Driver Mutation Zygosity Is a Critical Factor in Predicting Clonal Hematopoiesis Transformation Risk

Details

• Personal Author:
  Bejan CA ; Bick AG ; Dorand D ; Ferrell PB Jr. ; Khan MAW ; Kishtagari A ; Li Y ; Mack TM ; Marneni N ; Savona MR ; Silver AJ ; Snider C ; Sochacki A ; Spaulding T ; Stockton S ; Vlasschaert C ; von Beck K ; Xu Y
• Description:
  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 < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06-55.35, P < 0.001). Currently, the 'zygosity' of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include 'zygosity' status of CHIP mutations and that future prognostication systems should take mutation 'zygosity' into account. [Description provided by NIOSH]
• Subjects:
  Blood Chromosomes Cohort Studies Genetics Hematologic Tests Neoplasms Occupational Health Safety
• Keywords:
  Blood Cells Cancer Cell Alteration Chromosome Damage Cohort Studies DNA Damage Genes Genetic Factors Hematology Hematopoiesis Mutation

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• ISSN:
  2044-5385
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2 ; OSHA Region 4 ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  6
• Volume:
  14
• Issue:
  1
• NIOSHTIC Number:
  nn:20069246
• Citation:
  Blood Cancer J 2024 Jan; 14(1):6
• Contact Point Address:
  Alexander G. Bick, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
• Email:
  alexander.bick@vumc.org
• Federal Fiscal Year:
  2024
• Performing Organization:
  Albert Einstein College of Medicine, Bronx, New York
• Peer Reviewed:
  True
• Start Date:
  20210701
• Source Full Name:
  Blood Cancer Journal
• End Date:
  20240630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:20d0baca9d324c9ba620f0bf3840f3c415ff9ec54fb592480a183c1384d1bf08c42377172a1bfae62ee970ad83c1efa1c057aa9b8565c68d642159a4c98b57cf
• Download URL:
  https://stacks.cdc.gov/view/cdc/207755/cdc_207755_DS1.pdf
• File Type:
  [PDF - 1.20 MB ]