The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

Abstract

JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1‐like CALR, 3%/2%/5% type 2‐like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple‐negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1‐1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple‐negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high‐molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1‐1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically‐inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics‐clinical MIPSS70+ version 2.0 model (P = .4). Leukemia‐free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2‐mutated PMF.

Clinical Relevance of VEGFA (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes

“…According to the WHO classification, the PMF cohort includes prefibrotic myelofibrosis and overt myelofibrosis. We show that PMF subjects with the rs3025039 minor T-allele have an increased susceptibility to the JAK2 V617F driver mutation, in keeping with data indicating that other genetic polymorphisms in JAK2, MECOM, TERT, TET2, HBS1L-MYB, and the corticosteroid receptor predispose to acquiring JAK2 V617F [26][27][28][29][30][31][32][33].…”

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

“…In a first study published in 2010, nullizygosity for the JAK2 haplotype was associated to shortened survival in a cohort of 130 PMF patients [55]. Subsequently, in a follow-up study on a cohort of 414 molecularly annotated PMF, the authors confirmed that wild-type patients displayed inferior overall survival as compared to the other genotypes, independently from well-established genetic and cytogenetic markers of poor outcome (karyotype, driver mutational status, presence of high-molecular-risk mutations) [56].…”

Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis

“…Host genetic variants such as single nucleotide polymorphisms (SNPs) are emerging as important players in modulating the individual pro-inflammatory background by affecting cytokine/chemokine gene expression and mRNA levels [ 8 ]. Indeed, inherited genetic variants predisposing to MF onset, phenotype and outcome, such as the JAK2 GGCC_46/1 haplotype [ 9 , 10 ] and the rs6198 SNP of NR3C1 [ 11 ], have also the potential to predispose to enhanced inflammatory state and autoimmune disorders [ 12 , 13 , 14 ].…”