Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms.

Roland Jäger,Ashot S Harutyunyan,Richard S Houlston,Daniela Pietra,Mario Cazzola,Robert Kralovics,Damla Olcaydu,Elisa Rumi,Tiina Berg

doi:10.1002/ajh.23842

Abstract

The C allele of the rs2736100 single nucleotide polymorphism located in the second intron of the TERT gene has recently been identified as a susceptibility factor for myeloproliferative neoplasms (MPN) in the Icelandic population. Here, we evaluate the role of TERT rs2736100_C in sporadic and familial MPN in the context of the previously identified JAK2 GGCC predisposition haplotype. We have confirmed the TERT rs2736100_C association in a large cohort of Italian sporadic MPN patients. The risk conferred by TERT rs2736100_C is present in all molecular and diagnostic MPN subtypes. TERT rs2736100_C and JAK2 GGCC are independently predisposing to MPN and have an additive effect on disease risk, together explaining a large fraction of the population attributable fraction (PAF = 73.06%). We found TERT rs2736100_C significantly enriched (P = 0.0090) in familial MPN compared to sporadic MPN, suggesting that low-penetrance variants may be responsible for a substantial part of familial clustering in MPN. Am. J. Hematol. 89:1107–1110, 2014. © 2014 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

Highlights

Myeloproliferative neoplasms (MPN) constitute a group of phenotypically diverse chronic myeloid malignancies including three major disease entities: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)
Significant associations were detected for both JAK2-positive and CALRpositive MPN at similar strength (Table I), suggesting that there is no preferential susceptibility to any molecular subtype
Conditional logistic regression analysis revealed that TERT and JAK2 loci are independently predisposing to MPN, the total combined risk approximating the sum of the two genotypes (Fig. 1; Supporting Information Table 2)

Summary

Introduction

Myeloproliferative neoplasms (MPN) constitute a group of phenotypically diverse chronic myeloid malignancies including three major disease entities: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Exclusive oncogenic somatic mutations in three genes have been identified in more than 90% of MPN cases [1]. A common haplotype (GGCC or 46/1) at the JAK2 locus has been found to predispose to JAK2 mutation positive sporadic and familial MPN [12,13,14,15]. A recent study identified the germline sequence variant rs2736100_C located in the second intron of the TERT gene as risk variant for MPN in the Icelandic population [17]. We were seeking to confirm the TERT association in an independent cohort from a different ethnic background and evaluate the role of the TERT predisposition locus in familial clustering of MPN. We were testing the possibility of an interaction of TERT and JAK2 susceptibility loci in sporadic and familial MPN

Methods

Results

Conclusion