Bolton, Kelly L., Ptashkin, Ryan N., Gao, Teng ORCID: 0000-0002-0196-689X, Braunstein, Lior, Devlin, Sean M., Kelly, Daniel, Patel, Minal, Berthon, Antonin, Syed, Aijazuddin, Yabe, Mariko, Coombs, Catherine C., Caltabellotta, Nicole M., Walsh, Mike, Offit, Kenneth, Stadler, Zsofia, Mandelker, Diana, Schulman, Jessica, Patel, Akshar, Philip, John, Bernard, Elsa ORCID: 0000-0002-2057-7187, Gundem, Gunes, Ossa, Juan E. Arango, Levine, Max, Martinez, Juan S. Medina, Farnoud, Noushin, Glodzik, Dominik, Li, Sonya, Robson, Mark E., Lee, Choonsik, Pharoah, Paul D. P., Stopsack, Konrad H. ORCID: 0000-0002-0722-1311, Spitzer, Barbara, Mantha, Simon, Fagin, James, Boucai, Laura, Gibson, Christopher J., Ebert, Benjamin L., Young, Andrew L., Druley, Todd, Takahashi, Koichi, Gillis, Nancy ORCID: 0000-0002-7744-8490, Ball, Markus, Padron, Eric, Hyman, David M., Baselga, Jose, Norton, Larry, Gardos, Stuart, Klimek, Virginia M., Scher, Howard, Bajorin, Dean, Paraiso, Eder, Benayed, Ryma, Arcila, Maria E., Ladanyi, Marc, Solit, David B., Berger, Michael F., Tallman, Martin, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Diaz, Luis A., Jr., Levine, Ross L., Morton, Lindsay M., Zehir, Ahmet and Papaemmanuil, Elli . Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nature Genet.. BERLIN: NATURE RESEARCH. ISSN 1546-1718

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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. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bolton, Kelly L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ptashkin, Ryan N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gao, TengUNSPECIFIEDorcid.org/0000-0002-0196-689XUNSPECIFIED
Braunstein, LiorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devlin, Sean M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelly, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, MinalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berthon, AntoninUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syed, AijazuddinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yabe, MarikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coombs, Catherine C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caltabellotta, Nicole M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walsh, MikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stadler, ZsofiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mandelker, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulman, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, AksharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Philip, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernard, ElsaUNSPECIFIEDorcid.org/0000-0002-2057-7187UNSPECIFIED
Gundem, GunesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ossa, Juan E. ArangoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Levine, MaxUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez, Juan S. MedinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farnoud, NoushinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glodzik, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, SonyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robson, Mark E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, ChoonsikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stopsack, Konrad H.UNSPECIFIEDorcid.org/0000-0002-0722-1311UNSPECIFIED
Spitzer, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mantha, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fagin, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boucai, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gibson, Christopher J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ebert, Benjamin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, Andrew L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Druley, ToddUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takahashi, KoichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gillis, NancyUNSPECIFIEDorcid.org/0000-0002-7744-8490UNSPECIFIED
Ball, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Padron, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hyman, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baselga, JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norton, LarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardos, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klimek, Virginia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scher, HowardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bajorin, DeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paraiso, EderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benayed, RymaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arcila, Maria E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ladanyi, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solit, David B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, Michael F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tallman, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Closas, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chatterjee, NilanjanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz, Luis A., Jr.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Levine, Ross L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morton, Lindsay M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zehir, AhmetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papaemmanuil, ElliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-314340
DOI: 10.1038/s41588-020-00710-0
Journal or Publication Title: Nature Genet.
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SOMATIC MUTATIONS; POSITIVE SELECTION; MYELOID NEOPLASMS; EVOLUTION; RISK; MYELODYSPLASIA; CLASSIFICATION; PROGNOSIS; EXPANSION; NETWORKMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31434

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