Pre-malignant mutation landscape and risk factors for progression to hematologic cancers

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ABSTRACT Clonal hematopoesis (CH) defined as the presence of acquired mutations detectable in peripheral blood of normal healthy individuals without hematologic malignancies (HM) has been well characterized by sequencing population based cohort studies. The presence of CH is associated with >12-fold risk of eventual HMs. More data are needed to delineate disease specific and mutation specific risk as well as factors that might shape the evolutionary trajectory from CH to HM. We have demonstrated in our prior work that participants in the WHI who developed AML were four times more likely to harbor a mutation a median of 9.6 years before the onset of AML compared to controls (70% vs. 30%, OR 4.0, 95% C.I. 2.5-6.3) with mutations in TP53, IDH1/2, and spliceosome genes being highly associated with increased risk of AML and rarely present among controls. The long-term goal is to identify both mutational and cell-extrinsic factors that contribute to the development of HM and thus provide the basis for future clinical trials of HM interception and prevention. Published data indicate the ability of metabolic factors and inflammation to influence the expansion of CH. Our central hypothesis is that mutational, inflammatory and metabolic factors that predict the development of HM can be prospectively identified, thus enabling improved risk assessment. We will utilize peripheral blood samples collected at baseline from the Women’s Health Initiative (WHI) cohort that prospectively followed 168,808 women for a median of 10.8 years. All cancer outcomes were adjudicated by central review. Our specific aims will determine the following: (1) the risk of baseline pre-HM mutations and development of specific HM among participants in the WHI. We will select 400 cases of HM (200 chronic lymphocytic leukemia (CLL) and 200 cases of multiple myeloma) along with age matched 400 controls that did not develop HM during WHI follow up (2) To determine the impact of metabolic and inflammatory abnormalities in promoting CH expansion and impacting the progression from CH to HM. Our study is significant because there is no known intervention strategy to prevent or delay the progression of CH to HM and in general, prospective, randomized, controlled trials of prevention strategies require many years of follow-up to reach definitive conclusions. Our study will establish individuals at highest risk of HM based on mutational, inflammatory and metabolic factors and provide grounds for monitoring people individuals with CH at highest risk of HM. Moreover, these data will provide novel insight into intervention strategies to prevent the onset of HM. The proposed research is innovative in investigating mutational and metabolic as well as inflammatory factors that impact the progression of CH to HM using long term data from a large cohort of women.