ABSTRACT
Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
Subject(s)
Clonal Hematopoiesis/genetics , Genetic Predisposition to Disease , Genome, Human/genetics , Whole Genome Sequencing , Adult , Africa/ethnology , Aged , Aged, 80 and over , Black People/genetics , Cell Self Renewal/genetics , DNA-Binding Proteins/genetics , Dioxygenases , Female , Germ-Line Mutation/genetics , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Middle Aged , National Heart, Lung, and Blood Institute (U.S.) , Phenotype , Precision Medicine , Proto-Oncogene Proteins/genetics , Tripartite Motif Proteins/genetics , United States , alpha Karyopherins/geneticsABSTRACT
OBJECTIVE: Recent data suggest patients with epithelial ovarian cancers on statin therapy have improved survival. We have hypothesized that statins influence ovarian cancer outcome through alteration of lipoprotein profiles, and sought to determine correlations between lipoprotein levels and survival in women with advanced stage disease. METHODS: After IRB approval, we identified patients with stage IIIC/IV epithelial ovarian cancer with banked prediagnostic fasting serum. Serum was assayed for levels of total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG). LDL was calculated by subtraction of TG/5 and HDL from TC. Data were examined using Fisher's exact, Kaplan-Meier, and Cox regression analyses. RESULTS: One hundred thirty-two patients were studied. Twenty-six percent of patients had elevated LDL; 18% had elevated TC; 32% had elevated TG; and 48% had elevated HDL. No univariate associations were identified between elevated TC, HDL, TG, LDL and age, stage IV disease, high grade, or optimal cytoreduction. Median progression-free survival for patients with normal LDL levels was 27 months, compared to 12 months for patients with elevated LDL (p=0.0004). Overall disease-specific survival was longer for patients with normal LDL levels (59 months) compared to those with elevated LDL (51 months, p=0.04). Multivariate analysis indicated that LDL retained significance as an independent predictor of survival, after controlling for age, stage, grade, and suboptimal cytoreduction (p=0.003). CONCLUSIONS: These data suggest LDL is a significant predictor of clinical outcome, and warrant the further study of lipoproteins and statins on epithelial ovarian cancer biology.
