||5R01CA248747-03 Interpret this number
||Weill Medical Coll Of Cornell Univ
||Pre-Malignant Mutation Landscape and Risk Factors for Progression to Hematologic Cancers
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.
Association of Clonal Hematopoiesis of Indeterminate Potential with Incident Heart Failure with Preserved Ejection Fraction.
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Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones.
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Blood advances, 2023-05-09; 7(9), p. 1910-1914.