肿瘤遗传异质性

doi:10.3724/SP.J.1005.2013.00001

遗传 ›› 2013, Vol. 35 ›› Issue (1): 1-9.doi: 10.3724/SP.J.1005.2013.00001

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肿瘤遗传异质性

杨壹羚¹, 褚嘉祐², 王明荣³

1. 天津医科大学附属肿瘤医院乳腺病理室, 教育部乳腺癌防治重点实验室, 天津市肿瘤防治重点实验室, 天津 300060; 2. 中国医学科学院医学生物学研究所, 昆明 650118; 3. 中国医学科学院肿瘤医院肿瘤研究所, 北京 100021

收稿日期:2012-08-24 修回日期:2012-10-19 出版日期:2013-01-20 发布日期:2013-01-25
通讯作者: 王明荣 E-mail:wangmr2015@126.com
基金资助:
中国博士后科学基金(编号：20090450772)和国家高技术研究发展计划(编号：2012AA02A503)资助

Tumor genetic heterogeneity

YANG Yi-Ling¹, CHU Jia-You², WANG Ming-Rong³

1. Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China 2. Institute of Medical Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Kunming 650118, China 3. Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China

Received:2012-08-24 Revised:2012-10-19 Online:2013-01-20 Published:2013-01-25

摘要/Abstract

摘要： 尽管大多数自发性肿瘤源于单细胞, 但人们逐渐认识到个体肿瘤的内部存在异质性, 这种差异涉及分化程度、细胞增殖率、侵袭和转移能力及治疗反应等众多方面。分子生物学研究也证实肿瘤演进过程中不断产生新的突变, 为肿瘤内部存在异质性增加了更有力的佐证。文章综述了关于肿瘤遗传异质性研究的主要进展。鉴于遗传异质性分析可为揭示肿瘤细胞的产生、扩散、转移的时间段提供重要信息, 文章以瘤内异质性为主线, 列举了遗传异质性存在的实验依据; 阐述了遗传多样性在人类个体肿瘤发展进化史中的研究价值; 介绍了遗传异质性产生的两种模式, 包括肿瘤干细胞模型和克隆进化模型; 总结了遗传异质性在肿瘤转移、治疗中的重要临床意义。文章最后展示了常用的遗传异质性的研究方法, 包括特定基因的分析方法和基于基因组水平的方法, 并对各自的优缺点进行了分析。

关键词: 肿瘤, 遗传, 异质性

Abstract: Although the majority of spontaneous tumors derive from a single cell, people have come to realize intra-tumor heterogeneity of individual tumors. Human cancers frequently display substantial difference in phenotypic features, such as the degree of differentiation, cell proliferation rate, invasion and metastatic potential, response to therapy and many other aspects. Molecular biology studies have confirmed the occurrence of new mutations during the process of tumor progression, which provide more powerful evidences to show the existence of intra-tumor genetic heterogeneity. This re-view will focus on recent major advances in the study of tumor genetic heterogeneity. Considering that genetic heterogene-ity analysis can provide important information to indicate how long normal cells transform into tumor cells and how to spread and migrate, we firstly describe experimental evidences of intra-tumor genetic heterogeneity. Then we discuss the research value of genetic diversity in the evolutionary history of human individual tumor, introduce the two modes of the genetic heterogeneity — cancer stem cell model and the clonal evolution model, and summarize the implications of in-tra-tumor heterogeneity studies in metastasis and therapy. In addition, the article presents the research methods of genetic heterogeneity, including specific gene and genome-wide level, pointing out their strengths and limitations.

Key words: neoplasms, heredity, heterogeneity

杨壹羚褚嘉祐王明荣. 肿瘤遗传异质性[J]. 遗传, 2013, 35(1): 1-9.

YANG Yi-Ling CHU Jia-You WANG Ming-Rong. Tumor genetic heterogeneity[J]. HEREDITAS, 2013, 35(1): 1-9.

参考文献

[1] Novelli MR, Williamson JA, Tomlinson IP, Elia G, Hodg-son SV, Talbot IC, Bodmer WF, Wright NA. Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science, 1996, 272(5265): 1187-1190.
[2] Leroi AM, Koufopanou V, Burt A. Cancer selection. Nat Rev Cancer, 2003, 3(3): 226- 231.
[3] Gatenby RA, Vincent TL. Application of quantitative models from population biology and evolutionary game theory to tumor therapeutic strategies. Mol Cancer Ther, 2003, 2(9): 919- 927.
[4] Marusyk A, Almendro V, Polyak K. Intra-tumour hetero-geneity: a looking glass for cancer? Nat Rev Cancer, 2012, 12(5): 323-334.
[5] Longo DL. Tumor heterogeneity and personalized medi-cine. N Engl J Med, 2012, 366(10): 956-957.
[6] Shibata D. Cancer. Heterogeneity and tumor history. Science, 2012, 336(6079): 304- 305.
[7] Anderson K, Lutz C, van Delft FW, Bateman CM, Guo YP, Colman SM, Kempski H, Moorman AV, Titley I, Swans-bury J, Kearney L, Enver T, Greaves M. Genetic variegation of clonal architecture and propagating cells in leu-kaemia. Nature, 2011, 469(7330): 356-361.
[8] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endes-felder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, No-hadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 2012, 366(10): 883-892.
[9] Ashworth A, Lord CJ, Reis-Filho JS. Genetic interactions in cancer progression and treatment. Cell, 2011, 145(1): 30-38.
[10] Menard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2 as a prognostic factor in breast cancer. On-cology, 2001, 61(Suppl. 2): 67-72.
[11] Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, Traulsen A, Nowak MA, Siegel C, Velculescu VE, Kinzler KW, Vogelstein B, Willis J, Markowitz SD. Comparative lesion sequencing provides insights into tu-mor evolution. Proc Natl Acad Sci USA, 2008, 105(11): 4283-4288.
[12] Ding L, Ellis MJ, Li SQ, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang QY, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Crowder R, Tao Y, Snider JE, Smith SM, Dukes AF, Sanderson GE, Pohl CS, Delehaunty KD, Fronick CC, Pape KA, Reed JS, Robinson JS, Hodges JS, Schierding W, Dees ND, Shen D, Locke DP, Wiechert ME, Eldred JM, Peck JB, Oberkfell BJ, Lolofie JT, Du FY, Hawkins AE, O'Laughlin MD, Bernard KE, Cunningham M, Elliott G, Mason MD, Thompson DM Jr, Ivanovich JL, Goodfellow PJ, Perou CM, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER. Genome remodeling in a basal-like breast cancer metastasis and xenograft. Nature, 2010, 464(7291): 999-1005.
[13] Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu BJ, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacob-uzio-Donahue CA. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 2010, 467(7319): 1114- 1117.
[14] Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, Ritchey JK, Young MA, Lamprecht T, McLellan MD, McMichael JF, Wallis JW, Lu C, Shen D, Harris CC, Dooling DJ, Fulton RS, Fulton LL, Chen K, Schmidt H, Kalicki-Veizer J, Magrini VJ, Cook L, McGrath SD, Vickery TL, Wendl MC, Heath S, Watson MA, Link DC, Tomasson MH, Shannon WD, Payton JE, Kulkarni S, Westervelt P, Walter MJ, Graubert TA, Mardis ER, Wilson RK, DiPersio JF. Clonal evolution in relapsed acute mye-loid leukaemia revealed by whole-genome sequencing. Nature, 2012, 481(7382): 506-510.
[15] Pietras A. Cancer stem cells in tumor heterogeneity. Adv Cancer Res, 2011, 112: 255- 281.
[16] Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle, 2007, 6(19): 2332-2338.
[17] Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta, 2010, 1805(1): 105-117.
[18] Durrett R, Foo J, Leder K, Mayberry J, Michor F. Intratumor heterogeneity in evolutionary models of tumor progression. Genetics, 2011, 188(2): 461-477.
[19] Lleonart ME, Martin-Duque P, Sanchez-Prieto R, Moreno A, Ramon y Cajal S. Tumor heterogeneity: morphological, molecular and clinical implications. Histol Histopathol, 2000, 15(3): 881-898.
[20] Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 2012, 10(6): 717-728.
[21] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell, 2000, 100(1): 57-70.
[22] Torres L, Ribeiro FR, Pandis N, Andersen JA, Heim S, Teixeira MR. Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases. Breast Cancer Res Treat, 2007, 102(2): 143-155.
[23] Bissig H, Richter J, Desper R, Meier V, Schraml P, Schaffer AA, Sauter G, Mihatsch MJ, Moch H. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridiza-tion. Am J Pathol, 1999, 155(1): 267-274.
[24] Cheng L, Bostwick DG, Li G, Wang Q, Hu N, Vortmeyer AO, Zhuang Z. Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer, 1999, 85(9): 2017-2022.
[25] Kuukasjarvi T, Karhu R, Tanner M, Kähkonen M, Schäffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi OP, Isola J. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res, 1997, 57(8): 1597-1604.
[26] Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet, 2003, 33(1): 49-54.
[27] Weigelt B, Glas AM, Wessels LF, Witteveen AT, Peterse JL, van't Veer LJ. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci USA, 2003, 100(26): 15901-15905.
[28] Weigelt B, Hu ZY, He XP, Livasy C, Carey LA, Ewend MG, Glas AM, Perou CM, Van't Veer LJ. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res, 2005, 65(20): 9155-9158.
[29] Liu WN, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu GQ, Chen L, Ewing CM, Eisenberger MA, Carducci MA, Nelson WG, Yegnasubramanian S, Luo J, Wang Y, Xu JF, Isaacs WB, Visakorpi T, Bova GS. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med, 2009, 15(5): 559-565.
[30] Macintosh CA, Stower M, Reid N, Maitland NJ. Precise microdissection of human prostate cancers reveals geno-typic heterogeneity. Cancer Res, 1998, 58(1): 23-28.
[31] Alvarado C, Beitel LK, Sircar K, Aprikian A, Trifiro M, Gottlieb B. Somatic mosaicism and cancer: a micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res, 2005, 65(18): 8514-8518.
[32] Robbins CM, Tembe WA, Baker A, Sinari S, Moses TY, Beckstrom-Sternberg S, Beckstrom-Sternberg J, Barrett M, Long J, Chinnaiyan A, Lowey J, Suh E, Pearson JV, Craig DW, Agus DB, Pienta KJ, Carpten JD. Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res, 2011, 21(1): 47-55.
[33] Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao YJ, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S. Mutational evo-lution in a lobular breast tumour profiled at single nucleo-tide resolution. Nature, 2009, 461(7265): 809-813.
[34] Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci USA, 1999, 96(8): 4494-4499.
[35] Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell, 2008, 13(1): 58-68.
[36] Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmuller G. Genetic hetero-geneity of single disseminated tumour cells in minimal re-sidual cancer. Lancet, 2002, 360(9334): 683-689.
[37] Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol, 2007, 25(10): 1160-1168.
[38] Wu JM, Halushka MK, Argani P. Intratumoral heterogeneity of HER-2 gene amplification and protein overexpression in breast cancer. Hum Pathol, 41(6): 914-917.
[39] Arteaga CL, Baselga J. Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them? Cancer Cell, 2004, 5(6): 525-531.
[40] Tomlinson IP, Lambros MB, Roylance RR. Loss of heterozygosity analysis: practically and conceptually flawed? Genes Chromosomes Cancer, 2002, 34(4): 349-353.
[41] Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. Molecular definition of breast tumor heterogeneity. Cancer Cell, 2007, 11(3): 259-273.
[42] Mora J, Cheung NK, Gerald WL. Genetic heterogeneity and clonal evolution in neuroblastoma. Br J Cancer, 2001, 85(2): 182-189.
[43] Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li XH, Sanchez CA, Paulson TG, Blount PL, Risques RA, Rabinovitch PS, Reid BJ. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet, 2006, 38(4): 468-473.
[44] Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lon-ning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature, 2000, 406(6797): 747-752.
[45] Yang YL, Fan Y, Lang RG, Gu F, Ren MJ, Zhang XM, Yin D, Fu L. Genetic heterogeneity of HER2 in breast cancer: impact on HER2 testing and its clinicopathologic significance. Breast Cancer Res Treat, 2012, 134(3): 1095-1102.
[46] Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, Kang E, Kim SW, Park SY. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol, 2012, 25(7): 938-948.
[47] Vance GH, Barry TS, Bloom KJ, Fitzgibbons PL, Hicks DG, Jenkins RB, Persons DL, Tubbs RR, Hammond ME. Genetic heterogeneity in HER2 testing in breast cancer: panel summary and guidelines. Arch Pathol Lab Med, 2009, 133(4): 611-612.
[48] Campbell PJ, Pleasance ED, Stephens PJ, Dicks E, Rance R, Goodhead I, Follows GA, Green AR, Futreal PA, Stratton MR. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci USA, 2008, 105(35): 13081-13086.
[49] Mullighan CG, Phillips LA, Su XP, Ma J, Miller CB, Shurtleff SA, Downing JR. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science, 2008, 322(5906): 1377-1380.
[50] Houldsworth J, Chaganti RS. Comparative genomic hybridization: an overview. Am J Pathol, 1994, 145(6): 1253-1260.
[51] Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP, Snijders A, Albertson DG, Pinkel D, Marra MA, Ling V, MacAulay C, Lam WL. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet, 2004, 36(3): 299-303.
[52] Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M. Tumour evolution inferred by single-cell sequencing. Nature, 2011, 472(7341): 90-94.
[53] Hou Y, Song LT, Zhu P, Zhang B, Tao Y, Xu X, Li FQ, Wu K, Liang J, Shao D, Wu HJ, Ye XF, Ye C, Wu RH, Jian M, Chen Y, Xie W, Zhang RR, Chen L, Liu X, Yao XT, Zheng HC, Yu C, Li QB, Gong ZL, Mao M, Yang X, Yang L, Li JX, Wang W, Lu ZH, Gu N, Laurie G, Bolund L, Kristiansen K, Wang J, Yang HM, Li YR, Zhang XQ, Wang J. Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell, 2012, 148(5): 873-885.
[54] Xu X, Hou Y, Yin XY, Bao L, Tang A, Song LT, Li FQ, Tsang S, Wu K, Wu HJ, He WM, Zeng L, Xing MJ, Wu RH, Jiang H, Liu X, Cao DD, Guo GW, Hu XD, Gui YT, Li ZS, Xie WY, Sun XJ, Shi M, Cai ZM, Wang B, Zhong MM, Li JX, Lu ZH, Gu N, Zhang XQ, Goodman L, Bolund L, Wang J, Yang HM, Kristiansen K, Dean M, Li YR, Wang J. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell, 2012, 148(5): 886-895.

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肿瘤遗传异质性

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