Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.

Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.

Braunstein EM ，Imada E ，Pasca S ，Wang S ，Chen H ，Alba C ，Hupalo DN ，Wilkerson M ，Dalgard CL ，Ghannam J ，Liu Y ，Marchionni L ，Moliterno A ，Hourigan CS ，Gondek LP ... -  《-》

Evaluation of the ATM L2307F germline variant in 121 Italian pedigrees with familial myeloproliferative neoplasms.

Borsani O ，Jäger R ，Pietra D ，Flieder I ，Riccaboni G ，Kralovics R ，Rumi E ... -  《-》

Germline genetic factors in the pathogenesis of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are clonal hematological malignancies that lead to overproduction of mature myeloid cells. They are due to acquired mutations in genes encoding for AK2, MPL and CALR that result in the activation of the cytokine receptor/JAK2 signaling pathway. In addition, it exists germline variants that can favor the initiation of the disease or may affect its phenotype. First, they can be common risk alleles, which correspond to frequent single nucleotide variants present in control population and that contribute to the development of either sporadic or familial MPN. Second, some variants predispose to the onset of MPN with a higher penetrance and lead to familial clustering of MPN. Finally, some extremely rare genetic variants can induce MPN-like hereditary disease. We will review these different subtypes of germline genetic variants and discuss how they impact the initiation and/or development of the MPN disease.

Bellanné-Chantelot C ，Rabadan Moraes G ，Schmaltz-Panneau B ，Marty C ，Vainchenker W ，Plo I ... -  《-》

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

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.

Hinds DA ，Barnholt KE ，Mesa RA ，Kiefer AK ，Do CB ，Eriksson N ，Mountain JL ，Francke U ，Tung JY ，Nguyen HM ，Zhang H ，Gojenola L ，Zehnder JL ，Gotlib J ... -  《-》

Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are generally acquired as a result of a somatic stem cell mutation leading to clonal expansion of myeloid precursors. In addition to sporadic cases, familial MPN occurs when one or several MPN affect different relatives of the same family. MPN driver mutations (JAK2, CALR, MPL) are somatically acquired also in familial cases, so a genetic predisposition to acquire one of the MPN driver mutations would be inherited, even though the causative germline mutations underlying familial MPN remain largely unknown. Recently some germline variants [ATG2B and GSKIP duplication, RBBP6 mutations, SH2B3 (LNK) mutations], which can cause familial MPN, have been reported but these mutations are rare and do not explain most familial cases. Patients with familial MPN show the same clinical features and suffer the same complications as those with sporadic disease. This review aims to offer up-to-date information regarding the genetics of familial MPN.

Rumi E ，Cazzola M 《-》