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

Abstract

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

“…Previous studies had suggested that patients with type 2/like CALR mutations were phenotypically more aligned with JAK2 ‐mutated cases . Consistent with this conjecture, in one large study of 939 patients with MPN, the JAK2 46/1 MPN predisposition allele was significantly associated with JAK2 and type 2/like CALR and not with type 1/like CALR mutations . One notable exception is the risk of thrombosis, which is a characteristic feature of JAK2 and possibly MPL mutations, and not necessarily dependent on the presence or absence CALR mutations …”

The JAK2 GGCC (46/1) Haplotype in Myeloproliferative Neoplasms: Causal or Random?

“…However, in 2010, calreticulin ( CALR ) gene mutations had not yet been identified, therefore the mutational status of V617F negative TE and MF patients could not be correctly assessed. After the identification of CALR mutations, further studies produced conflicting results regarding the frequency of the haplotype GGCC_46/1 in this group of MPN patients, mostly suggesting a lack of association [ 14 , 21 , 22 , 23 ]. Therefore, the possible association between the occurrence of the haplotype GGCC_46/1 and JAK2 V617F negative MPN cases warrants further investigation.…”

“…These findings suggest that that the JAK2 haplotype GGCC_46/1 does not explain familial MPNs, which account for 5–10% of all MPN cases [ 28 , 29 , 30 , 31 ]. At the same time, it was found that the rs2736100 SNP, located in the second intron of the telomerase reverse transcriptase ( TERT ) gene, had a different allele frequency in familial MPN compared to sporadic cases [ 27 ] and exhibited a strong cancer predisposition effect in all MPN subtypes, regardless of the JAK2 gene mutations occurrence [ 23 , 32 ]. The TERT gene at 5p15.33 encodes the catalytic subunit of the telomerase complex, playing an important role in maintaining telomere length [ 33 ].…”

“…This study confirmed the role of the JAK2 haplotype GGCC_46/1 and TERT SNPs as germline factors predisposing to MPN but also identified significant associations between the occurrence of polymorphisms near SH2B3 , TET2 , ATM , CHEK2 , PINT , and GFI1B genes and JAK2 V617F clonal hematopoiesis and/or MPN development ( Figure 1 ) [ 42 ]. Another recent study investigated the contribution of additional germline polymorphisms, such as MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647, to the onset of MPN [ 23 ]. The SNP rs2201862, located downstream of MECOM gene, had the third strongest influence on the risk of developing MPN, after the JAK2 46/1 haplotype and TERT rs2736100 polymorphisms, MECOM rs2201862 was found to predispose especially to PV and to CALR mutated ET and PMF ( Figure 1 ) [ 23 ].…”

“…Another recent study investigated the contribution of additional germline polymorphisms, such as MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647, to the onset of MPN [ 23 ]. The SNP rs2201862, located downstream of MECOM gene, had the third strongest influence on the risk of developing MPN, after the JAK2 46/1 haplotype and TERT rs2736100 polymorphisms, MECOM rs2201862 was found to predispose especially to PV and to CALR mutated ET and PMF ( Figure 1 ) [ 23 ].…”