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 | |
| State | Published - Nov 1 2020 |
Funding
The authors declare the following competing interests: K.L.B. has received research funding from GRAIL. C.C.C. has received honoraria from AbbVie, Loxo, H3 Biomedicine, Medscape, Octapharma and Pharmacyclics; has served as a consultant for AbbVie, Covance, Cowen & Co. and Dedham Group; and has received institutional research funding from AROG, Gilead, Loxo, H3 Biomedicine and Incyte. Z.S. has an immediate family member who holds consulting/advisory roles within the field of ophthalmology with Allergan, Adverum Biotechnologies, Alimera Sciences, Biomarin, Fortress Biotech, Genentech, Novartis, Optos, Regeneron, Regenxbio and Spark Therapeutics. E.B. receives research funding from Celgene. D.G. is a consultant of MNM Diagnostics and has received honoraria for speaking and scientific advisory engagements with Celgene, Prime Oncology, Novartis, Illumina and Kyowa Hakko Kirin. S.L. is an employee of GRAIL. M.E.R. holds an uncompensated advisory role with AstraZeneca, Daiichi-Sankyo, Merck and Pfizer and receives institutional research funding from AstraZeneca, AbbVie, Medivation and Pfizer. B.L.E. has received research funding from Celgene and Deerfield. T.D. is the Chief Medical Officer, ArcherDX, Inc. and receives salary from and holds an ownership stake in the company. K.T. receives consultancy fees from Symbio Pharmaceuticals. D.M.H. has consulted for Fount, Chugai, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer and Genentech/Roche; has equity in Fount; and has received research grants from Loxo, Bayer, Puma and AstraZeneca. J.B. is an employee of AstraZeneca; is on the Board of Directors of Foghorn and is a past board member of Varian Medical Systems, Bristol‐Myers Squibb, Grail, Aura Biosciences and Infinity Pharmaceuticals; has performed consulting and/or advisory work for Grail, PMV Pharma, ApoGen, Juno, Eli Lilly, Seragon, Novartis and Northern Biologics; has stock or other ownership interests in PMV Pharma, Grail, Juno, Varian, Foghorn, Aura, Infinity Pharmaceuticals, ApoGen and Northern Biologics, as well as Tango and Venthera, for which he is a co‐founder; and has previously received honoraria or travel expenses from Roche, Novartis and Eli Lilly. M. Ladanyi serves on the advisory boards for AstraZeneca, Bristol Myers Squibb, Takeda, Bayer and Merck, and has received research support from Loxo Oncology and Helsinn Therapeutics. D.B.S. has served as a consultant for or received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, Illumina and Vivideon Therapeutics. M.F.B. is on the advisory board for Roche and receives research support from Illumina. M.S.T. receives research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics and Biosight; serves on the advisory boards of Daiichi-Sankyo, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze and Jazz Pharma; has received royalties from UpToDate; and has received research funding from Incyte, Kura Oncology and Celgene. L.A.D. is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics; is a paid consultant to PGDx and Neophore; is an uncompensated consultant for Merck (with the exception of travel and research support for clinical trials); is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University, some of which are associated with equity or royalty payments directly to Johns Hopkins and L.A.D.; and holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection and Neophore; his wife holds equity in Amgen. The terms of all of these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo, Imago, C4 Therapeutics and Isoplexis, which include equity interest; receives research support from and has consulted for Celgene and Roche and has consulted for Lilly, Janssen, Astellas, Morphosys and Novartis; and has received honoraria from Roche, Lilly and Amgen for invited lectures and from Gilead for grant reviews. A.Z. received honoraria from Illumina. E. Papaemmanuil receives research funding from Celgene and is a cofounder in Isabl Technologies, a software analytics company for high-throughput clinical whole-genome and RNA-sequencing analyses. The remaining authors declare no competing interests. This work was supported by the National Institutes of Health (grant no. K08 CA241318 to K.L.B., grant no. K12 CA120780 to C.C.C., grant no. P50 CA172012 to L.B., grant no. P50 CA172012 to J.F., grant no. UG1 HL069315 to V.M.K.), the American Society of Hematology (K.L.B. and E. Papaemmanuil), the EvansMDS Foundation (K.L.B.), the European Hematology Association (E. Papaemmanuil), Gabrielle’s Angels Foundation (E. Papaemmanuil), the V Foundation (E. Papaemmanuil), the Geoffrey Beene Foundation (E. Papaemmanuil), the UNC Oncology Clinical Translational Research Training Program (C.C.C.), Cycle for Survival (V.M.K.), the Starr Cancer Consortium (to R.L.L., A.Z., M.F.B., R.N.P.) and the Cancer Colorectal Cancer Dream Team Translational Research Grant (grant no. SU2C-AACR-DT22-17 to L.A.D.). E. Papaemmanuil is a Josie Robertson Investigator. C.C.C. is a recipient of the Conquer Cancer Foundation Young Investigator Award and the Prostate Cancer Foundation Young Investigator Award. K.H.S. is a recipient of the Defense Early Investigator Research Award (grant no. W81XWH-18-1-0330), the Prostate Cancer Foundation Young Investigator Award and the Prostate Cancer Foundation Challenge Award. C.L., M.G.-C. and L.M.M. are supported by funds from the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Work performed at Memorial Sloan Kettering Cancer Center was supported in part by the Cancer Center Support Grant (grant no. P30 CA008748). N.G.’s work was supported in part by the Tissue Core and Genomic Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (grant no. P30 CA076292). The University of Cambridge has received salary support in respect of P.D.P.P. from the NHS in the East of England through the Clinical Academic Reserve.
ASJC Scopus subject areas
- Genetics
