Germline Predisposition in the Field of Myeloproliferative Neoplasms

Philadelphia-negative myeloproliferative neoplasms (MPN) are a group of clonal malignancies of the myeloid lineage, characterized by a deregulated cellular proliferation driven by somatically acquired driver mutations that ultimately result in a hyperactivated JAK/STAT signaling. MPN have traditionally been described as sporadic, late-onset cancers. However, it has been increasingly recognized that a subset of these neoplasms has early onset and/or aggregates within family, thus suggesting that they may occur on the background of germline mutations, both inherited or occurring de novo. Several lines of evidence support the role of germline genetic factors in the pathogenesis of MPN. The inherited predisposition to MPN occurs either because of rare but highly penetrant gene variants (i.e., true familial MPN with Mendelian inheritance, which consists in malignant disorder that occurs in two or more family members and that mimics sporadic cases as regards rate of vascular events and risk of disease progression) or because of more common but weakly penetrant risk factors. Some of the most important predisposing genetic variations include the JAK2 46/1 haplotype and the rs2736100 variant of the telomerase reverse transcriptase (TERT) gene. On the other hand, germline copy number variations – such as duplication of autophagy-related 2B (ATG2B) and GSK3B-interacting protein (GSKIP) genes – and mutations of the retinoblastoma binding protein 6 (RBBP6) gene have been identified as highly penetrant predisposition loci for familial myeloid neoplasms, including MPN. Taken together, recent discoveries support the notion that MPN might occur on a background of germline mutations more frequently than previously thought; moreover, the spectrum of known tumor predisposition syndromes can be broader than anticipated. Finally, environmental and lifestyle influences on susceptibility to MPN have also been reported.