Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers (original) (raw)
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2023
Supplementary Table 8. CHIP mutations not exclusive to hotspots identified in the three non-cancer cohorts. Listed are 189 CHIP mutations identified in 183 persons of the three non-cancer cohorts (N=4,530) occurring in hematopoietic-associated genes but not required to occur at a hematologic hotspot, identified as per the criteria used in Jaiswal et al. 14. These mutations were required to meet a variant allele frequency (VAF) threshold of 4%. Cohort* SRR ID # Chr. Start pos. (hg19) End pos. (hg19) Ref. Alt. Ref. reads Alt. reads VAF Ref./Alt. reads on both strands Transcript Mutation M/F † Age ‡ No. patients/ hemat. disorders/ studies hotspot observed in 48 studies § gnomAD allele frequency (exome) gnomAD allele frequency (genome)
Supplementary Table 5. Unique mutations allowed at hotspots. Listed are 350 mutations reported across the 48 somatic landscape studies that were not listed as queried variants for CHIP in Jaiswal et al. 14 (many of those 48 studies were published around or after that landmark CHIP paper). Columns show the number of mutations resulting in the exact protein exchange and for the total number of protein-altering mutations reported for each amino acid position or splice site locus across the 48 studies. Tallies are for the total number of patients with a reported mutation (No. patients), number of hematological malignancies having at least one reported patient with the mutation (No. hemat. disorders), and the number of studies reporting at least one patient with the mutation (No. studies).
JAMA oncology, 2018
Although clonal hematopoiesis (CH) is well described in aging healthy populations, few studies have addressed the practical clinical implications of these alterations in solid-tumor sequencing. To identify and quantify CH-related mutations in patients with solid tumors using matched tumor-blood sequencing, and to establish the proportion that would be misattributed to the tumor based on tumor-only sequencing (unmatched analysis). Retrospective analysis of samples from 17 469 patients with solid cancers who underwent prospective clinical sequencing of DNA isolated from tumor tissue and matched peripheral blood using the MSK-IMPACT assay between January 2014 and August 2017. We identified the presence of CH-related mutations in each patient's blood leukocytes and quantified the fraction of DNA molecules harboring the mutation in the corresponding matched tumor sample. The mean age of the 17 469 patients with cancer at sample collection was 59.2 years (range, 0.3-98.9 years); 53.6%...
2022
Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with s...