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Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk

Medicine and Health

Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk

A. Kishtgari, M. A. W. Khan, et al.

This groundbreaking study explores how the zygosity of CHIP mutations influences the risk of hematologic malignancies. Conducted by Ashwin Kishtgari and colleagues, it reveals that individuals with concurrent somatic mutations and mosaic chromosomal alterations face significantly heightened risk, especially those with a homozygous JAK2 V617F mutation. This research emphasizes the critical need to assess mutation zygosity in clonal hematopoiesis risk evaluation.

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~3 min • Beginner • English
Abstract
Clonal hematopoiesis (CH) arises from mutations that enhance hematopoietic stem cell fitness and includes both single-gene mutations in myeloid driver genes (CHIP) and mosaic chromosomal alterations (mCAs). Although CH increases the risk of hematologic malignancies, the absolute annual transformation rate is low, and better prognostication is needed. We hypothesized that co-occurrence of CHIP and mCAs at the same locus, which can convert a heterozygous driver mutation into a homozygous state (e.g., JAK2 V617F with 9p loss of heterozygosity), has important prognostic implications. Using the UK Biobank (n = 451,180) as a discovery cohort and BioVU (n = 91,335) as validation, we show that individuals with concurrent somatic mutation and mCA have significantly increased risk of hematologic malignancy. For example, in BioVU, co-occurring JAK2 V617F and 9p CN-LOH was associated with higher incidence of hematologic malignancies (HR = 54.76, 95% CI = 33.92–88.41, P < 0.001) compared with JAK2 V617F alone (HR = 4.05, 95% CI = 3.56–6.35, P < 0.0001). Currently, mutation zygosity is not routinely reported in clinical assays; our results support incorporating zygosity into future prognostication systems.
Publisher
Blood Cancer Journal
Published On
Jan 15, 2024
Authors
Ashwin Kishtgari, M. A. Wasay Khan, Yajing Li, Caitlyn Vlasschaert, Naimisha Marenin, Alexander J. Silver, Kelly von Beck, Travis Spaulding, Shannon Stockton, Christina Snider, Andrew Sochak, Dixon Dorand, Taralynn M. Mack, P. Brent Ferrell, Yaomin Xu, Cosmin A. Bejan, Michael R. Savona, Alexander G. Bick
Tags
clonal hematopoiesis
hematic malignancy
zygosity
somatic mutations
mosaic chromosomal alterations
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