人类癌症基因组的检验分析与临床应用

doi:10.3969/j.issn.1673-8640.2014.05.002

摘要/Abstract

摘要：

基因组的改变会导致癌症的发生, 这一切是通过癌症基因活化与继后细胞程序或信号转导通路的功能性改变所形成的。随着科技的不断发展, 我们不仅仅能够对单一癌症基因序列的改变进行研究, 还能够对一系列癌症基因或整个人类癌症基因组序列的改变进行探索。新型基因组改变的发现, 提升了我们对癌病变的认知与了解, 同时这一发现对人类癌症的诊断、分类与治疗有着一定的变革性作用。这篇综述对人类基因组的结构、人类基因组的检验方法、人类癌症基因组的变化、以及人类癌症基因组学的临床应用做了相应的介绍。

关键词: 基因组, 癌症基因组学, 突变, 单核苷酸多态性, 拷贝数变异, 聚合酶链反应, 下一代基因测序

Abstract:

Genomic aberrations cause cancers through activation of cancer genes and consequently functional changes of cellular processes or signal transduction pathways. Technological advances have allowed us to interrogate DNA aberrations not only in a single cancer gene, but also in a panel of cancer genes or the entire human cancer genome. Discovery of new genomic aberrations has increased our understanding of carcinogenesis, and revolutionalized the diagnosis, classification and treatment of human cancers as well. This review provides an overview of the organization of the human genome, laboratory methods of human genome analysis, genomic alterations in human cancers, and clinical application of human cancer genomics.

Key words: Genome, Cancer genomics, Mutation, Single nucleotide polymorphism, Copy number variant, Polymerase chain reaction, Next generation sequencing

中图分类号:

Q343.1

李仕勇. 人类癌症基因组的检验分析与临床应用[J]. 检验医学, 2014, 29(5): 414-434.

LI Shiyong. The Human Cancer Genome: Laboratory Analysis and Clinical Application[J]. , 2014, 29(5): 414-434.

参考文献

[1] Stratton MR, Campbell PJ, Futreal PA. The cancer genome[J]. Nature, 2009, 458(7239):719-724.
[2] Stratton MR. Exploring the genomes of cancer cells: progress and promise[J]. Science, 2011, 331(6024): 1553-1558.
[3] Boveri T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris[J]. J Cell Sci, 2008, 121(Suppl 1): 1-84.
[4] Garraway LA, Lander ES. Lessons from the cancer genome[J]. Cell, 2013, 153(1): 17-37.
[5] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674.
[6] Tabin CJ, Bradley SM, Bargmann CI, et al. Mechanism of activation of a human oncogene[J]. Nature, 1982, 300(5888): 143-149.
[7] Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes[J]. Nat Rev Cancer, 2004, 4(3): 177-183.
[8] Stricker T, Catenacci DV, Seiwert TY. Molecular profiling of cancer--the future of personalized cancer medicine: a primer on cancer biology and the tools necessary to bring molecular testing to the clinic[J]. Semin Oncol, 2011, 38(2): 173-185.
[9] International Human Genome Sequencing Consontium. Finishing the euchromatic sequence of the human genome[J]. Nature, 2004, 431(7011): 931-945.
[10] Metzker ML. Sequencing technologies-the next generation[J]. Nat Rev Genet, 2010, 11(1): 31-46.
[11] Mardis ER. A decade′s perspective on DNA sequencing technology[J]. Nature, 2011, 470(7333): 198-203.
[12] Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome[J]. Nature, 2001, 409(6822): 860-921.
[13] Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome[J]. Science, 2001, 291(5507): 1304-1351.
[14] McDermott U, Downing JR, Stratton MR. Genomics and the continuum of cancer care[J]. N Engl J Med, 2011, 364(4): 340-350.
[15] Green ED, Guyer MS, National Human Genome Research Institute. Charting a course for genomic medicine from base pairs to bedside[J]. Nature, 2011, 470(7333): 204-213.
[16] Vogelstein B, Papadopoulos N, Velculescu VE, et al., Cancer genome landscapes[J]. Science, 2013, 339(6127): 1546-1558.
[17] Tuna M, Amos CI. Genomic sequencing in cancer[J]. Cancer Lett, 2013, 340(2): 161-170.
[18] Dias-Santagata D, Akhavanfard S, David SS, et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine[J]. EMBO Mol Med, 2010, 2(5): 146-158.
[19] Chin L, Andersen JN, Futreal PA. Cancer genom-ics: from discovery science to personalized medicine[J]. Nat Med, 2011, 17(3): 297-303.
[20] ENCODE Project Consortium, Bernstein BE, Birney E, et al. An integrated encyclopedia of DNA elements in the human genome[J]. Nature, 2012, 489(7414): 57-74.
[21] Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388.
[22] Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer[J]. Annu Rev Pathol, 2014, 9:287-314.
[23] Mortazavi A, Williams BA, McCue K, et al. Mapping and quantifying mammalian transcriptomes by RNA-Seq[J]. Nat Methods, 2008, 5(7): 621-628.
[24] Wheeler DA, Srinivasan M, Egholm M, et al. The complete genome of an individual by massively parallel DNA sequencing[J]. Nature, 2008, 452(7189): 872-876.
[25] Fu W, O′Connor TD, Jun G, et al. Analysis of 6, 515 exomes reveals the recent origin of most human protein-coding variants[J]. Nature, 2013, 493(7431): 216-220.
[26] Khurana E, Fu Y, Colonna V, et al. Integrative annotation of variants from 1 092 humans: application to cancer genomics[J]. Science, 2013, 342(6154): 1235587.
[27] Kilpivaara O, Aaltonen LA. Diagnostic cancer genome sequencing and the contribution of germline variants[J]. Science, 2013, 339(6127): 1559-1562.
[28] Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes[J]. J Natl Cancer Inst, 1960, 25: 85-109.
[29] Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining[J]. Nature, 1973, 243(5405): 290-293.
[30] Lichter P, Tang CJ, Call K, et al. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones[J]. Science, 1990, 247(4938): 64-69.
[31] Maciejewski JP, Mufti GJ. Whole genome scanning as a cytogenetic tool in hematologic malignancies[J]. Blood, 2008, 112(4): 965-974.
[32] Ladanyi M, Hogendoorn PC. Cancer biology and genomics: translating discoveries, transforming pathology[J]. J Pathol, 2011, 223(2): 99-101.
[33] Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer[J]. Nat Genet, 2007, 39(3): 347-351.
[34] Su Z, Dias-Santagata, Duke M, et al. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer[J]. J Mol Diagn, 2011, 13(1): 74-84.
[35] Sequist LV, Heist RS, Shaw AT, et al. Implemen-ting multiplexed genotyping of non-small-cell lung cancers into routine clinical practice[J]. Ann Oncol, 2011, 22(12): 2616-2624.
[36] Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors[J]. Proc Natl Acad Sci USA, 1977, 74(12): 5463-5467.
[37] Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing[J]. Nat Rev Genet, 2010, 11(10): 685-696.
[38] Loman NJ, Misra RV, Dallman TJ, et al. Perfor-mance comparison of benchtop high-throughput sequencing platforms[J]. Nat Biotechnol, 2012, 30(5): 434-439.
[39] Mwenifumbo JC, Marra MA. Cancer genome-sequencing study design[J]. Nat Rev Genet, 2013, 14(5): 321-332.
[40] Rinke J, Schfer V, Schmidt M, et al. Genotyping of 25 leukemia-associated genes in a single work flow by next-generation sequencing technology with low amounts of input template DNA[J]. Clin Chem, 2013, 59(8): 1238-1250.
[41] De Abreu FB, Wells WA, Tsongalis GJ. The emerging role of the molecular diagnostics laboratory in breast cancer personalized medicine[J]. Am J Pathol, 2013, 183(4): 1075-1083.
[42] Tsongalis GJ, Peterson JD, de Abreu FB, et al. Routine use of the Ion Torrent AmpliSeq Cancer Hotspot Panel for identification of clinically actionable somatic mutations[J]. Clin Chem Lab Med, 2013: 1-8.
[43] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing[J]. Nat Biotechnol, 2013, 31(11): 1023-1031.
[44] Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens[J]. J Mol Diagn, 2014, 16(1): 56-67.
[45] Cottrell CE, Al-Kateb H, Bredemeyer AJ, et al. Validation of a next-generation sequencing assay for clinical molecular oncology[J]. J Mol Diagn, 2014, 16(1): 89-105.
[46] Singh RR, Patel KP, Routbort MJ, et al. Clinical validation of a next-generation sequencing screen for mutational hotspots in 46 cancer-related genes[J]. J Mol Diagn, 2013, 15(5): 607-622.
[47] Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types[J]. Nature, 2013, 502(7471): 333-339.
[48] Ciriello G, Miller ML, Aksoy BA, et al. Emerging landscape of oncogenic signatures across human cancers[J]. Nat Genet, 2013, 45(10): 1127-1133.
[49] Harris TJ, McCormick F. The molecular pathology of cancer[J]. Nat Rev Clin Oncol, 2010, 7(5): 251-265.
[50] Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer[J]. Nature, 2002, 417(6892): 949-954.
[51] Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis[J]. Cancer Cell, 2005, 7(4): 387-397.
[52] Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes[J]. Nature, 2012, 486(7403): 405-409.
[53] Imielinski M, Berger AH, Hammerman PS, et al., Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing[J]. Cell, 2012, 150(6): 1107-1120.
[54] Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma[J]. Nat Genet, 2012, 44(9): 1006-1014.
[55] Mullighan CG. Genome sequencing of lymphoid malignancies[J]. Blood, 2013, 122(24): 3899-3907.
[56] Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma[J]. Nat Genet, 2014, 46(2): 171-175.
[57] Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes[J]. Nature, 2012, 491(7424): 399-405.
[58] Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms[J]. N Engl J Med, 2013, 369(25): 2379-2390.
[59] Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia[J]. N Engl J Med, 2011, 364(24): 2305-2315.
[60] Zack TI, Schumacher SE, Carter SL, et al. Pan-cancer patterns of somatic copy number alteration[J]. Nat Genet, 2013, 45(10): 1134-1140.
[61] Dawson MA, Kouzarides T, Huntly BJ. Targeting epigenetic readers in cancer[J]. N Engl J Med, 2012, 367(7): 647-657.
[62] Brennan CW, Verhoak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma[J]. Cell, 2013, 155(2): 462-477.
[63] Rivera CM, Ren B. Mapping human epigenomes[J]. Cell, 2013, 155(1): 39-55.
[64] Zhu X, He F, Zeng H, et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia[J]. Nat Genet, 2014, 46(3): 287-293.
[65] Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia[J]. N Engl J Med, 2010, 363(25): 2424-2433.
[66] Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers[J]. N Engl J Med, 2009, 360(22): 2289-2301.
[67] Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma[J]. Nature, 2013, 497(7447): 67-73.
[68] Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas[J]. Nat Genet, 2013, 45(2): 136-144.
[69] Huang FW, Hodis E, Xu MJ, et al. Highly recurrent TERT promoter mutations in human melanoma[J]. Science, 2013, 339(6122): 957-959.
[70] Horn S, Figl A, Rachakonda PS, et al. TERT promoter mutations in familial and sporadic melanoma[J]. Science, 2013, 339(6122): 959-961.
[71] Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal[J]. Proc Natl Acad Sci USA, 2013, 110(15): 6021-6026.
[72] Kulis M, Heath S, Bibikova M, et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia[J]. Nat Genet, 2012, 44(11): 1236-1242.
[73] Quesada V, Ramsay AJ, Lopez-Otin C. Chronic lymphocytic leukemia with SF3B1 mutation[J]. N Engl J Med, 2012, 366(26): 2530.
[74] Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia[J]. Nature, 2011, 478(7367): 64-69.
[75] Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition[J]. Nature, 2012, 486(7403): 353-360.
[76] Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer[J]. Nature, 2013, 500(7463): 415-421.
[77] Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome[J]. N Engl J Med, 2009, 361(11): 1058-1066.
[78] Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme[J]. Science, 2008, 321(5897): 1807-1812.
[79] Yang H, Ye D, Guan KL, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives[J]. Clin Cancer Res, 2012, 18(20): 5562-5571.
[80] Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes[J]. Cell, 2013, 153(3): 666-677.
[81] Tamborero D, Gonzalez-Perez A, Perez-Llamas C, et al. Comprehensive identification of mutational cancer driver genes across 12 tumor types[J]. Sci Rep, 2013, 3: 2650.
[82] Watson IR, Takahashi K, Futreal PA, et al. Emerging patterns of somatic mutations in cancer[J]. Nat Rev Genet, 2013, 14(10): 703-718.
[83] Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors[J]. Science, 2011, 331(6021): 1199-1203.
[84] Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma[J]. Science, 2011, 333(6046): 1157-1160.
[85] Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer[J]. Nat Genet, 2012, 44(6): 685-689.
[86] Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer[J]. Nat Med, 2012, 18(3): 378-381.
[87] Zhang J, Wu G, Miller CP, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas[J]. Nat Genet, 2013, 45(6): 602-612.
[88] Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing identifies a recurrent N.AB2-STAT6 fusion in solitary fibrous tumors[J]. Nat Genet, 2013, 45(2): 131-132.
[89] Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types[J]. Nature, 2014, 505(7484): 495-501.
[90] Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells[J]. Science, 2013, 340(6132): 626-630.
[91] Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation[J]. Science, 2013, 340(6132): 622-626.
[92] Folco EG, Coil KE, Reed R. The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region[J]. Genes Dev, 2011, 25(5): 440-444.
[93] Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes[J]. Nature, 2013, 499(7457): 214-218.
[94] Stephens PJ, Greenman CD, Fu B, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development[J]. Cell, 2011, 144(1): 27-40.
[95] Shen MM. Chromoplexy: a new category of complex rearrangements in the cancer genome[J]. Cancer Cell, 2013, 23(5): 567-569.
[96] Welch JS, Westervelt P, Ding L, et al. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene[J]. JAMA, 2011, 305(15): 1577-1584.
[97] Massard C, Loriot Y, Fizazi K. Carcinomas of an unknown primary origin--diagnosis and treatment[J]. Nat Rev Clin Oncol, 2011, 8(12): 701-710.
[98] Simon R, Roychowdhury S. Implementing personalized cancer genomics in clinical trials[J]. Nat Rev Drug Discov, 2013, 12(5): 358-369.
[99] Wheeler DA, Wang L. From human genome to cancer genome: the first decade[J]. Genome Res, 2013, 23(7): 1054-1062.
[100] Diaz LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers[J]. Nature, 2012, 486(7404): 537-540.
[101] Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer[J]. Nature, 2012, 486(7404): 532-536.
[102] Leary RJ, Sausen M, Kinde I, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing[J]. Sci Transl Med, 2012, 4(162): 162ra154.
[103] Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer[J]. N Engl J Med, 2013, 368(13): 1199-1209.
[104] Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA[J]. Nature, 2013, 497(7447): 108-112.
[105] Weiss L, Hufnagl C, Greil R. Circulating tumor DNA to monitor metastatic breast cancer[J]. N Engl J Med, 2013, 369(1): 93.