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

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...

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Published in:Blood cancer journal (New York) 2024-01, Vol.14 (1), p.6-6, Article 6
Main Authors: Kishtagari, Ashwin, Khan, M. A. Wasay, Li, Yajing, Vlasschaert, Caitlyn, Marneni, Naimisha, Silver, Alexander J., von Beck, Kelly, Spaulding, Travis, Stockton, Shannon, Snider, Christina, Sochacki, Andrew, Dorand, Dixon, Mack, Taralynn M., Ferrell, P. Brent, Xu, Yaomin, Bejan, Cosmin A., Savona, Michael R., Bick, Alexander G.
Format: Article
Language:English
Subjects:
38/61
631/67/69
692/699
Biomedical and Life Sciences
Biomedicine
Cancer Research
Chromosome Aberrations
Clonal Hematopoiesis
Hematologic Neoplasms - genetics
Hematology
Humans
Mutation
Oncology
Point Mutation
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Summary: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  
ISSN:2044-5385
2044-5385
DOI:10.1038/s41408-023-00974-9