcinoma: a case-control analysis [J]. Thyroid, 2009,19(2): 129-135.
[169] Sigurdson AJ, Land CE, Bhatti P, Pineda M, Brenner A, Carr Z, Gusev BI,Zhumadilov Z, Simon SL, Bouville A and others. Thyroid nodules,polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan [J].Radiat Res, 2009,171(1):77-88.
[170] Coelho SM, Carvalho DP, Vaisman M. New perspectives on the treatment of differentiated thyroid cancer [J]. Arq Bras Endocrinol Metabol,2007, 51(4): 612-624.
[171] Riesco-Eizaguirre G, Santisteban P. New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy [J]. Endocr Relat Cancer, 2007,14(4): 957-977.
[172] McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE,Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB and others. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance [J]. Adv Enzyme Regul, 2006,46:249-279.
[173] Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, E1-Naggar AK, Xing M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers [J]. J Clin Endocrinol Metab, 2008, 93(8):3106-3116.
[174] Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R,Hermsem MJ, Herrero A, Fusco A, Cameselle-Tei jeiro J, Santoro M. Mutation of the PIK3CA gene in anaplastic thyroid cancer [J]. Cancer Res,2005, 65(22): 10199-10207.
[175] Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S and others. Somatic mutation and gain of copy number of PIK3CA in human breast cancer [J]. Breast Cancer Res,2005, 7(5) :R609-616.
[176] Zhang H, Liu G, Dziubinski M, Yang Z, Ethier SP, Wu G. Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells [J]. Breast Cancer Res Treat, 2008,112(2) :217-227.
[177] Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA, Wu X. Genetic variations in the PI3K/PTEN/AKT/mT0R pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy [J]. J Clin Oncol, 2009,27(6):857-871.
[178] Santoro M, Fusco A. New drugs in thyroid cancer [J]. Arq Bras Endocrinol Metabol, 2007, 51(5):857-861.
[179] deGroot JW, Links TP, Plukker JT, Lips CJ, HofstraRM. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors [J].Endocr Rev, 2006, 27(5):535-560.
[180] Akeno-Stuart N, CroyleM, Knauf JA, Malaguarnera R, VitaglianoD, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R and others. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells [J]. Cancer Res,2007, 67(14):6956-6964.
[181] Fagin JA. How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy [J]. J Endocrinol,2004,183(2): 249-256.
[182] Mandal M, Kim S, Younes MN, Jasser SA, E1-Naggar AK, Mills GB, Myers JN. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells [J]. Br J Cancer, 2005, 92(10):1899-1905.
[183] Durante C, Puxeddu E, Ferretti E, Morisi R, Moretti S, Bruno R, Barbi F, Avenia N, Scipioni A, Verrienti A and others. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism [J]. J Clin Endocrinol Metab, 2007,92(7): 2840-2843.
[184] Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G,Carlomagno F, Melillo RM, Wilhelm SM, Santoro M. BRAF is a therapeutic target in aggressive thyroid carcinoma [J]. Clin Cancer Res, 2006,12(5): 1623-1629.
[185] Mitsiades CS, Negri J, McMullanC, McMillinDW, Sozopoulos E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Poulaki V, Batt D and others.Targeting BRAFV600E in thyroid carcinoma: therapeutic implications [J].Mol Cancer Ther, 2007, 6(3):1070-1078.
[186] Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, Nelkin BD.Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 [J]. J Clin Endocrinol Metab, 2007, 92(12):4712-4718.
[187] Mitsiades CS, Kotoula V, Poulaki V, Sozopoulos E, Negri J, Charalambous E, Fanourakis G, Voutsinas G, Tseleni-Balafouta S, Mitsiades N. Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma:mutational and functional analysis [J]. J Clin Endocrinol Metab,2006,91(9): 3662-3666.
[188] Chattopadhyay C, E1-Naggar AK, Williams MD, dayman GL. Small molecule c-MET inhibitor PHA665752: effect on cell growth andmotility in papillary thyroid carcinoma [J]. Head Neck, 2008, 30(8):991-1000.
[189] Robinson-White AJ, Hsiao HP, Leitner WW, Greene E, Bauer A, Krett NL,Nesterova M, Stratakis CA. Protein kinase A-independent inhibition of proliferation and induction of apoptosis in human thyroid cancer cells by 8-C1-adenosine [J]. J Clin Endocrinol Metab, 2008, 93(3): 1020-1029.
[190] Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P,Monia BP, Nguyen NT and others. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients [J]. Cancer Cell, 2004, 6(2):117-127.
[191] Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha [J]. Cancer Cell, 2008,14(2):180-192.
[192] Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M,Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L and others. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies [J]. Cancer Res, 2009, 69(5): 1851-1857.
[193] Libertini S, Iacuzzo I, Perruolo G, Scala S, Ierano C, Franco R, Hallden G, Portella G. Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922-947 [J]. Clin Cancer Res,2008,14(20): 6505-6514.
[194] Kurebayashi J, Okubo S, Yamamoto Y, Ikeda M, Tanaka K, Otsuki T, Sonoo H. Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells [J]. Cancer Chemother Pharmacol,2006, 58(4): 460-470.
[195] Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors [J]. Cancer Control, 2007,14(3): 285-294.
[196] Sherman SI. Early clinical studies of novel therapies for thyroid cancers [J]. Endocrinol Metab Clin North Am, 2008, 37(2): 511-524, xi.