TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms – a multicentric study on 529 patients

Abstract

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F-positive MPN and, to a lesser extent, CALR-positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F- or CALR-positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F-positive MPN, and TERT rs2736100 A>C having a more general, non-specific effect on all MPN, regardless of phenotype or major molecular subtype.

TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations

“…The TERT rs2736100_C allele has recently been identified to be associated with increased risk of MPNs based on analyses of Caucasian patients [ 13 – 16 ]. This finding provides significant insights into genetic susceptibility to MPN.…”

“…This observation is likely unbiased, because there is no difference in the rs2736100 genotype distribution between males and females in the general population in Sweden or China. Information on association between gender and allele variant of TERT rs2736100 in MPN patients is lacking in the majority of published studies [ 14 – 16 ], but one study reported a similar variant distribution in men and women [ 13 ]. Among MPN patients, women have been reported to have superior survival compared to men [ 31 , 32 ].…”

“…Similarly, high telomerase activity and TERT expression has been observed in MPNs [ 11 , 12 ]. More recently, a number of studies uncovered an association between the rs2736100 A>C single nucleotide polymorphism (SNP) in the TERT gene and the risk of developing MPNs [ 13 – 17 ]. The rs2736100 is located at intron 2 of the TERT locus, and its CC genotype was previously observed to enhance TERT transcription, thereby increasing cancer risk [ 18 ].…”

MECOM, HBS1L‐MYB, THRB‐RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients

“…JAK2 46/1 haplotype predisposes especially to JAK2 V617F‐mutated MPN, while rs2736100, located in the TERT (telomerase reverse transcriptase) gene, predisposes to all MPN, regardless of the clinical or molecular sub‐type . We previously replicated these findings in our patients …”

The JAK2 46/1 (GGCC) MPN‐predisposing haplotype: A risky haplotype, after all

“…In particular, according to recent data in 2035 MPN patients, of which 356 with a diagnosis of polycythemia vera (PV), who were extensively genotyped for a number of single nucleotide polymorphisms (SNPs) associated with hematologic traits and/or diseases, the JAK2 46/1 haplotype was found to strongly associate with diagnosis of PV (hazard ratio, 2.3). Additional genetic variations predisposing to MPN were later described in MECOM , TERT and HBS1L‐MYB ; the combined effect of JAK2/TER/MECOM variants was estimated to have a population association rate of 51% for JAK2 ‐negative MPN …”