TY - JOUR T1 - Oncologic therapy shapes the fitness landscape of clonal hematopoiesis JF - bioRxiv DO - 10.1101/848739 SP - 848739 AU - Kelly L Bolton AU - Ryan N Ptashkin AU - Teng Gao AU - Lior Braunstein AU - Sean M Devlin AU - Daniel Kelly AU - Minal Patel AU - Antonin Berthon AU - Aijazuddin Syed AU - Mariko Yabe AU - Catherine C. Coombs AU - Nicole M. Caltabellotta AU - Mike Walsh AU - Kenneth Offit AU - Zsofia Stadler AU - Diana Mandelker AU - Jessica Schulman AU - Akshar Patel AU - John Philip AU - Elsa Bernard AU - Gunes Gundem AU - Juan E Arango AU - Max Levine AU - Juan S Medina AU - Noushin Farnoud AU - Dominik Glodzik AU - Sonya Li AU - Marc E Robson AU - Choonsik Lee AU - Paul D P Pharoah AU - Konrad Stopsack AU - Barbara Spitzer AU - Simon Mantha AU - James Fagin AU - Laura Boucai AU - Christopher J Gibson AU - Benjamin L Ebert AU - Andrew Young AU - Todd Druley AU - Koichi Takahasi AU - Nancy Gillis AU - Markus Ball AU - Eric Padron AU - David M Hyman AU - Jose Baselga AU - Larry Norton AU - Stuart Gardos AU - Virginia M Klimek AU - Howard Scher AU - Dean Bajorin AU - Eder Paraiso AU - Ryma Benayed AU - Maria E Arcila AU - Marc Ladanyi AU - David B Solit AU - Michael F Berger AU - Martin Tallman AU - Montserrat Garcia-Closas AU - Nilanjan Chatterjee AU - Luis A Diaz, Jr. AU - Ross L Levine AU - Lindsay M Morton AU - Ahmet Zehir AU - Elli Papaemmanuil Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/20/848739.abstract N2 - Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and gene-treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy-related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions. ER -