摘要
目的非小细胞肺癌是我国发病最高的恶性肿瘤,由于缺乏有效的早期发现方法,因而确诊时多属晚期,除了手术之外,尚无其他的有效治疗方法。术后5年生存率只有约15%。同其他肿瘤一样,非小细胞肺癌的发生、发展是一个多阶段,受多基因调控的过程,由多种肿瘤相关基因表达失常或肿瘤抑制基因失活所致。因此要了解癌变过程中的基因变化,需要研究整个基因组的异常。研究表明染色体区段拷贝数增加和减少即拷贝数变异(copy number variationCNV)直接造成位于该区段的基因拷贝数发生变化,影响基因表达水平,导致表型差异。抑癌基因所在的染色体区段的杂合性缺失(loss of heterzygosity LOH)是一些上皮和间质来源的肿瘤发生、发展过程中的重要事件。肺癌遗传变异的研究方法主要包括核型分析,荧光原位杂交(fluorescent in situ hybridizationFISH),比较基因组杂交(comparative genomic hybridization CGH)等。CGH只能检测到扩增或缺失数目的异常,但不能发现Allelic homozygosity(AH),这需要研究在肿瘤细胞中是一种非常常见的DNA变异一杂合性缺失,抑癌基因的杂合性缺失会导致肿瘤的发生,全基因组扫描LOH传统方法包括微卫星标记法(polymorphic microsatellite markers)和限制性片段长度多态性(retriction fragment length polymorphism,RFLP),但是这两种方法很费时费劲。SNP是人类基因组里最普遍的多态性遗传标志。Affymectrix Genome-wide SNP 6.0芯片选取约906,600个位点分析各位点的基因型,同时芯片又能提供各位点两种等位基因型的拷贝数(CN),得到位点所在区段的CN和LOH情况,对基因组分析达到极高的分辨率(<10kb)。本研究的目的是通过应用SNP芯片对肺癌肿瘤组织进行全基因组扫描,探讨肺癌组织基因拷贝数扩增、缺失,以及杂合性缺失等遗传变异与肺癌发生的相关性,旨在揭示肺鳞癌发生的分子机制,提高早期诊断和提供治疗新方法。本研究应用SNP芯片检测15例肺鳞癌全基因组CNV和LOH遗传变异信息,进一步研究全基因组的拷贝数扩增,缺失,以及杂合性缺失等染色体异常,从全基因组水平对肺鳞癌的分子遗传机制异常进行初步探讨。
方法提取15例肺鳞癌患者的肺癌组织和配对的远癌肺组织的全基因组DNA并用于Affymetrix Genome-wide SNP 6.0芯片检测。芯片探针杂交信号强度的数据使用Affymetrix专用软件GTC3.0分析SNP位点基因型和拷贝数得到全基因组的CNV,LOH,纯合性缺失区域等信息。
结果1.Genome-wide SNP 6.0芯片的QC Call rate都超过了质控标准。15张芯片的QC Call rate最低的为95.07%,最高的为99.26%,平均为97.49%,Contrast QC最低为2.08,最高为3.75,平均为2.73,MAPD最低为0.16,最高为0.28,平均为0.22,表明芯片杂交质量良好。
2.15例肺癌组织分析结果中CN为2的片段共181个,占1.26%,片段长度最短的为100kb,最长的为3,995kb。CN为4的片段共226个,占1.57%,片段长度最短的为100kb,最长的为34,862kb。CN为3的片段共6,018个,占41.9%,片段长度最短的为100kb,最长的为25,654kb。CN为1的片段共7,837个,占54.6%,片段长度最短的为100kb,最长的为86,897kb。
3.15例肺癌组织中CNV中Loss主要分布在第4号染色体(7.11%,1001/14081),3号染色体(6.22%,876/14081),5号染色体(4.92%,693/14081),1号染色体(4.06%,572/14081),10号染色体(3.14%,442/14081)等染色体上,gain主要分布在7号染色体(4.99%,702/14081),2号染色体(4.57%,643/14081),8号染色体(4.09%,576/14081),1号染色体(3.88%,547/14081),12号染色体(3.49%,491/14081)等染色体上。其中gain片段数量最少的是C08-0342,共7个片段,最多的是C08-0027,共877个片段；loss片段数量最少的是C08-0085,共4个片段,最多的是C08-0027,共1,628个片段。
4.15例肺癌组织分析结果中都有不同程度的杂合性缺失,15例肺癌组织检测出各个样本含有不同数量的LOH位点。15例肺癌组织总共检出1,921,845个LOH位点,其中LOH位点数量最少的为C08-0142,共计54,274个LOH位点,LOH位点数量最多的为C08-0027,共计400,078个LOH位点。其中不同染色体也有不同的LOH位点数量,其发生率由高至低依次前5条染色体为第X号染色体(28.1%,540105/1921845),第1号染色体(7.14%,137282/1921845),第5号染色体(6.89%,132347/1921845),第3号染色体(6.19%,119014/1921845),第4号染色体(6.11%117336/1921845)。15例肺癌组织的X染色体上均能检测到LOH位点,共检测到31,793个LOH位点。
5.15例肺癌组织分析结果中检测到纯合性缺失区域(CN=0)共92处,分别位于第1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,21,X,Y号染色体上,其发生率由高到低依次为第4号染色体(21.7%,20/92),第5号染色体(11.9%,11/92),第3号染色体(9.8%,9/92),Y染色体(8.7%,8/92),第X染色体(7.6%,7/92),第19号染色体(6.5%,6/92),第17号染色体(5.4%,5/92),第1号染色体(4.3%,4/92),第8,10,15,18号染色体(3.3%,3/92),第7号染色体(2.2%,2/92),第2,6,9,12,13,14,16,21号染色体(1.1%,1/92)。最小的缺失片段在第19号染色体的q13.1,长度为101kb,最长的缺失片段在第3号染色体的p12.3～p12.2,长度为7,146kb。
结论(1)Genome-wide SNP 6.0基因芯片和分析软件Genome Typing Console 3.0,可以同时详细分析肺鳞癌的染色体缺失,扩增和LOH,纯合性缺失区域；(2)Genome-wide SNP 6.0基因芯片筛选出多处肺鳞癌相关基因,表明多个基因可能参与了肺鳞癌的发生,发展过程；(3)发现的扩增和纯合性缺失以及杂合性缺失区域可能含有新的癌基因或抑癌基因,为今后的研究提供了新的线索和方向。
Object In the last few years,reports have demonstrated that copy number gain/or loss (copy number variation CNV) influences gene expression and result in phenotypic variation by disrupting genes and altering gene dosage.Loss of heterozygosity (LOH) of chromosomal regions bearing tumor suppressor genes is a key event in the oncogenesis and development of epithelial and mesenchymal tumors. But the functions of LOH and CNV have not been fully understood. Previous studies attempting to identify genetic changes occurring in non small cell lung cancers have relied on cytogenetic studies, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH).LOH can be analysed through allelotyping of tumors with polymorphic genetic markers.Restriction fragment length polymorphism (RFLP) or microsatellites are reliable genetic markers, but the genotyping procedure is rather laborious and time-comsuming on a genome-wide scale.Genome-wide detection of LOH, as well as CNV in cancer genomes, has drawn recent attention in the field of cancer genetics.SNPs are the most common form of sequence variation in the human genome, occurring approximately every～1000 bp.Affymetrix Single Nucleotide Polymorphism Microarray was originally developed for large-scale genome-wide association studies, provide a powerful platform for both genome-wide LOH analysis and CN detection. In this platform, the use of large numbers of SNP-specific probes showing linear hybridization kinetics allows not only high-resolution(<10Kb) LOH analysis at 906,600 SNP loci but also accurate determination of the CN status at each LOH region compared with the low resolution of array-CGH. The aim of this study is to obtain the genetic changes of non small cell squamous lung cancer by using Affymetrix genome-wide SNP 6.0 array for screening out genes that are related to their phenotypes, and ultimately try to study the melocular mechanisms of non small cell squamous lung cancer.
Method Genomic DNA extracted from 15 non small cell squamous lung cancer tissues and matched normal lung tissues were used to be analysed by genome-wide SNP 6.0 arrays.The hybridization intensity of each probe was analyzed using Affymetrix proprietary software for genotyping and copy number at each locus and inorder to obtain global profiles of CNV and LOH of the tumors.
Result 1.The SNP call rate of 15 arrays ranged from 95.07% to 99,26%,with average call rate of 97.49%. QC call rate of the 15 arrays ranged from 2.08 to 3.05,averaged 2.73.All the call rates of the arrays were in excess of 93%,the cardinal quality control standard.
2.Of the 15 arrays,There are 7837 regions which CN=1,accounted for 54.6% of all the CNV regions; There are 6018 regions which CN=3,accounted for 41.9% of all the CNV regions;There are 226 regions which CN=4,accounted for 1.57% of all the CNV regions; The majority of the chromosome loss alterations were located on chromosome 4,3,5,1,10;The majority of the chromosome gain alterations were located on chromosome 7,2,8,1,12.
3.LOH was detected in all the 15 arrays with different degrees,a total number of 1,921,845 were detected in the 15 arrays.The minimum number of 54,274 LOH was detected in sample C08-0142 and the maximum number of 400,078 LOH was detected in sample C08-0027.The percentage of LOH incidence rate ranged from 0.03% to 28.1%.
4.92 homozyous deletion regions were detected in the 15 arrays,which were located on chromosome1,2,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,21,X,Y.The percentage of HD occurred among all the chromosome were chromosome 4(21.7%), chromosome 5(11.9%),chromosome 3(9.8%),chromosome Y(8.7%),chromosome X(7.6%),chromosome 19(6.5%),chromosome 17(5.4%),chromosome 1(4.3%), chromosome 8,10,15,18(3.3%),chromosome 7(2.2%),chromosome 2,6, 9,12,13,14,16,21(1.1%).The shortest HD region was located on q13.1 of chromosome 19,covering 101kb;the longest HD region was located on p12.3～p12.2 of chromosome 3,covering 7,146kb.
Conclusion(1)Genome-wide chromosone copy number variation and LOH can be detected by using high resolution Affymetrix Genome-wide SNP 6.0 array simultaneousl.(2) We could identify narrow amplified and deleted region to find new oncogenes and tumor suppressor genes by using the Affymetrix Genome-wide SNP 6.0 array and software Genome Typing Console 3.0.(3).The novel amplified or deleted genes discovered here might beeome targets for the early diagnosis and therapy for non small cell squmous lung cancer.
引文
1.Parkin DM.Bray FB.Pisani P, et al.Global cancer statistics,2002. CA Cancer J Clin[J],2005,55(2):74-108.
2.李连弟,鲁凤珠,张思维等,中国恶性肿瘤死亡率20年变化趋势和近期预测分析.中华肿瘤杂志[J],1997,19(1)：3-9.
3.陈万青,张思维,李连弟,等.中国部分县市1998-2002年肺癌的发病与死亡.中国肿瘤[J],2006,15(9)：570-574.
4.Weinberg R A. Tumor suppressor genes. Science[J],1991,254:1138-1146.
5.dson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer[J],2001, 2:157-162.
6.Lengauer C,Kinzler KW,Vogelstein,BG.Genetic instabilities in human cancer.Nature[J],1998,396:643-649.
7.hard R, Shumpei I, Karen RF, et al. Global variation in copy number in the human genome. Nature[J],2006,444:444-454.
8.Kallioniemi A,Kallionlemi O,Sudar D,et al.Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors.Science[J],1992,258:818-821
9.Ishkanian AS,Malloff CA,Wastson SK,et al.A tiling resolution DNA microarray with complete coverage of the human genome.Nat Genet[J],2004,36:299-303.
10.Weissenbach J, Gyapay G,Dib C,et al.A second-generation linkage map of the human genome. Nature[J].1992 Oct 29;359(6398):794-801.
11.Wang DG, et al.Large-scale identification, mapping, and genotyping of singlenucleotide polymorphisms in the human genome. Science[J],1998,280: 1077-1082.
12.Kennedy GC, Matsuzaki H, Dong S,et al. Large-scale genotyping of complex DNA. Nat Biotechnol[J],2003,21:1233-1237.
13.Burton PR, Clayton DG, Cardon LR, et al.Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature[J], 2007,447:661-678.
14.Neil V.Morgan,Shanaz Pasha,Colin A.Johnson,et al.A Germline Mutation in BLOC1S3/Reduced Pigmentation Causes a Novel Variant of Hermansky-Pudlak Syndrome (HPS8).Am J Hum Genet[J],2006,78(1):160-166.
15.Zhao X, Li C, Paez JG, et al.An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res[J],2004,64:3060-3071.
16.Huang J, Wei W, Zhang J, Liu G,et al. Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics[J], 2004,1:287-299.
17.Bignell GR, Huang J, Greshock J, et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays.Genome Res[J],2004,14:287-295.
18.Wang ZC, Buraimoh A, Iglehart JD, et al. Genome-wide analysis for loss of heterozygosity in primary and recurrent phyllodes tumor and fibroadenoma of breast using single nucleotide polymorphism arrays.Breast Cancer Res Treat[J], 2006,97:301-309.
19.Zhou X, Mok SC,Chen Z, et al.Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum Genet [J].2004,115: 327-330.
20.dford IR. Chromosomal rearrangement as the basis for human tumourigenesis.Int J Radiat Biol[J],2004,80(8):543-557.
21.Duesberg P, Li R, Rasnick D.Aneuploidy approaching a perfect score in predicting and preventing cancer:highlights from a conference held in Oakland, CA in January,2004. Cell Cycle[J],2004,3(6):823-828.
22.Huang Q, Yu CG, Klein M, et al.A comparison of CAS 200 and Automated Cellular Imaging System(ACIS) in DNA aneuploidy determination in Barrett's esophagus. BMC Clin Pathol[J].2005 Aug 12;5:7.
23.CG,Huang Q, Klein M, et al.Quantitative Targeted DNA Content Analysis in Barett's mucosa,dysplasia and carcinoma. Gastroenterology[J],2005, 128(4Suppl2):A34.
24. Ninomiya H,Nomura K,Satoh Y,et al. Genetic instability in lung cancer:concurrent analysis of chromosomal,mini and microsatellite instability and loss of heterozygosity.Br J Cancer[J],2006,94(10):1485-1491.
25.丛文铭。肿瘤抑制基因变异的分子病理学研究进展[J]。中华病理学杂志,2001,30(1)：58-60.
26.GREPMEIER U, D IET MA IER W, MERK J, et al.Deletions at chromosome 2q and 12p are early and freqauent molecular alterations in bronchial epithelium and NSCLC of long-term smokers[J].Int J Oncol,2005,27(2):481-488.
27.王晓玫,彭全洲,单军等。3p杂合性缺失与非小细胞肺癌的相关性[J].广东医学,2007,28(7)：1060-1062。
28.Zborovskaia IB,Tatosian AGMolecular markers of various stages of non small cell lung cancer development. Mol Biol[J],2004,38(2):191-202.
29.李红,赵明,白艳军,等。非小细胞肺癌微切割组织中3p杂合性丢失的研究[J]。中国肿瘤临床,2004,31(3)：124-126。
30.shino I,Osoegawa A,Yohena T,et al.Loss of heterozygosity (LOH) in non-small cell lung cancer:difference between adenocarcinoma and squamous cell carcinoma.Respir Med[J],2005,99(3):308-312.
31.Sheu JC,Lin YW,Chou HC,et al.Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan.British J Cancer[J],1999, 80:468-476.
32.Southern EM,Maskos U,Elder JK.Analyzing and comparing nucleic acid sequences by hybridization to arrays of oligonucleotides:evaluation using experimental models.Genomics[J].1992 Aug;13(4):1008-1017.
33.Schena M,SShalon D,Davis RW,et al.Quantitative monitoring of gene expression patterns with a complementary DNA microarray.Science[J],1995,270:467-470.
34.Ishkanian AS,Malloff CA,Watson SK,et al.A tiling resolution DNA microarray with complete coverage of the human genome.Nat Genet[J].2004,36(3):299-303.
35.Nao Nishida, Asako Koike, Atsushi Tajima,et al.Evaluating the performance of Affymetrix SNP Array 6.0 platform with 400 Japanese individuals.BMC Genomics[J],2008,9:431-440.
36. Nannya Y, Sanada M, Nakazaki K, et al.A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res[J],2005,65:6071-6079.
37. Kloth JN, Oosting J, van Wezel T, et al.Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex genetic alterations in cervical cancer. BMC Genomics[J].2007, 20;8:53.
38. Calhoun ES,Gallmeier E,Cunningham SC,et al.Copy-number methods dramatically underestimate loss of heterozygosity in cancer. Genes Chromosomes Cancer[J],2006,45:1070-1071.
39.Larizza L,Schirrmacher V.Somatic cell fusion as a source of genetic rearrangement leading to metastatic variants.Cancer Metastasis Rev[J].1984,3(3): 193-222.
40.Qu HQ, Jacob K, Fatet S,et al.Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas.Neuro Oncol[J].2010,12(2):153-63.
41.Caren H, Kryh H, Nethander M,et al.High-risk neuroblastoma tumors with 11 q-deletion display a poor prognostic, chromosome instability phenotype with later onset.Proc Natl Acad Sci U S A[J].2010,107(9):4323-4328.
42.Volchenboum SL, Li C, Li S,et al.Comparison of primary neuroblastoma tumors and derivative early-passage cell lines using genome-wide single nucleotide polymorphism array analysis.Cancer Res[J].2009,15;69(10):4143-4149.
43.Yin D, Ogawa S,Kawamata N,et al.High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray.Mol Cancer Res[J].2009,7(5):665-677.
44.Solomon DA,Kim JS,Cronin JC,et al.Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.Cancer Res[J].2008,15;68 (24):103-106.
45.Gardina PJ, Lo KC, Lee W,et al.Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays.BMC Genomics[J]. 2008,17;9:489-495.
46.Caren H, Erichsen J, Olsson L,et al.High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors:four cases of homozygous deletions of the CDKN2A gene.BMC Genomics[J].2008,29;9:353-261.
47. Krupp W, Holland H, Koschny R,et al. Genome-wide genetic characterization of an atypical meningioma by single-nucleotide polymorphism array-based mapping and classical cytogenetics.Cancer Genet Cytogenet[J].2008,15;184(2):87-93.
48.Zhang SG, Song WQ, Gao YT,et al. CD1d gene is a target for a novel amplicon at 1q22-23.1 in human hepatocellular carcinoma.Mol Biol Rep[J]. 2010,37(1):381-387.
49. Kanda M, Nomoto S,Okamura Y,et al. Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis.Int J Oncol[J]. 2009,35(3):477-483.
50.Belinsky MG, Skorobogatko YV, Rink L,et al. High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors.Genes Chromosomes Cancer[J].2009,48(10):886-896.
51.Sheffer M, Bacolod MD, Zuk O,et al.Association of survival and disease progression with chromosomal instability:a genomic exploration of colorectal cancer.Proc Natl Acad Sci U S A[J].2009,106(17):7131-7136.
52.Melcher R, Zopf W, Hartmann E,et al.Spectral karyotyping and SNP microarray analysis define uniparental disomy (UPD) as a novel mutational mechanism in MSI-and CSI-colorectal cancers.Cell Oncol[J].2008;30(6):507-510.
53.Lin LJ, Asaoka Y, Tada M,et al.Integrated analysis of copy number alterations and loss of heterozygosity in human pancreatic cancer using a high-resolution, single nucleotide polymorphism array.Oncology[J].2008;75(1-2):102-112.
54.Papaemmanuil E, Carvajal-Carmona L, Sellick GS,et al.Deciphering the genetics of hereditary non-syndromic colorectal cancer.Eur J Hum Genet[J]. 2008,16(12):1477-1486.
55.Kurashina K, Yamashita Y, Ueno T,et al.Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma.Cancer Sci[J].2008,99(9):1835-1840.
56.Monzon FA, Alvarez K, Gatalica Z,et al.Detection of chromosomal aberrations in renal tumors:a comparative study of conventional cytogenetics and virtual karyotyping with single-nucleotide polymorphism microarrays.Arch Pathol Lab Med[J].2009,133(12):1917-1922.
57.Chen M, Ye Y, Yang H,et al. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays.Int J Cancer[J].2009,15; 125(10):2342-2348.
58.Kim HJ, Shen SS,Ayala AG,et al. Virtual-karyotyping with SNP microarrays in morphologically challenging renal cell neoplasms:a practical and useful diagnostic modality.Am J Surg Pathol[J].2009,33(9):1276-1286.
59.Coenen MJ,Ploeg M, Schijvenaars MM,et al.Allelic imbalance analysis using a single-nucleotide polymorphism microarray for the detection of bladder cancer recurrence.Clin Cancer Res[J].2008,14(24):8198-8204.
60.Zhang ZF, Matsuda D, Khoo SK,et al.A comparison study reveals important features of agreement and disagreement between summarized DNA and RNA data obtained from renal cell carcinoma.Mutat Res[J].2008,657(1):77-83.
61.Liu W,Xie CC, Zhu Y,et al.Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer.Neoplasia[J]. 2008,10(8):897-907.
62.Toma MI, Grosser M, Herr A,et al.Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array.Neoplasia[J]. 2008,10(7):634-642.
63.Sircar K, Yoshimoto M, Monzon FA,et al.PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer.J Pathol[J].2009,218(4):505-513.
64.Gorringe KL, Ramakrishna M, Williams LH,et al.Are there any more ovarian tumor suppressor genes? A new perspective using ultra high-resolution copy number and loss of heterozygosity analysis.Genes Chromosomes Cancer[J]. 2009,48(10):931-942.
65.Bowden W,Skorupski J, Kovanci E,et al.Detection of novel copy number variants in uterine leiomyomas using high-resolution SNP arrays.Mol Hum Reprod[J].2009,15(9):563-568.
66.Walsh CS,Ogawa S,Scoles DR,et al. Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas.Clin Cancer Res[J].2008,14(23):7645-751.
67.Huang YT, Heist RS,Chirieac LR,et al.Genome-wide analysis of survival in early-stage non-small-cell lung cancer.J Clin Oncol[J].2009,27(16):2660-2667.
68.You M, Wang D, Liu P, Vikis H,et al.Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.Clin Cancer Res[J].2009,15(8):2666-2674.
69.胡彬,陈军,周清华等。利用单核苷酸多态性芯片全基因组检测人大细胞肺癌细胞株的杂合性缺失和拷贝数变异。中国肺癌杂志[J],11(3)：327-332。
70.Akagi T, Ito T, Kato M,et al.Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma.Int J Cancer[J].2009,15;125(10):2349-2359.
71.Zheng YL, Hu N, Sun Q,et al. Telomere attrition in cancer cells and telomere length in tumor stroma cells predict chromosome instability in esophageal squamous cell carcinoma:a genome-wide analysis.Cancer Res[J]. 2009,15;69(4):1604-1614.
72.Zhang X, Zhu ZH, Lin P,et al. Analyzing the profile of chromosomal imbalances in esophageal atypical hyperplasia and early stage esophageal squamous cell carcinoma by 250K Snp Array.Zhonghua Yi Xue Za Zhi[J]. 2008,14;88(37):2636-2641.
73.Wiech T,Nikolopoulos E,Weis R,et al.Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays.Lab Invest[J].2009,89(4):385-397.
74.XJ Zhao,Barbara AWeir,Thomas LaFramboise,et al.Homozygous Deletions and Chromosome Amplifications in Human Lung Carcinomas Revealed by Single Nucleotide Polymorphism Array Analysis.Cancer Res[J],65(13):5561-5570.
75.Nowak D, Ogawa S,Muschen M,et al.SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations.Blood[J].2010,4;115(5):1049-1053.
76.Bardini M, Spinelli R, Bungaro S,et al.DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4.Leukemia[J].2010,24(1):169-176.
77. Caprini E, Cristofoletti C, Arcelli D,et al.Identification of key regions and genes important in the pathogenesis of sezary syndrome by combining genomic and expression microarrays.Cancer Res[J].2009,1;69(21):8438-8446.
78.IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse:a GIMEMA AL WP report. J Clin Oncol.2009, 1;27(31):5202-5207
79.Tiu RV, Gondek LP, O'Keefe CL,et al. New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.J Clin Oncol[J].2009,1;27(31):5219-5226.
80. Akagi T, Shih LY, Ogawa S,et al.Single nucleotide polymorphism genomic arrays analysis of t(8;21)acute myeloid leukemia cells.Haematologica[J].20 09,94(9):1301-1306.
81.Kawamata N, Ogawa S,Gueller S,et al. Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array.Exp Hematol[J].2009,37(8):937-946.
82.Nowak D, Le Toriellec E, Stern MH,et al. Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy.Haematologica[J].2009,94(4):518-527.
83.Loo LW,Ton C,Wang YW,et al.Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.Genes Chromosomes Cancer[J].2008,47(12):1049-1066.
84.Purdie KJ,Harwood CA,Gibbon K,et al.High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia.Br J Cancer[J].2010,16;10 2(6):1044-1051.
85.Bouron-Dal Soglio D, Rougemont AL, Absi R,et al.SNP genotyping of a sclerosing rhabdomyosarcoma:reveals highly aneuploid profile and a specific MDM2/HMGA2 amplification.Hum Pathol[J].2009,40(9):1347-1352.
86.Baras A, Yu Y, Filtz M,et al.Combined genomic and gene expression microarray profiling identifies ECOP as an upregulated gene in squamous cell carcinomas independent of DNA amplification.Oncogene[J].2009,28(32):2919-2924.
87. Purdie KJ, Harwood CA, Gulati A,et al.Single nucleotide polymorphism array analysis defines a specific genetic fingerprint for well-differentiated cutaneous SCCs.J Invest Dermatol[J].2009,129(6):1562-1568.
88.Rauch A, Ruschendorf F, Huang J,et al.molecular karyotyping using SNP array for genomewide genotyping. J Med Genet[J].2004 Dec;41(12):916-922.
89. Di X, Matsuzaki H, Webster TA,et al.Dynamic model based algorithms for screening and genotyping over 100K SNPs on oligonucleotide microarrays. Bioinformatics[J].2005 May 1;21(9):1958-1963.
90.Jen KY, Cheung VG. Identification of Novel p53 target genes in ionizing radiation response.Cancer Res[J].2005 Sep 1;65(17):7666-7673.
91.Nessling M, Richter K, Schwaenen C,et al.Candidate genes in breast cancer revealed by microarray-based comparative genomic hybridization of archived tissue. Cancer Res[J].2005 Jan 15;65(2):439-447.
92.Kim B, Bang S,Lee S,et al.Expression profiling and subtype-specific expression of stomach cancer. Cancer Res[J].2003 Dec 1;63(23):8248-8255.
93.Holzmann K,Kohlhammer H,Schwaenen C,et al.Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes.Cancer Res[J].2004,64(13):4428-4433.
94.Yan PS,Chen CM, Shi H, dissecting complex epigenetic alterations in breast cancer using CpG island microarray. Cancer Res[J].2001,1;61(23):8375-8380.
95.Heidenblad M, Lindgren D, Veltman JA, et al.Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer:implications for the interpretation of genomic amplifications. Oncogene[J].2005,24(10):1794-1801.
96.Bustin SA. Quantification of mRNA using real-time reverse transcription PCR (RT-PCR):trends and problems.J Mol Endocrinol[J].2002,29(1):23-39.
97.Tricarico C,Pinzani P, Bianchi S,et al.Quantitative real-time reverse transc ription polymerase chain reaction:normalization to rRNA or single houseke eping genes is inappropriate for human tissue biopsies.Anal Biochem[J].2 002,309(2):293-300.
98.Bustin SA. Real-time, fluorescence-based quantitative PCR:a snapshot of current procedures and preferences.Expert Rev Mol Diagn[J].2005,5(4):493-498.
99.Bustin SA, Benes V, Nolan T,et al.Quantitative real-time RT-PCR--a perspective. J Mol Endocrinol[J].2005 Jun;34(3):597-601.
100.Stagliano KE,Carchman E, Deb S.Real-time polymerase chain reaction quantitation of relative expression of genes modulated by p53 using SYBR Green I. Methods Mol Biol[J].2003;234:73-91.
101.Hernandez M, Rodriguez-Lazaro D, Esteve T, Development of melting temperature-based SYBR Green I polymerase chain reaction methods for multiplex genetically modified organism detection. Anal Biochem[J].2003, 15;323(2):164-170.
102.Czechowski T, Bari RP, Stitt M,et al.Real-time RT-PCR profiling of over 1400 Arabidopsis transcription factors:unprecedented sensitivity reveals novel root-and shoot-specific genes.Plant J[J].2004 Apr;38(2):366-379.
103.Zhao M, Chow A, Powers J,et al. Microarray analysis of gene expression after transverse aortic constriction in mice. Physiol Genomics[J].2004,19(1):93-105.
1.Parkin D M,Bray F B,Pisani P.Global cancer statistics[J].CA Cancer J Clin,2005,55(2):74-108.
2.陈万青；张思维；李连弟等,中国部分县市1998～2002年肺癌的发病与死亡。中国肿瘤[J].2006.15(9)：570-574.
3.Tolle R. Information technology tools for efficient SNP studies. Am J Pharmacogenomics[J],2001,1(4):303-314
4.Orita M,lwahana H,Kanazawa H,et al. Detection of polymorphisms of human DNA by gel electrophorosis as single-strand conformation polymorphisms[J].Proc Nat Acad Sci USA,1989,86(8):2766-2770.
5.Collins F S,Guyer M S,Chakravarti A.Variations on a theme:Cataloging human DNA sequence variation[J].Science,1997,278(5343):1580-1581.
6. Gottgens B,Barton L M,Gilbert J G,et al.Analysis of vertebrate SCL loci identifies conserved enhancers.Nature Biotechnol[J],2000,18:181-186.
7.Nao Nishida,Asako Koike,Atsushi Tajima,et al.Evaluating the performance of Affymetrix SNP Array 6.0 platform with 400 Japanese individuals.BMC Genomics[J],2008,9:431-440.
8.dor SP,Read JL,Pirrung MC,et al.Light-directed,spatially addressable parallel chemical synthesis.Seience[J],1991,251 (4995):767-773.
9.ase AC,Solas D,Sullivan EJ,et al.Light-generated oligonucleotide arrays for rapid DNA sequence analysis.Proc Natl Acad Sci USA[J],1994,91 (11):5022-5026.
10. einberg R A.Tumor suppressor genes.Science[J],1991,254:1138-1146.
11.nudson AG. Two genetic hits (more or less) to cancer.Nat Rev Cancer[J],2001,2:157-162.
12.ichard R,Shumpei I,Karen RF,et al.Global variation in copy number in the human genome.Nature[J],2006,444:444-454.
13.Zhao X,Li C,Paez JG,et al.An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays.Cancer Res[J],2004,64:3060-3071.
14.uang J,Wei W,Zhang J,Liu G,et al.Whole genome DNA copy number changes identified by high density oligonucleotide arrays.Hum Genomics[J],2004,1: 287-299.
15.Bignell GR,Huang J,Greshock J,et al.High-resolution analysis of DNA copy number using oligonucleotide microarrays.Genome Res[J],2004,14:287-295.
16.Wang ZC,Buraimoh A,Iglehart JD,et al.Genome-wide analysis for loss of heterozygosity in primary and recurrent phyllodes tumor and fibroadenoma of breast using single nucleotide polymorphism arrays.Breast Cancer Res Treat[J].2006,97:301-309.
17.hou X,Mok SC,Chen Z,et al.Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array.Hum Genet[J].2004,115(4):327-330.
18.Botstein D,White RL, Skolnick M,et al.Construction of a genetic linkage map in man using restriction fragment length polymorphisms[J].Am J Hum Genet,1980,32:314-331
19.Tong Sun,Yang Gao,WenTan et al,A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers[J].nature genetic,39(5)605-613.
20.Yoshimasa Maniwa,Masahiro Yoshimura,Vladimir P.Bermudez el al.His239Arg SNP of HRAD9 Is Associated with Lung Adenocarcinoma[J]:Cancer 2006,106(5),1117-1122.
21.Jian Gu,Xi feng Wu,Qiong Dong et al,A Nonsynonymous Single-Nucleotide Polymorphismin The PDZ-RhoGuanine Nucleotide Exchange Factor(Ser1416G ly) Modulates the Risk of Lung Cancer in Mexican Americans.Cancer[J],200 6,106(12),2716-2724
22.母新华,邵康,赫捷等.FUS2基因多态位点SNP767(A/T)在肺癌中的研究[J]：中国肺癌杂志,2006,9(5)：409-412
23.Judith N Kloth,Jan Oosting,Tom van Wezel,et al.Combined array-comparative genomic hybridazition and single-nucleotide polymorphism-loss of hererozygosity analysis reveals complex genetic alterations in cervical cancer[J].BMC Genomics 2007,8:53-58.
24. Mohammad Obaidu Hoque,Chyi-Chia R Lee,Paul Cairns,et al.Genome-Wide Genetic Characterization of Bladder Cancer:A Comparison of High-Density Single-Nucleotide Polymorphism Arrays and PCR-based Microsatellite Analysis.Cancer Reserch[J].2003,63:2216-2222
25.Schaid D J,Guent her J C,Christensen GB,et al.Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility Loci.Am J Hum Genet[J],2004,75 (6):948-965
26.Sugimura H,Kohno T,Wakai K,et al.HOGG 1 Ser326Cys polmorphism and lung cancer susceptibility.Caucer Epidemiol Biomark[J],1999,8:669-674.
27.ItO H. Hamajima N.Takezaki T,el al.A limited association of OGGI Ser326Cys polymorphism for adenocarcinoma of the lung.J Epidemiol[J],2 002,12(3):258-265.
28.Qu HQ,Jacob K, Fatet S,et al.Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas.Neuro Oncol[J].2010,12(2):153-163.
29. Caren H, Kryh H, Nethander M,et al.High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset.Proc Natl Acad Sci U S A[J].2010,107(9):4323-4328.
30.Volchenboum SL, Li C, Li S,et al.Comparison of primary neuroblastoma tumors and derivative early-passage cell lines using genome-wide single nucleotide polymorphism array analysis.Cancer Res[J].2009,15;69(10):4143-4149.
31.Yin D, Ogawa S,Kawamata N,et al. High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray.Mol Cancer Res[J].2009,7(5):665-677.
32.Solomon DA, Kim JS,Cronin JC,et al.Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.Cancer Res[J]. 2008,15;68(24):103-106.
33.Gardina PJ, Lo KC, Lee W,et al.Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays. BMC Genomics[J]. 2008,17;9:489-495.
34.Caren H, Erichsen J, Olsson L,et al. High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors:four cases of homozygous deletions of the CDKN2A gene.BMC Genomics[J].2008,29;9:353-359.
35.Krupp W,Holland H, Koschny R,et al.Genome-wide genetic characterization of an atypical meningioma by single-nucleotide polymorphism array-based mapping and classical cytogenetics.Cancer Genet Cytogenet[J].2008,15;184(2):87-93.
36.Zhang SG,Song WQ, Gao YT,et al.CD1d gene is a target for a novel amplicon at 1q22-23.1 in human hepatocellular carcinoma.Mol Biol Rep[J].2010,37(1):381-387.
37.Kanda M, Nomoto S,Okamura Y,et al.Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis.Int J Oncol[J]. 2009,35(3):477-483.
38.Belinsky MG,Skorobogatko YV, Rink L,et al.High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors.Genes Chromosomes Cancer[J].2009,48(10):886-896.
39.Sheffer M, Bacolod MD, Zuk O,et al.Association of survival and disease progression with chromosomal instability:a genomic exploration of colorectal cancer.Proc Natl Acad Sci U S A[J].2009,106(17):7131-7136.
40.Melcher R, Zopf W, Hartmann E,et al. Spectral karyotyping and SNP microarray analysis define uniparental disomy (UPD) as a novel mutational mechanism in MSI-and CSI-colorectal cancers.Cell Oncol[J].2008;30(6):507-510.
41.Lin LJ, Asaoka Y, Tada M,et al. Integrated analysis of copy number alterations and loss of heterozygosity in human pancreatic cancer using a high-resolution, single nucleotide polymorphism arrayOncology[J].2008;75(1-2):102-112.
42.Papaemmanuil E, Carvajal-Carmona L, Sellick GS,et al.Deciphering the genetics of hereditary non-syndromic colorectal cancer.Eur J Hum Genet[J]. 2008,16(12):1477-1486.
43.Kurashina K, Yamashita Y, Ueno T,et al. Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma.Cancer Sci[J].2008,99(9):1835-1840.
44.Monzon FA, Alvarez K, Gatalica Z,et al.Detection of chromosomal aberrations in renal tumors:a comparative study of conventional cytogenetics and virtual karyotyping with single-nucleotide polymorphism microarrays.Arch Pathol Lab Med[J].2009,133(12):1917-1922.
45.Chen M, Ye Y, Yang H,et al. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays.Int J Cancer[J].2009,15;125(10):2342-2348.
46.Kim HJ, Shen SS,Ayala AG,et al.Virtual-karyotyping with SNP microarrays in morphologically challenging renal cell neoplasms:a practical and useful diagnostic modality.Am J Surg Pathol[J].2009,33(9):1276-1286.
47. Coenen MJ, Ploeg M, Schijvenaars MM,et al.Allelic imbalance analysis using a single-nucleotide polymorphism microarray for the detection of bladder cancer recurrence.Clin Cancer Res[J].2008,14(24):8198-8204.
48.Zhang ZF, Matsuda D,Khoo SK,et al.A comparison study reveals important features of agreement and disagreement between summarized DNA and RNA data obtained from renal cell carcinoma.Mutat Res[J].2008,657(1):77-83.
49.Liu W, Xie CC,Zhu Y,et al.Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer.Neoplasia[J]. 2008,10(8):897-907.
50.Toma MI, Grosser M, Herr A,et al.Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array.Neoplasia[J]. 2008,10(7):634-642.
51.Sircar K, Yoshimoto M, Monzon FA,et al.PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer.J Pathol[J].2009,218(4):505-513.
52.Gorringe KL, Ramakrishna M, Williams LH,et al.Are there any more ovarian tumor suppressor genes? A new perspective using ultra high-resolution copy number and loss of heterozygosity analysis.Genes Chromosomes Cancer[J]. 2009,48(10):931-942.
53.Bowden W,Skorupski J, Kovanci E,et al.Detection of novel copy number variants in uterine leiomyomas using high-resolution SNP arrays.Mol Hum Reprod[J].2009,15(9):563-568.
54.Walsh CS,Ogawa S,Scoles DR,et al.Genome-wide loss of heterozygosity and uniparental disomy in BRCAl/2-associated ovarian carcinomas.Clin Cancer Res[J].2008,14(23):7645-7651.
55.Huang YT, Heist RS,Chirieac LR,et al.Genome-wide analysis of survival in early-stage non-small-cell lung cancer.J Clin Oncol[J].2009,27(16):2660-2667.
56.You M, Wang D,Liu P, Vikis H,et al.Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.Clin Cancer Res[J].2009,15(8):2666-2674.
57.胡彬,陈军,周清华等。利用单核苷酸多态性芯片全基因组检测人大细胞肺癌细胞株的杂合性缺失和拷贝数变异。中国肺癌杂志[J],11(3)：327-332。
58.Akagi T, Ito T, Kato M,et al. Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma.Int J Cancer[J].2009,15;125(10):2349-2359.
59.Zheng YL, Hu N, Sun Q,et al. Telomere attrition in cancer cells and telomere length in tumor stroma cells predict chromosome instability in esophageal squamous cell carcinoma:a genome-wide analysis.Cancer Res[J]. 2009,15;69(4):1604-1614.
60.Zhang X, Zhu ZH, Lin P,et al.Analyzing the profile of chromosomal imbalances in esophageal atypical hyperplasia and early stage esophageal squamous cell carcinoma by 250K Snp Array.Zhonghua Yi Xue Za Zhi[J]. 2008,14;88(37):2636-41.
61.Wiech T, Nikolopoulos E, Weis R,et al.Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays.Lab Invest[J].2009,89(4):385-397.
62.XJ Zhao,Barbara AWeir,Thomas LaFramboise,et al.Homozygous Deletions and Chromosome Amplifications in Human Lung Carcinomas Revealed by Single Nucleotide Polymorphism Array Analysis.Cancer Res[J],65(13):5561-5570.
63.Nowak D, Ogawa S,Miischen M,et al.SNP array analysis of tyrosinekinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations.Blood[J].2010,4;115(5):1049-1053.
64.Bardini M, Spinelli R, Bungaro S,et al. DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4.Leukemia[J].2010 Jan;24(1):169-176.
65.Caprini E, Cristofoletti C, Arcelli D,et al.Identification of key regions and genes important in the pathogenesis of sezary syndrome by combining genomic and expression microarrays.Cancer Res[J].2009,1;69(21):8438-8446.
66. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse:a GIMEMA AL WP report. J Clin Oncol.2009, 1;27(31):5202-5207
67.Tiu RV, Gondek LP, O'Keefe CL,et al.New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.J Clin Oncol[J].2009,1;27(31):5219-5226.
68.Akagi T, Shih LY, Ogawa S,et al.Single nucleotide polymorphism genomic arrays analysis of t(8;21)acute myeloid leukemia cells.Haematologica[J].20 09,94(9):1301-1306.
69.Kawamata N, Ogawa S,Gueller S,et al.Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array.Exp Hematol[J],2009,37(8):937-946.
70.Nowak D,Le Toriellec E, Stern MH,et al. Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy.Haematologica[J].2009,94(4):518-527.
71.Loo LW,Ton C,Wang YW,et al.Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.Genes Chromosomes Cancer[J].2008,47(12):1049-1066.
72.Purdie KJ,Harwood CA,Gibbon K,et al.High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia.Br J Cancer[J].2010,102(6):1044-1051.
73.Bouron-Dal Soglio D, Rougemont AL, Absi R,et al.SNP genotyping of a sclerosing rhabdomyosarcoma:reveals highly aneuploid profile and a specific MDM2/HMGA2 amplification.Hum Pathol[J].2009,40(9):1347-1352.
74.Baras A,Yu Y,Filtz M,et al.Combined genomic and gene expression microarray profiling identifies ECOP as an upregulated gene in squamous cell carcinomas independent of DNA amplification.Oncogene[J].2009,28(32):2919-2924.
75.Purdie KJ, Harwood CA, Gulati A,et al.Single nucleotide polymorphism array analysis defines a specific genetic fingerprint for well-differentiated cutaneous SCCs.J Invest Dermatol[J].2009,129(6):1562-1568.
76.David B,Matthew AB,Lon RC et al.Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature[J],2007,447:661-678.
77.Jonkers YM, Claessen SM, Perren A, et al.DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients. Endocr Relat Cancer[J],2007,14(3):769-779.
78.Paris PL, Andaya A, Fridlyand J, et al.Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors.Hum Mol Genet[J].2004 Jul 1;13(13):1303-1313.