Cancer therapy shapes the fitness landscape of clonal hematopoiesis

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

doi:10.1038/s41588-020-00710-0

Cancer therapy shapes the fitness landscape of clonal hematopoiesis

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 BernardGunes 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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1219-1226
Number of pages	8
Journal	Nature genetics
Volume	52
Issue number	11
DOIs	https://doi.org/10.1038/s41588-020-00710-0
State	Published - Nov 1 2020

ASJC Scopus subject areas

Genetics

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Bolton, K. L., Ptashkin, R. N., Gao, T., Braunstein, L., Devlin, S. M., Kelly, D., Patel, M., Berthon, A., Syed, A., Yabe, M., Coombs, C. C., Caltabellotta, N. M., Walsh, M., Offit, K., Stadler, Z., Mandelker, D., Schulman, J., Patel, A., Philip, J., ... Papaemmanuil, E. (2020). Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nature genetics, 52(11), 1219-1226. https://doi.org/10.1038/s41588-020-00710-0

Bolton, KL, Ptashkin, RN, Gao, T, Braunstein, L, Devlin, SM, Kelly, D, Patel, M, Berthon, A, Syed, A, Yabe, M, Coombs, CC, Caltabellotta, NM, Walsh, M, Offit, K, Stadler, Z, Mandelker, D, Schulman, J, Patel, A, Philip, J, Bernard, E, Gundem, G, Ossa, JEA, Levine, M, Martinez, JSM, Farnoud, N, Glodzik, D, Li, S, Robson, ME, Lee, C, Pharoah, PDP, Stopsack, KH, Spitzer, B, Mantha, S, Fagin, J, Boucai, L, Gibson, CJ, Ebert, BL, Young, AL, Druley, T, Takahashi, K, Gillis, N, Ball, M, Padron, E, Hyman, DM, Baselga, J, Norton, L, Gardos, S, Klimek, VM, Scher, H, Bajorin, D, Paraiso, E, Benayed, R, Arcila, ME, Ladanyi, M, Solit, DB, Berger, MF, Tallman, M, Garcia-Closas, M, Chatterjee, N, Diaz, LA, Levine, RL, Morton, LM, Zehir, A & Papaemmanuil, E 2020, 'Cancer therapy shapes the fitness landscape of clonal hematopoiesis', Nature genetics, vol. 52, no. 11, pp. 1219-1226. https://doi.org/10.1038/s41588-020-00710-0

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title = "Cancer therapy shapes the fitness landscape of clonal hematopoiesis",

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.",

author = "Bolton, {Kelly L.} and Ptashkin, {Ryan N.} and Teng Gao and Lior Braunstein and Devlin, {Sean M.} and Daniel Kelly and Minal Patel and Antonin Berthon and Aijazuddin Syed and Mariko Yabe and Coombs, {Catherine C.} and Caltabellotta, {Nicole M.} and Mike Walsh and Kenneth Offit and Zsofia Stadler and Diana Mandelker and Jessica Schulman and Akshar Patel and John Philip and Elsa Bernard and Gunes Gundem and Ossa, {Juan E.Arango} and Max Levine and Martinez, {Juan S.Medina} and Noushin Farnoud and Dominik Glodzik and Sonya Li and Robson, {Mark E.} and Choonsik Lee and Pharoah, {Paul D.P.} and Stopsack, {Konrad H.} and Barbara Spitzer and Simon Mantha and James Fagin and Laura Boucai and Gibson, {Christopher J.} and Ebert, {Benjamin L.} and Young, {Andrew L.} and Todd Druley and Koichi Takahashi and Nancy Gillis and Markus Ball and Eric Padron and Hyman, {David M.} and Jose Baselga and Larry Norton and Stuart Gardos and Klimek, {Virginia M.} and Howard Scher and Dean Bajorin and Eder Paraiso and Ryma Benayed and Arcila, {Maria E.} and Marc Ladanyi and Solit, {David B.} and Berger, {Michael F.} and Martin Tallman and Montserrat Garcia-Closas and Nilanjan Chatterjee and Diaz, {Luis A.} and Levine, {Ross L.} and Morton, {Lindsay M.} and Ahmet Zehir and Elli Papaemmanuil",

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AU - Bolton, Kelly L.

AU - Ptashkin, Ryan N.

AU - Gao, Teng

AU - Braunstein, Lior

AU - Devlin, Sean M.

AU - Kelly, Daniel

AU - Patel, Minal

AU - Berthon, Antonin

AU - Syed, Aijazuddin

AU - Yabe, Mariko

AU - Coombs, Catherine C.

AU - Caltabellotta, Nicole M.

AU - Walsh, Mike

AU - Offit, Kenneth

AU - Stadler, Zsofia

AU - Mandelker, Diana

AU - Schulman, Jessica

AU - Patel, Akshar

AU - Philip, John

AU - Bernard, Elsa

AU - Gundem, Gunes

AU - Ossa, Juan E.Arango

AU - Levine, Max

AU - Martinez, Juan S.Medina

AU - Farnoud, Noushin

AU - Glodzik, Dominik

AU - Li, Sonya

AU - Robson, Mark E.

AU - Lee, Choonsik

AU - Pharoah, Paul D.P.

AU - Stopsack, Konrad H.

AU - Spitzer, Barbara

AU - Mantha, Simon

AU - Fagin, James

AU - Boucai, Laura

AU - Gibson, Christopher J.

AU - Ebert, Benjamin L.

AU - Young, Andrew L.

AU - Druley, Todd

AU - Takahashi, Koichi

AU - Gillis, Nancy

AU - Ball, Markus

AU - Padron, Eric

AU - Hyman, David M.

AU - Baselga, Jose

AU - Norton, Larry

AU - Gardos, Stuart

AU - Klimek, Virginia M.

AU - Scher, Howard

AU - Bajorin, Dean

AU - Paraiso, Eder

AU - Benayed, Ryma

AU - Arcila, Maria E.

AU - Ladanyi, Marc

AU - Solit, David B.

AU - Berger, Michael F.

AU - Tallman, Martin

AU - Garcia-Closas, Montserrat

AU - Chatterjee, Nilanjan

AU - Diaz, Luis A.

AU - Levine, Ross L.

AU - Morton, Lindsay M.

AU - Zehir, Ahmet

AU - Papaemmanuil, Elli

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Cancer therapy shapes the fitness landscape of clonal hematopoiesis

Abstract

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