Inherited predisposition to myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are haematological disorders characterized by an overproduction of mature myeloid cells with a tendency to transform to acute myeloid leukaemia. Clonal proliferation of myeloid progenitor cells is driven by somatically acquired mutations, most notably JAK2 V617F, but there are important features relating to pathogenesis and phenotypic diversity that cannot be explained by acquired mutations alone. In this review we consider what is currently known about the role that inherited factors play in the development and biology of both sporadic and familial forms of MPN. Although most MPN cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles. Currently the JAK2 46/1 haplotype (also referred to as 'GGCC') is the strongest known predisposition factor for sporadic MPNs carrying a JAK2 V617F mutation, explaining a large proportion of the heritability of this disorder. Less is known about what genetic variants predispose to MPNs that lack JAK2 V617F, but there have been recent reports of interesting associations in biologically plausible candidates, and more loci are set to emerge with the application of systematic genome-wide association methodologies. Several highly penetrant predisposition variants that affect erythropoietin signalling, thrombopoietin signalling or oxygen sensing have been characterized in families with nonclonal hereditary erythrocytosis or thrombocytosis, but much less is known about familial predisposition to true clonal MPN. The heterogeneous pattern of inheritance and presumed genetic heterogeneity in these families makes analysis difficult, but whole exome or genome sequencing should provide novel insights into these elusive disorders.

Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms

“…This analysis yielded a mutation rate of 1 somatic mutation per 45 patient years, which is fairly close to the result obtained by the longitudinal analysis (1/66 patient years). These observations do not support the presence of a strong hypermutable state in MPN 24,25 and also question the magnitude of the genomic instability caused by expressing JAK2 V617F. [26][27][28] Consistent with the low mutation rate that we observed, a recent exome-based 14,29 Our analyses illustrate that one of the strongest predictors of outcome is the number of somatic mutations that occur in addition to JAK2, CALR, or MPL ( Figure 3B).…”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…In fact, the relative risk of acquiring ET has been estimated to be approximately 12 times higher in first-degree relatives of MPN patients. 83 This strongly points to the existence of germline susceptibility factors.…”

The evolving genomic landscape of myeloproliferative neoplasms

“…81 In terms of predisposition to MPNs in the general population, the strongest inherited factor remains the JAK2 constitutional 46/1 or "GGCC" haplotype, which has been estimated to account for 50% of the population-attributable risk of developing an MPN. 80 Recently, another germline sequence variant, rs2736100_C, in the gene TERT has been reported to be associated with both MPNs and higher blood count indices in healthy individuals in an Icelandic cohort and awaits confirmation in other populations. 82 …”