Antecedent Clonal Hematopoesis and Risk of and Mortality after Solid and Hematological Malignancies: Analyses from the Women's Health Initiative Study
Authors: Desai Pinkal , Handelman Samuel , Wu Alan , Christos Paul J , Lee Sangmin , Samuel Michael B. , Ritchie Ellen K. , Guzman Monica L. , Jackson Rebecca , Hassane Duane C. , Manson Joann , Reiner Alexander , Simon Michael S. , Roboz Gail J. 
Published: November 2019

Background: Whole genome analyses of peripheral blood has demonstrated that acquired somatic mutations in peripheral blood also known as clonal hematopoiesis of indeterminate potential (CHIP) is present in up to 10% of individuals older than 60 years and associated with increased risk of cardiovascular mortality and hematologic malignancies (Jaiswal et al, Genovese et al, NEJM 2014). We have demonstrated that CHIP is associated specifically with increased risk of leukemia (Desai et al, Nat. Medicine 2018). CHIP has also been detected in 25% of individuals with concomitant advanced solid malignancies using targeted deep sequencing (Coombs et al, 2017). However, the role of antecedent CHIP in risk of solid malignancies has not been established due to lack of non-cancer controls and absence of CHIP data before the diagnosis of cancer in the published literature. The role of antecedent CHIP in cancer specific and non-cancer specific mortality after diagnosis of cancer is also not known.
Methods: We analyzed whole genome sequencing data (30X coverage) from 10,089 participants in the Women's Health Initiative (WHI) enrolled in the Trans-Omics for Precision Medicine (TOPMED) consortium to assess the relationship between antecedent CHIP measured at baseline entry into the study, and cancer risk and mortality after cancer. Cox proportional hazards regression models were used to evaluate the relationship between CHIP and cancer risk, all-cause mortality as well as mortality due to cancer, cardiovascular disease (CVD) and other causes. All statistical tests are two-sided with an alpha level of 0.05.
Results: Of 10,089 eligible participants, the overall rate of CHIP mutations was 9.3 % and the most common CHIP mutations included DNMT3A (55%), TET2 (19%), and ASXL1 (7.1%). CHIP was associated with both current and past history of smoking and the best-fit model suggested a dose dependent relationship by pack years. Over 13±6 years of follow-up, there were 2,337 women diagnosed with at least one cancer including (at 7±5 years of follow-up) 774 with breast cancer, 319 with colon, 355 with lung and 282 with hematologic malignancies. Among patients with cancer, there were 813 cancer specific deaths and 3,946 non-cancer related deaths. Among participants with and without a previous history of cancer, CHIP was detected in 8.4% and 9.3% of participants respectively. PPM1D or TP53 (n=50, of whom 8 had a previous history of malignancy) mutations were detected in 3.6% and 1.7 % of total participants with CH. 29% of participants with TP53 or PPM1D CHIP developed a future cancer , compared to 26% in non TP53/PPM1D CHIP and 21% without CHIP. There was no significant difference in TP53 CHIP in patients with or without previous history of cancer.
After excluding 697 participants with a previous history of malignancy, antecedent CHIP (prior to the diagnosis of cancer) was not significantly associated with risk of solid malignancy overall (Hazards Ratio (HR), 95% confidence interval (CI) 1.07, (0.94−1.23) p=0.31). However, there was a borderline increased risk of breast cancer (HR, 95% CI, 1.23, (1.003−1.25) P=0.04) and no association with lung (HR 1.23, P=0.15) or colon cancer (HR 0.96, P=0.86). Among participants with solid malignancies, CHIP was associated with an increased cancer specific mortality (HR, 95% CI, 1.24 (1.02−1.51), p=0.03) but no association with mortality due to CVD post diagnosis of solid malignancy (HR 0.63, P=0.51) was seen. Any antecedent CHIP mutation was associated with increased risk of hematological malignancies (HR, 95% CI, 1.76, (1.25−2.48), p<0.002) with a higher risk of hematological malignancy seen with increased clonal complexity. Among patients with hematological malignancies, antecedent CHIP was associated with increased mortality from hematological malignancy (HR, 95% CI 1.45, (1.10−1.92) p=0.007) and not associated with increased cardiovascular mortality post diagnosis of the hematological disorder (HR 0.63, p=0.51).
Conclusion: This is the first report to relate antecedent CHIP with solid tumor risk and mortality in a multi-site study of post-menopausal women. Antecedent CHIP was associated with increased solid cancer specific mortality but not with risk of solid malignancy or CVD mortality post cancer diagnosis. It is possible that deeper, targeted sequencing may identify an association between antecedent CHIP and the incidence of solid tumors; further investigation is warranted.

Disclosures
Desai: Sanofi: Consultancy; Astellas: Honoraria; Astex: Research Funding; Cellerant: Consultancy; Celgene: Consultancy. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Ritchie:Celgene, Incyte, Novartis, Pfizer: Consultancy; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board; Genentech: Other: Advisory board. Guzman:Samus Therapeutics: Patents & Royalties: intellectual rights to the PU-FITC assay; SeqRx: Consultancy; Cellectis: Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees.