美国纪念斯隆·凯特琳癌症中心Elli Papaemmanuil课题组探明了癌症治疗重塑克隆性造血的适应性。该项研究成果发表在2020年10月26日出版的《自然-遗传学》上。
在本研究中，研究人员在克隆性造血（CH）和与治疗有关骨髓瘤（tMNs）的发展中探究了克隆转化为癌症这一现象。研究发现突变是根据治疗手段差异而被选择的。ASXL1中的突变在吸烟者或戒烟者中富集，而采用放射、铂和拓扑异构酶II抑制剂作为癌症治疗方案则优先选择DNA损伤反应基因（TP53、PPM1D、CHEK2）的突变。顺序采样提供的证据表明当应用某些疗法时，DNA损伤应答克隆比其他克隆更具竞争优势。
在先前检测到CH的病例中， tMN诊断中已存在CH突变。研究人员确定了增加tMN风险的CH分子特征。在临床诊断过程中越来越多应用测序手段，这为鉴别具有tMN风险的患者提供了可能。
据悉，获得性突变在正常组织中普遍存在。但是，对于诱导某些克隆转化为癌症的机制仍知之甚少。
附：英文原文
Title: Cancer therapy shapes the fitness landscape of clonal hematopoiesis
Author: Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Daniel Kelly, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine C. Coombs, Nicole M. Caltabellotta, Mike Walsh, Kenneth Offit, Zsofia Stadler, Diana Mandelker, Jessica Schulman, Akshar Patel, John Philip, Elsa Bernard, Gunes Gundem, Juan E. Arango Ossa, Max Levine, Juan S. Medina Martinez, Noushin Farnoud, Dominik Glodzik, Sonya Li, Mark E. Robson, Choonsik Lee, Paul D. P. Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin L. Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David M. Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia M. Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria E. Arcila, Marc Ladanyi, David B. Solit, Michael F. Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis A. Diaz, Ross L. Levine, Lindsay M. Morton, Ahmet Zehir, Elli Papaemmanuil
Issue&Volume: 2020-10-26
Abstract: Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
DOI: 10.1038/s41588-020-00710-0
Source: https://www.nature.com/articles/s41588-020-00710-0
Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex
本期文章：《自然—遗传学》：Online/在线发表
