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肿瘤遗传异质性

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  • 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

  网络出版日期: 2013-01-25

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

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  • 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 date: 2012-08-24

  Revised date: 2012-10-19

  Online published: 2013-01-25

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

本文引用格式

杨壹羚 褚嘉祐 王明荣 . 肿瘤遗传异质性[J]. 遗传, 2013 , 35(1) : 1 -9 . DOI: 10.3724/SP.J.1005.2013.00001

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.

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
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