DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms

Abstract

The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility.

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…The gender distribution observed in the current population was consistent with previous data regarding this group of disorders (67). Furthermore, although certain published studies consider smoking as a contributing factor for PN-MPNs (68,69), the present study did not reveal a significant association, potentially due to the small number of smoking individuals that was included.…”

Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea

“…The characteristics of each SNP under study were previously described and published (16,41,42), while the genotype frequencies and therapeutic distribution determined according to survival are shown in Table II.…”

“…Uphold of genetic integrity, through DNA repair mechanisms, is essential for preventing cellular damage and the development of leukaemia (16). Protein function and thus DNA damage repair may be affected by several polymorphisms in DNA repair genes, leading to susceptibility to malignancy (16).…”

“…General characteristics for PN-MPNs patients at time of diagnosis and related to disease outcome are summarized in Table I. DNA extraction, SNP selection and genotyping. SNP selection was previously reported for BER genes (16), for caspases genes (41) as well as for JAK2 mutation (42). Peripheral blood samples (7-8 ml) of all patients and controls were collected and maintained thereafter at -80˚C until used.…”

“…On the other hand, several single nucleotide polymorphisms (SNPs) at various loci, influencing DNA repair capacity and apoptotic status, and additional somatic genetic effects may confer genetic predisposition to PN-MPNs (16), influencing phenotype definition and determining therapeutic response (8,(17)(18)(19)(20)(21)(22)(23). Moreover, despite the development of more efficient drugs in the last years, some patients with PN-MPNs still show disease progression to conditions more aggressive and difficult to treat (1,2).…”