Co-occurrence of Myeloproliferative Neoplasms and Solid Tumors Is Attributed to a Synergism Between Cytoreductive Therapy and the Common TERT Polymorphism rs2736100

Abstract

Background: The germline telomerase reverse transcriptase (TERT) rs2736100_C variant was identified as a susceptibility factor for a variety of solid tumors and recently for myeloproliferative neoplasms (MPN).Methods: LightCycler melting curve analysis was applied to detect risk alleles of TERT rs2736100_C and Janus kinase 2 (JAK2) rs12343867_C tagging 46/1 haplotype in 584 BCR-ABL1-negative MPN, 308 acute, and 86 chronic myeloid leukemia (AML and CML) patients and 400 healthy individuals.Results: TERT rs2736100_C showed an increased allele frequency in BCR-ABL1-negative MPN patients compared with controls (62.7%AE2.8% vs. 48.8%AE3.5%, P < 0.0001) regardless of molecular background or disease type, but not in CML or AML. Combined TERT and JAK2 hetero-or homozygosity conferred even higher risk for classic MPN. Common complications (throm-

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

“…We found a very significant association between the TERT rs2736100 A>C SNP and MPNs, regardless of the MPN phenotype (PV, ET and PMF) or molecular subtype (JAK2 V617F and CALR), which is in agreement with previous reports (J€ ager et al, 2014;Oddsson et al, 2014;Krahling et al, 2016).…”

“…On the other hand, the JAK2 46/1 haplotype had a much more significant effect on JAK2 V617F-positive MPN, the effect being stronger in JAK2 V617F-positive PV and PMF than in JAK2 V617F-positive ET. The JAK2 46/1 haplotype was much more weakly associated with CALRpositive ET and PMF, which is also in agreement with previously reported results (J€ ager et al, 2014;Krahling et al, 2016). In the latter case, the association was statistically significant only in patients with a homozygous variant genotype.…”

“…This is slightly different from J€ ager et al (2014) and Krahling et al (2016), who reported a similar effect of the TERT SNP on both CALR and JAK2 V617F-positive MPN. On the other hand, the JAK2 46/1 haplotype had a much more significant effect on JAK2 V617F-positive MPN, the effect being stronger in JAK2 V617F-positive PV and PMF than in JAK2 V617F-positive ET.…”

“…By contrast, the TERT rs2736100 A>C SNP probably has more general genomic effects, involving predisposition to the acquisition of various mutations, in different loci (e.g JAK2 V617F, CALR or MPL), which would not be surprising, taking into account the role of the telomerase. We observed similar frequencies of the JAK2 46/1 haplotype and TERT SNP in the triple-negative subgroup compared to controls, as did Krahling et al (2016), while J€ ager et al (2014) observed a trend for a positive association between the TERT SNP and triple-negative MPN. We might speculate that the lack of (Milosevic Feenstra et al, 2016).…”

“…It is well known that MPN patients have an increased risk of developing solid cancers, not necessary in the context of cytoreductive therapy. Krahling et al (2016) made an interesting observation on their MPN cohort: they found that the TERT rs2736100 SNP was associated with the development of solid cancers in MPN patients and that this association was independent of the cytoreductive therapy administered to the MPN patients (Krahling et al, 2016). TERT rs2736100 SNP is associated with both solid cancers and MPN, so we could expect a more frequent co-occurrence of these types of cancers, on a common TERT background.…”