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

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%±2.8% vs. 48.8%±3.5%, 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 (thrombosis, myelofibrosis, or leukemia) were not associated with the TERT variant; however, adverse survival was noted in TERT variant carrier polycythemia vera patients. MPN patients with the TERT CC genotype had a higher probability (44.4%) to die from solid tumors compared with TERT AC/AA individuals (5.3%; P = 0.004). TERT rs2736100_C carriers had increased risk of solid tumors independently from cytoreductive treatment [3.08 (1.03-9.26), P = 0.045]. CONCLUSIONS TERT rs2736100_C polymorphism predisposes to the development of BCR-ABL1-negative MPN with the co-occurrence of solid tumors, especially with the usage of cytoreductive treatment. IMPACT The high frequency of TERT variant in the classic MPN population highlights the importance of the avoidance of long-term cytoreductive treatment in MPN patients.