摘要
BRCA1/2等高外显率的易感基因只能解释10%左右的中国汉族人群遗传性乳腺癌的发病,这一方面这说明汉族人群具有不同于国外其他种族的遗传背景,同时也提示还存在其他低外显率基因变化的影响。为阐明BRCA1/2突变阴性的汉族人遗传性乳腺癌的发病原因,我们在前期研究的基础上,进一步对p53、BRIP1及PALB2等基因的胚系突变在汉族有遗传倾向的乳腺癌人群中的流行情况进行了筛查研究,全面了解上述低外显率易感基因的突变发生率,致病性突变位点、类型有何特点以及有无明确的“突变热点”或“突变热点区域”甚至是“始祖突变”,以及突变相关乳腺癌的临床和病理学特征,从而结合前期关于BRCA1/2等高外显率易感基因的研究结果,进一步完善中国汉族人群乳腺癌遗传风险评估系统,制定适合于汉族乳腺癌高风险人群的遗传咨询策略和基因筛查策略。同时为了更加全面地了解PALB2基因的遗传变异和汉族人乳腺癌遗传易感性的关系,我们还进行了PALB2常见的SNPs和上海地区乳腺癌发病风险之间的关联研究,以鉴定出与乳腺癌发病有关的PALB2基因的风险SNP位点、基因型或等位基因型。
第一部分
背景:抑癌基因p53的胚系突变是导致Li-Fraumeni或Li-Fraumeni样综合征的明确病因。但在不符合上述遗传性乳腺癌综合征表现的乳腺癌家系中却很少有报道p53基因的致病性突变的存在,其在汉族有遗传背景的高风险乳腺癌人群中的流行情况依然未知。
目的:探讨P53基因的胚系突变在汉族有遗传背景且非Li-Fraumeni或Li-Fraumeni样综合征表现的乳腺癌家系中的流行情况,根据研究结果,制定适合于汉族乳腺癌高危人群的p53基因突变筛查策略。
方法:根据以下入组标准筛选汉族有遗传背景的乳腺癌240例:(1)家族性乳腺癌:家系中至少有2个一级或二级亲属患原发性乳腺癌(包括研究病例在内),不论其发病年龄;(2)早发性乳腺癌:病例乳腺癌发病年龄≤35岁,不论其家族史如何。所有乳腺癌家系均不符合Li-Fraumeni或Li-Fraumeni样综合征的诊断标准。入组病例来自中国4个不同的乳腺病诊疗中心。本研究同时有768例无恶性肿瘤病史及家族史的良性乳腺病人或健康体检者入组作为对照组人群。应用PCR-DHPLC和基因测序为基础的方法对p53基因所有编码序列和剪切点序列进行突变筛查。进而对研究中发现的2个未曾报道的p53基因胚系突变进行功能学论证。构建表达野生型p53和两个p53突变体的pEGFP—N1质粒载体,转染H1299、MCF-7及MDA-MB-231细胞系,通过流式细胞仪检测转染不同质粒载体后细胞的凋亡情况,通过realtime—PCR和western blot检测转染后细胞p53、p21及p27的mRNA和蛋白的表达情况。
结果:本研究在汉族有遗传背景的乳腺癌家系中鉴定出2个未曾报道的p53基因胚系突变,563T＞C和643_660del18,二者分别出现在2个独立的乳腺癌家系中,且均未在对照组人群中出现。功能学分析提示在汉族人群中发现的这2个p53突变体与野生型p53相比诱导细胞凋亡及转录激活能力均有明显下降。
结论:p53基因的胚系致病性突变可以解释近1%的汉族BRCA1/2突变阴性的家族性/早发性乳腺癌发病,我们的研究结果为将p53基因纳入针对汉族乳腺癌高危易感人群的基因突变筛查的候选对象提供了依据。
第二部分
背景:BRIP1和PALB2是最近在西方人群中鉴定的和遗传性乳腺癌发病相关的低外显率易感基因,其基因突变被认为可增加2倍左右的乳腺癌发病风险,但二者在中国汉族有遗传背景的乳腺癌人群中的流行情况并无研究报道。
目的:探讨中国汉族BRCA1/2突变阴性的遗传性乳腺癌的发病原因,同时了解BRIP1和PALB2基因的胚系突变在中国汉族有遗传背景的乳腺癌人群中的流行情况。
方法:根据以下入组标准筛选汉族有遗传背景的乳腺癌360例:(1)家族性乳腺癌:家系中至少有2个一级或二级亲属患原发性乳腺癌(包括研究病例在内),不论其发病年龄;(2)早发性乳腺癌:病例乳腺癌发病年龄≤35岁,不论其家族史情况如何。入组病例来自中国5个不同的乳腺病诊疗中心。本研究同时有864例无恶性肿瘤病史及家族史的良性乳腺病人或健康体检者入组作为对照组人群。应用PCR-DHPLC和基因测序为基础的方法对BRIP1和PALB2基因所有编码序列和剪切点序列进行突变筛查。对病例组发现的某些变异位点同时在对照组进行携带频率的比较分析。
结果:本研究在3个独立的汉族乳腺癌家系中发现了2种不同的PALB2基因的蛋白截短性突变,751C＞T和1050_1051delAAinsTCT。其中751C＞T为本研究发现的PALB2基因的重复突变。而这2种突变均未在对照组人群中出现(p=0.025)。出现在PALB2基因第4外显子的突变人次占突变总人次的44.1%(15/34)。对于BRIP1基因,本研究在2个独立的乳腺癌家系中发现了重复出现的BRIP1第19外显子的Q944E突变,而此突变也未在对照组人群中出现。巧合的是,Q944E突变发生在BACH1蛋白和BRCA1作用的BRCT功能结构域,对家系的疾病“共分离”分析结果提示其可能是和乳腺癌发病相关的突变。
结论:PALB2基因的致病性突变可以解释近1%的汉族BRCA1/2突变阴性的家族性/早发性乳腺癌发病,而在对PALB2基因进行基因突变检测时,实施在全基因序列分析之前先对其第4外显子的检测的策略可能会节约检测成本,提高检测效率。本研究没有发现和汉族遗传性乳腺癌发病相关的BRIP1基因的蛋白截短性突变,对于本研究发现的BRIP1 Q944E突变,有必要进行进一步的功能学实验论证其确切的致病意义,暂不推荐其作为针对汉族乳腺癌高危易感人群基因检测的候选对象。
第三部分
背景:基因突变仅仅解释了极少部分的乳腺癌发生,那么在人群中广泛存在的多态性遗传背景,则赋予了个体不同的乳腺癌易感特性。PALB2是最新鉴定的遗传性乳腺癌的低外显率易感基因,其常见的SNP位点与乳腺癌易感性的确切关系尚不清楚。
目的:研究PALB2基因多态性与上海地区乳腺癌遗传易感性的关系,试图找出有意义的风险SNP位点,从而通过与基因突变不同的角度阐明PALB2基因的变异对上海地区乳腺癌发病的影响。
方法:根据以下入组标准筛选上海地区乳腺癌660例:(1)两代以内居住在上海及周边地区;(2)经组织病理证实的单侧原发乳腺癌。同期因良性乳腺病或参加复旦大学附属肿瘤医院门诊体检的健康人作为对照组人群,入选条件(1)两代以内居住在上海及周边地区;(2)病理为良性乳腺疾病或未患任何乳腺疾病;(3)无乳腺癌/卵巢癌或其他恶性肿瘤家族史。病例组和对照组进行年龄匹配,对照组共入组756例。使用SNPstream技术对5个PALB2常见SNP位点进行基因分型,对基因分型结果进行统计学分析。
结果:年龄和初产年龄晚是上海地区乳腺癌发病危险因素,而绝经状态则是乳腺癌发生的保护性因素。对基因分型的结果进行统计分析显示,PALB2常见SNP位点及其基因型或等位基因型是上海地区乳腺癌发病的独立因素。PALB2rs447529位点的等位基因型G在是上海地区乳腺癌发病的保护性因素,其在病例组和对照组中的分布频率分别为0.848和0.821。而PALB2 rs249935位点的等位基因型G可增加乳腺癌发病风险,其在病例组和对照组中的分布频率分别为0.155和0.181,在其他因素不变的情况下,rs249935 G基因型的携带者发生乳腺癌的风险是rs249935 A基因型携带者的1.21倍(95%CI 1.02-1.43)。
结论:PALB2常见SNP位点和上海地区乳腺癌发病风险相关。PALB2 rs249935和rs447529为疾病相关性位点,考虑均为内含子变异且处于同一个连锁不平衡区域,推断为可能存在和它们紧密连锁的某个或某些未知的功能区位点有致病作用。PALB2 rs447529位点的等位基因型G可是上海地区乳腺癌发病的保护性因素,而rs249935位点的等位基因型G可增加乳腺癌发病风险。PALB2标签SNPsrs249935和rs447529可成为上海地区乳腺癌发病风险的独立风险评估指标。
Germline mutations of the high penetrance susceptibility genes BRCA1/2 could only explain about 10%Chinese inherited breast cancers,which indicated that our population had a different hereditary background from other ethnic groups and there might exist other low penetrance genes correlated with the etiology of Chinese breast cancer.To explore the etiology of Chinese non-BRCA1/2 high-risk breast cancers,we fatherly made a mutation analysis of p53、BRIP1 and PALB2 in the potentially inherited breast cancers of Chinese Han nationality in order to get a fundamental knowledge of the prevalence of some low penetrance genes in our population,and whether there were some mutation hot-spots、hot-regions or founder mutations about these genes,and also the pathologic features of disease-related breast cancer specimens.Combining with the results of our series of studies about the high penetrance susceptibility genes BRCA1/2,we can make a suitable strategy of genetic testing among the high-risk individuals of Chinese Han nationality.At the same time, we performed a case-control study about the common single nucleotide polymorphisms of PALB2 gene and its correlation with the breast cancer susceptibility of Shanghai female breast cancer to evaluate the role of genetic variants of PALB2 in the etiology of Chinese breast cancer,and then we had identified some disease-related SNPs of PALB2 gene.
PartⅠ
Germ line mutations in the tumor suppressor gene,p53,are known to cause Li-Fraumeni syndrome(LFS) or Li-Fraumeni-like syndrome(LFL).We sought to identify p53 germ line mutations in potential hereditary breast cancer patients without LFS/LFL phenotype,which will help us establish the genetic testing strategy for p53 in Chinese high-risk breast cancer families.We screened all coding exons and intron-exon boundaries of p53 in 240 women with early-onset breast cancer or affected relatives from four breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis.Additionally,three cell lines(H1299, MCF-7 and MDA-MB-231) were transfected with pEGFP-N1-only or pEGFP-N1 vectors expressing either wild-type or two novel identified mutant p53.And then we performed flow cytometry analysis in the transfected cells to determine the status of cell apoptosis,and real-time PCR as well as western blot analysis to ascertain the expression of p53,p21,and p27.Two novel germ line mutations[563T＞C and 643_660del18) were detected in two independent families.Neither of them,however, was present in the 768 normal controls.Functional assays revealed that the ability to trigger cell apoptosis and transcriptional activation of target gene under similar expression of p53 were lower in two mutants versus wild-type p53.Deleterious mutations of p53 seemed to be responsible for approximately 1%of non-BRCA1/BRCA2 hereditary breast cancer in Chinese population,and our findings suggested that p53 should be included in genetic testing of Chinese non-LFS/non-LFL high-risk breast cancer families.
PartⅡ
PALB2 and BRIP1 have been identified as breast cancer susceptibility genes in western populations.To investigate the contribution of PALB2 and BRIP1 mutations to Chinese non-BRCA1/BRCA2 hereditary breast cancer,we screened all coding exons and intron-exon boundaries of PALB2 and BRIP1 in 360 Chinese women with early-onset breast cancer or affected relatives from five breast disease clinical centers in China,using PCR-DHPLC and DNA sequencing analysis.Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer.Two protein-truncating PALB2 mutations,751C＞T and 1050_1051delAAinsTCT,were identified in 3 separate families,and 751C＞T was a recurrent mutation,none of them presented in the controls(p=0.025).All the truncating mutations presented in exon 4 of PALB2,and there were still 3 unclassified variants were detected in the same fragment.We counted that exon 4 accounted for 44.1%(15/34) of the person-times carrying any variant in our study.In BRIP1,we detected a novel non-synonymous variant(2971C＞G,resulting in Q944E) in two independent families compared with none in the controls.Interestingly,this variant occurs in the BRCA1 binding domain of the BACH1 protein.PALB2 mutations are responsible for approximately 1%of Chinese women with early-onset breast cancer and affected relatives,and a detection of exon 4 before the assay of the whole PALB2 gene suggests to be a cost-effective approach to screening of Chinese population, nevertheless,there is no evidence for the recommendation of BRIP1 for genetic testing in China..
PartⅢ
Germline mutations of some known susceptibility genes can explain only a small fraction of breast cancers.Single nucleotide polymorphisms were found in all the known breast cancer predisposing genes,and PALB2 was recently identified as a low penetrance gene of breast cancer,a further study is warrant to explore the effect of common SNPs of PALB2 on the increasing risk of breast cancer in Chinese population.We conducted a case-control study to validate whether there were some disease-related SNPs of PLAB2 in Shanghai female breast cancer patients.In the current study,660 cases and 756 controls were included,and we genotyped 5 common SNPs of PALB2 among 660 cases and 756 controls by SNPstream assay,and then we made a statistical analysis according to the genotyping data.Multivariate analysis showed that the age of each individuals and the postponed first birth increased the risk of Shanghai female breast cancer while the postmenopausal status was a protective factor.The PALB2 rs447529 G was present in 84.8%of the cases and 82.1%of the controls,the odd ration for rs447529 G is 0.82(95%CI 0.69-0.98). and PALB2 rs249935 G was present in 15.5%of the cases and 18.1%of the controls, the odd ration for rs249935 is 1.21(95%CI 1.02-1.43).The results indicated that common SNPs might become an independent factor which was associated with Shanghai female breast cancer susceptibility as well as the age,the postponed first birth and the postmenopausal status.
引文
1.Smith RA,Cokkinides V,Eyre HJ.Cancer screening in the United States,2007:a review of current guidelines,practices,and prospects.CA Cancer J Clin.2007,57(2):90-104.
2.Parkin DM,Bray F,Ferlay J,et al.Global cancer statistics,2002.CA Cancer J Clin.2005,55:74-108.
3.乳腺肿瘤学.2005,沈镇宙,邵志敏主编.
4.Yager JD,Davidson NE.Estrogen carcinogenesis in breast cancer.N Engl J Med.2006,354(3):270-282.
5.Boyd J.BRCA1:More than a hereditary breast cancer gene? Nat Genet.1995,9(4):335-336.
6.Offit K.BRCA mutation frequency and penetrance:new data,old debate.J Natl Cancer Inst.2006,98:1675-1677.
7.Li WF,Hu Z,Rao NY,et al.The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified.Breast Cancer Res Treat.2008,110(1):99-109.
8.Walsh,King MC.Ten genes for inherited breast cancer.Cancer Cell.2007,11(2):103-105.
9.Harris CC.Structure and function of the P53 tumor suppressor gene:clues for rational cancer therapeutic strategies.J Natl Cancer.1996,88(20):1442-1455.
10.Nigro JM,Baker SJ.Mutations in the P53 gene occur in diverse tumor types.Nature.1989,34:705.
11.Vogelstein B,KinZier KW.P53 function and dysfunction.Cell.1992,70:523.
12.Feng Z,Hu W,Rajagopal G,et al.The tumor suppressor p53:cancer and aging.Cell Cycle.2008,7(7):842-7
13.May P,May E.Twenty years of p53 research:structural and functional aspects of the p53 protein.Oncogene.1999,18:7621-7636.
14.Strahm B,Malkin D.Hereditary cancer predisposition in children:genetic basis and clinical implications.Int J Cancer.2006,119(9):2001-2006.
15.Akashi M,Koeffler HP.Li-Fraumeni syndrome and the role of the p53 tumor suppressor gene in cancer susceptibility.Clin Obstet Gynecol.1998,41(1):172-199.
16. Malkin D.p53 and the Li-Fraumeni syndrome. Cancer Genet Cytogenet. 1993,66(2):83-92.
17. Varley JM.Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003,21(3):313-320.
18. Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001,105(1):149-160.
19. Xia B, Sheng Q, Nakanishi K, et al.Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.Mol Cell. 2006,22(6):719-729.
20. Yu X, Chini CC, He M, et al.The BRCT domain is a phospho-protein binding domain. Science.2003,302(5645):639-642.
21. Seal S, Thompson D, Renwick A, et al.Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet.2006,38(11):1239-1241.
22. Wang W.Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet.2007,8(10):735-748.
23. Xia B, Dorsman JC, Ameziane N,et al.Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet.2007,39(2): 159-161.
24. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res.2000,2:77-81.
25. Taneja C, Edelsberg J, Weycker D, et al.Cost effectiveness of breast cancer screening with contrast-enhanced MRI in high-risk women. J Am Coll Radiol.2009,6(3):171-179.
26. Gynecol Endocrinol. How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer? Gynecol Endocrinol.2006,22(3): 155-159.
27. Schork NJ, Fallin D, Lanchbury JS.Single nucleotide polymorphisms and the future of genetic epidemiology. Clin Genet.2000,58(4):250-264.
28. Cooper RS, Tayo B, Zhu X. Genome-wide association studies: implications for multiethnic samples. Hum Mol Genet.2008, 15;17(R2):R151-5.
29. Deloukas P, Bentley D. The HapMap project and its application to genetic studies of drug response. Pharmacogenomics J. 2004, 4(2):88-90.
30. Giancola S, McKhann HI, Berard A, et al. Utilization of the three high-throughput SNP genotyping methods, the GOOD assay, Amplifluor and TaqMan, in diploid and polyploid plants.Theor Appl Genet.2006,112(6):1115-1124.
1. Borresen AL. Role of genetic factors in breast cancer susceptibility. Acta Oncol. 1992,31: 151-155.
2. Malkin D. p53 and the Li-Fraumeni syndrome. Bi °C him Biophys Acta. 1994,1198(2-3): 197-213.
3. May P, May E. Twenty years of p53 research: structural and functional aspects of thep53 protein. Oncogene. 1999,18:7621-7636.
4. Li WF, Hu Z, Rao NY, et al. The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified. Breast Cancer Res Treat. 2008,110(1):99-109.
5. Manoukian S, Peissel B, Pensotti V, et al. Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families. Eur J Cancer. 2007,43:601-606.
6. Gross E, Kiechle M, Arnold N. Mutation analysis of p53 in ovarian tumors by DHPLC. J Bi°Chem Biophys Methods. 2001,47:73-81.
7. den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.Hum Mutat. 2000,15(1):7-12.
8. Shinmura K, Tao H, Goto M, et al. Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer. Carcinogenesis. 2004,25:2311-2317.
9. Lu C, Xu HM, Ren Q,et al.Somatic mutation analysis of p53 and ST7 tumor suppressor genes in gastric carcinoma by DHPLC.World J Gastroenterol. 2003,9(12):2662-2665.
10. Malecka KA, Ho WC, Marmorstein R, et al. Crystal structure of a p53 core tetramer bound to DNA. Oncogene. 2009,22;28(3):325-333.
11. Jing Y, Wang M, Tang W,et al.c-Abl tyrosine kinase activates p21 transcription via interaction with p53. J Bi°Chem. 2007,141(5):621-626.
12. Offit K. BRCA mutation frequency and penetrance: new data, old debate. J Natl Cancer Inst. 2006,98:1675-1677.
13. El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. Oncogene. 2003,22(47):7486-7495.
14. Xu Y. Induction of genetic instability by gain-of-function p53 cancer mutants. Oncogene. 2008,27(25):3501-3507.
15. Song H, Xu Y. Gain of function of p53 cancer mutants in disrupting critical DNA damage response pathways. Cell Cycle. 2007,6(13):1570-1573.
16. Joerger AC, Fersht AR. Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene. 2007,26(15):2226-2242.
17. Strano S, Dell'Orso S, Di Agostino S, et al. Mutant p53: an oncogenic transcription factor. Oncogene. 2007,26( 15):2212-2219.
18. Walsh, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007,11(2):103-105.
19. Balz V, Prisack HB, Bier H, et al. Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families. Cancer Genet Cytogenet. 2002,138:120-127.
20. Evans DG, Birch JM, Thorneycroft M, et al. Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome. J Med Genet. 2002,39:941-944.
21. Hedau S, Jain N, Husain SA et al. Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India. Breast Cancer Res Treat. 2004,88:177-186.
22. Martin AM, Kanetsky PA, Amirimani B et al. Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1? J Med Genet. 2003,40: e34.
23. Patel UA, Perry M, Crane-Robinson C. Screening for germline mutations of the p53 gene in familial breast cancer patients. Eur J Clin Invest.1995,25:132-137.
24. Rapakko K, Allinen M, Syrjakoski K et al. Germline TP53 alterations in Finnish breast cancer families are rare and ℃cur at conserved mutation-prone sites. Br J Cancer. 2001,84:116-119.
25. Xiao W, Oefner PJ. Denaturing high-performance liquid chromatography: A review. Hum Mutat. 2001,17:439-474.
26. Jones RJ, Chen Q, Voorhees PM et al. Inhibition of the p53 E3 ligase HDM-2 induces apoptosis and DNA damage—independent p53 phosphorylation in mantle cell lymphoma. Clin Cancer Res. 2008,14:5416-5425.
27. Shimada A, Kato S, Enjo K et al. The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. Cancer Res. 1999,59:2781-2786.
28. Nho RS, Sheaff RJ. p27kipl contributions to cancer. Prog Cell Cycle Res. 2003,5:249-259.
29. Foijer F, te Riele H. Check, double check: the G2 barrier to cancer. Cell Cycle. 2006,5(8):831-6.
30.NCBI[http://www.ncbi.nlm.nih.gov/]
1. Li WF, Hu Z, Rao NY, et al. The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified. Breast Cancer Res Treat. 2008,110(1):99-109.
2. Walsh, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007,11(2):103-105.
3. Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.Cell. 2001,105(1):149-160.
4. Xia B, Sheng Q, Nakanishi K, et al.Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.Mol Cell. 2006,22(6):719-729.
5. Yu X, Chini CC, He M, et al.The BRCT domain is a phospho-protein binding domain.Science.2003,302(5645):639-642.
6. Simpson S.PALB2-new breast-cancer susceptibility gene. Lancet Oncol. 2007,8(2):105.
7. Levitus M, Waisfisz Q, Godthelp BC, et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005,37:934-935.
8. Reid S, Schindler D, Hanenberg H et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39:162-164.
9. Den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000,15(1):7-12.
10. Fuller S, Liebens F, Carly B,et al. Breast cancer prevention in BRCA1/2 mutation carriers: a qualitative review. Breast J. 2008,14(6):603-604.
11. Serova OM, Mazoyer S, Puget N, et al. Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997,60:486-495.
12. Vehmanen P, Friedman LS, Eerola H, et al. Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997,6:2309-2315.
13. Rahman N, Stratton MR. The genetics of breast cancer susceptibility. Annu Rev Genet. 1998,32:95-121.
14. Shen Y, Tong L. Structural evidence for direct interactions between the BRCT domains of human BRCAl and a phospho-peptide from human ACCl. Biochemistry. 2008,47(21):5767-5773.
15. Garcia MJ, Benitez J. The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. Clin Transl Oncol. 2008,10(2):78-84.
16. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007,39:165-167.
17. Garcia MJ, Fernandez V, Osorio A, et al. Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Res Treat. 2009,113(3):545-551.
18. Foulkes WD, Ghadirian P, Akbari MR, et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007,9:R83.
19. Erkko H, Xia B, Nikkila J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007,446:316-319.
20. Tischkowitz M, Xia B, Sabbaghian N, et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci. 2007,104:6788-6793.
21. Gunnarsson H, Arason A, Gillanders EM, et al. Evidence against PALB2 involvement in Icelandic breast cancer susceptibility. J Negat Results Biomed. 2008,7:5.
22. Karppinen SM, Vuosku J, Heikkinen K et al. No evidence of involvement of germline BACH1 mutations in Finnish breast and ovarian cancer families. Eur J Cancer. 2003,39:366-371.
23. Rutter JL, Smith AM, Davila MR, et al. Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIPl/BACHl among BRCAl and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Hum Mutat. 2003,22:121-128.
24. Luo L, Lei H, Du Q, et al. No mutations in the BACH1 gene in BRCAl and BRCA2 negative breast-cancer families linked to 17q22. Int J Cancer. 2002,98:638-639.
25. Vahteristo P, Yliannala K, Tamminen A, et al. BACH1 Ser919Pro variant and breast cancer risk. BMC Cancer. 2006,6:19.
26. Byrnes GB, Southey MC, Hopper JL. Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008,10(3):208.
27. Cantor SB, Bell DW, Ganesan S, et al. A novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001,105:149-160.
28. Yu X, Chini CC, He M, et al. The BRCT domain is a phospho-protein binding domain. Science, 2003,302:639-642.
29. Offit K. Are BRCA1- and BRCA2-associated breast cancers different? J Clin Oncol. 2000,18:104-106.
30. Phillips KA. Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol. 2000,18:107-112.
31. Armes JE, Venter DJ. The pathology of inherited breast cancer. Pathology. 2002,34:309-314.
32. Klein B, Weirich G, Brauch H. DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations. Hum Genet. 2001,108:376-384.
33. Xiao W, Oefner PJ. Denaturing high-performance liquid chromatography: a review. Hum Mutat. 2001,17:439-474.
34. Song CG, Hu Z, Wu J, et al. The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer. J Cancer Res Clin Oncol. 2006,32:617-626.
35. Hu Z, Wu J, Liu CH, et al. The analysis of BRCA1 mutations in eastern Chinese patients with early onset breast cancer and affected relatives. Hum Mutat. 2003,22:104.
36. NCBI [http://www.ncbi.nlm.nih.gov/]
1. Yu KD, Di GH, Wu J,et al. Development and trends of surgical modalities for breast cancer in China: a review of 16-year data. Ann Surg Oncol. 2007,14(9):2502-2509.
2. Rubinstein WS. Hereditary breast cancenpathobiology, clinical translation, and potential for targeted cancer therapeutics. Fam Cancer. 2008,7(1):83-89.
3. Liede A, Narod SA. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat.2002,20(6):413-424.
4. Li WF, Hu Z, Rao NY, et al. The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified. Breast Cancer Res Treat. 2008,110(1):99-109.
5. Cao AY, Jin W, Shi PC, et al. Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population. Breast Cancer Res Treat. 2009 Feb 24. DOI 10.1007/s10549-009-0349-6
6. Cao AY, Huang J, Hu Z, et al. Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat. 2008 May 16.DOI 10.1007/s10549-008-0052-z
7. Cao AY, Huang J, Hu Z, et al. The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat. 2009,114(3):457-462.
8. Roeder K, Luca D. Searching for disease susceptibility variants in structured populations. Genomics. 2009,93(1):1-4.
9. Pattaro C, Ruczinski I, Fallin DM,et al. Haplotype block partitioning as a tool for dimensionality reduction in SNP association studies. BMC Genomics. 2008,29;9:405.
10. Tempfer CB, Hefler LA, Schneeberger C,et al. How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer? Gynecol Endocrinol. 2006,22(3): 155-159.
11. Deloukas P, Bentley D. The HapMap project and its application to genetic studies of drug response. Pharmacogenomics J. 2004,4(2):88-90.
12. Giancola S, McKhann HI, Berard A, et al. Utilization of the three high-throughput SNP genotyping methods, the GOOD assay, Amplifluor and TaqMan, in diploid and polyploid plants. Theor Appl Genet. 2006,112(6):1115-1124.
13. Byrnes GB, Southey MC, Hopper JL.Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008,10(3):208.
14. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009,360(8):790-800.
15. Coyle YM. Lifestyle, genes, and cancer. Methods Mol Biol. 2009,472:25-56.
16. Rosman DS, Kaklamani V, Pasche B. New insights into breast cancer genetics and impact on patient management. Curr Treat Options Oncol. 2007,8(1):61-73.
17. Turnbull C, Hodgson S.Genetic predisposition to cancer.Clin Med. 2005 Sep-Oct;5(5):491-498.
18. Brown P. Risk assessment: controversies and management of moderate- to high-risk individuals. Breast J. 2005,11 Suppl 1:S11-9.
19. Cuzick J. Hormone replacement therapy and the risk of breast cancer. Eur J Cancer. 2008,44(16):2344-2349.
20. Giacomini KM, Brett CM, Altaian RB, et al. The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther. 2007,81(3):328-345.
21. Feuk L, Marshall CR, Wintle RF,et al. Structural variants: changing the landscape of chromosomes and design of disease studies. Hum Mol Genet. 2006,15 Spec No 1:R57-66.
22. Kiyohara C, Takayama K, Nakanishi Y. Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis.Lung Cancer. 2006,54(3):267-283.
23. Dutt A, Beroukhim R. Single nucleotide polymorphism array analysis of cancer. Curr Opin Oncol. 2007,19(1 ):43-49.
24. Engle LJ, Simpson CL, Landers JE. Using high-throughput SNP technologies to study cancer. Oncogene. 2006,25(11):1594-1601.
25. Ma CX, Adjei AA, Salavaggione OE, et al. Human aromatase: gene resequencing and functional genomics. Cancer Res. 2005,65:11071-11082.
26. Barroso E, Milne RL, Fernandez LP, et al. FANCD2 associated with sporadic breast cancer risk. Carcinogenesis. 2006,27(9): 1930-1937.
27. Walsh, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007,11(2):103-105.
28. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007,39:165-167.
29.Garcia M J,Fernandez V,Osorio A,et al.Analysis of FANCB and FANCN/PALB2Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families.Breast Cancer Res Treat.2009,113(3):545-551.
30.Foulkes WD,Ghadirian P,Akbari MR,et al.Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.Breast Cancer Res.2007,9:R83.
31.Erkko H,Xia B,Nikkil? J,et al.A recurrent mutation in PALB2 in Finnish cancer families.Nature.2007,446:316-319.
32.Tischkowitz M,Xia B,Sabbaghian N,et al.Analysis of PALB2/FANCN-associated breast cancer families.Proc Natl Acad Sci.2007,104:6788-6793.
33.Chen P,Liang J,Wang Z,et al.Association of common PALB2 polymorphisms with breast cancer risk:a case-control study.Clin Cancer Res.2008,14(18):5931-5937.
34.Tao W,Wang C,Han R,et al.HER2 codon 655 polymorphism and breast cancer risk:a meta-analysis.Breast Cancer Res Treat.2009,114(2):371-376.
35.Johnson GC,Esposito L,Barratt B J,et al.Haplotype tagging for the identification of common disease genes.Nat Genet.2001,29(2):233-237.
36.Fu W,Wang Y,Wang Y,et al.Missing call bias in high-throughput genotyping.BMC Genomics.2009,10(1):106.
37.Shapero MH,Leuther KK,Nguyen A,et al.SNP genotyping by multiplexed solid-phase amplification and fluorescent minisequencing.Genome Res.2001,11(11):1926-1934.
38.Matsuzaki H,Loi H,Dong S,et al.Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array.Genome Res.2004,14(3):414-425.
39.Bell PA,Chaturvedi S,Gelfand CA,et al.SNPstream UHT:ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery.Biotechniques.2002,Suppl:70-72,74,76-77.
40.Mayo NE,Goldberg MS.When is a case-control study not a case-control study? J Rehabil Med.2009,41(4):209-216.
1. Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006,107(11):4223-4233.
2. Howlett NG, Taniguchi T, Olson S,et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002,297(5581):606-609.
3. Litman R, Peng M, Jin Z, et al. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005,8(3):255-265.
4. Xia B, Dorsman JC, Ameziane N, et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007,39(2):159-161.
5. Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006,22(6):719-729.
6. Reid S, Schindler D, Hanenberg H, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007,39(2): 162-164.
7. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007,39(2):165-167.
8. Erkko H, Xia B, Nikkila J, Schleutker J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007,446(7133):316-319.
9. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002,31(1):55-59.
10. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006,295(12):1379-1388.
11. Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006,38(11):1239-1241.
12. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006,38(8):873-875.
13. Heikkinen K, Rapakko K, Karppinen SM, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.Carcinogenesis.2006,27(8):1593-1599.
14.Shen WH,Balajee AS,Wang J,et al.Essential role for nuclear PTEN in maintaining chromosomal integrity.Cell.2007,128(1):157-170.
15.Levy-Lahad E,Lahad A,Eisenberg S,et al.A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.Proc Natl Acad Sci USA.2001,98(6):3232-3236.