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Blood. 2016 Aug 25;128(8):1121-8. doi: 10.1182/blood-2015-06-652941. Epub 2016 Jun 30.

Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms.

Author information

1
23andMe, Inc, Mountain View, CA;
2
Division of Hematology & Medical Oncology, Mayo Clinic, Scottsdale, AZ;
3
Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
4
Department of Pathology, Stanford University School of Medicine, Stanford, CA; and.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA; and Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.
6
Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.

Abstract

We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.

PMID:
27365426
PMCID:
PMC5085254
DOI:
10.1182/blood-2015-06-652941
[Indexed for MEDLINE]
Free PMC Article

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