title: The JAK2 46/1 haplotype does not predispose to CALR-mutated myeloproliferative neoplasms.
abstract: Somatic mutations in the CALR gene were recently discovered in a substantial proportion of Philadelphia-negative chronic myeloproliferative neoplasm (cMPN) patients lacking JAK2 and MPL mutations. Somatically acquired defects are not the only pathogenic mechanism involved in these disorders. Since germline JAK2 46/1 haplotype predisposes to cMPN-associated mutations, including JAK2V617F and MPLW515K7L, we evaluated whether the 46/1 haplotype also confers susceptibility to CALR-mutated cMPN, both in sporadic and familial cases. The single-nucleotide polymorphism rs10974944, which tags 46/1, was investigated in 155 sporadic MPN patients and 270 unrelated controls, as well as in 11 familial cMPN cases and 36 unaffected relative controls. As described elsewhere, the 46/1 haplotype was overrepresented, both in sporadic and familial cMPN. In sporadic cMPN, the JAK2 46/1 haplotype was closely associated with JAK2V617F (p = 0.0003) but not with JAK2-nonmutated cases. Analysis of CALR-mutated sporadic cMPN (n = 22) showed no association between CALR mutations and 46/1 haplotype (p = 0.87). Regarding the familial cMPN, the prevalence of carriers of the G allele was higher in familial (81.8%) than in sporadic (62%) cMPN, but it did not differ significantly (p = 0.3). Although we described a family with carriers of both JAK2V617F and CALR mutations, due to the low number of CALR-mutated familial cases, we could not determinate whether the JAK2 46/1 haplotype predisposes or does not to CALR-mutated familial cMPN. We conclude, for the first time, that the 46/1 haplotype, unlike JAK2V617F and MPLW515K7L, is not associated with CALR-mutated cMPN.
authors.affiliation: Hematology and Medical Oncology Unit, Hospital Universitario Morales-Meseguer, Centro Regional de Hemodonacion, IMIB-Arrixaca, C/Ronda de Garay, sn. 3003, Murcia, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Soler
authors.forename: A
authors.initials: A
authors.lastname: Bernal-Vicente
authors.forename: A I
authors.initials: AI
authors.lastname: Antón
authors.forename: J M
authors.initials: JM
authors.lastname: Torregrosa
authors.forename: E
authors.initials: E
authors.lastname: Caparrós-Pérez
authors.forename: I
authors.initials: I
authors.lastname: Sánchez-Serrano
authors.forename: A
authors.initials: A
authors.lastname: Martínez-Pérez
authors.forename: B
authors.initials: B
authors.lastname: Sánchez-Vega
authors.forename: V
authors.initials: V
authors.lastname: Vicente
authors.forename: F
authors.initials: F
authors.lastname: Ferrer-Marin
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010677:Philadelphia Chromosome; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2