Oncologic Therapy Shapes the Fitness Landscape of ClonalHematopoiesis

Kelly L. Bolton; Ryan N. Ptashkin; Teng Gao; Lior Zvi Braunstein; Sean M. Devlin; Daniel John Kelly; Minal A. Patel; Antonin Berthon; Aijazuddin Syed; Mariko Yabe; Catherine Callaghan Coombs; Nicole M. Caltabellotta; Mike Walsh; Kenneth Offit; Zsofia Kinga Stadler; Diana L. Mandelker; Jessica Schulman; Akshar Patel; John Philip; Elsa Bernard; Gunes Gundem; Juan E. Arango; Max Fine Levine; Juan Santiago Medina-Martinez; Noushin Rahnamay Farnoud; Dominik Głodzik; Sonya Li; Marc E Robson; Choonsik Lee; Paul D.P. Pharoah

doi:10.1101/848739

GeneticsbioRxivNov 20, 2019

Preprint

Oncologic Therapy Shapes the Fitness Landscape of ClonalHematopoiesis

Kelly L. Bolton iD, Ryan N. Ptashkin iD, Teng Gao iD, Lior Zvi Braunstein iD, Sean M. Devlin iD, Daniel John Kelly iD, Minal A. Patel, Antonin Berthon, Aijazuddin Syed iD, Mariko Yabe iD, Catherine Callaghan Coombs iD, Nicole M. Caltabellotta iD, Mike Walsh, Kenneth Offit iD, Zsofia Kinga Stadler iD, Diana L. Mandelker iD, Jessica Schulman iD, Akshar Patel, John Philip iD, Elsa Bernard iD, Gunes Gundem iD, Juan E. Arango, Max Fine Levine iD, Juan Santiago Medina-Martinez iD, Noushin Rahnamay Farnoud iD, , Elli Papaemmanuil iD

Abstract

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.

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