학술논문
Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk
Document Type
article
Author
Ashwin Kishtagari; M. A. Wasay Khan; Yajing Li; Caitlyn Vlasschaert; Naimisha Marneni; Alexander J. Silver; Kelly von Beck; Travis Spaulding; Shannon Stockton; Christina Snider; Andrew Sochacki; Dixon Dorand; Taralynn M. Mack; P. Brent Ferrell; Yaomin Xu; Cosmin A. Bejan; Michael R. Savona; Alexander G. Bick
Source
Blood Cancer Journal, Vol 14, Iss 1, Pp 1-6 (2024)
Subject
Language
English
ISSN
2044-5385
Abstract
Abstract Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92–88.41, P