Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome

Abstract

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strandbreaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematologicalcancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. Thisreport aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPDrs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America(173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCRusing TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have anormal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, thehomozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated withan increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for thers1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 £ 1010), and intermediate (p < 0.001, OR=3.08 £ 1010),according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to beclassified as good (p < 0.001, OR=4.03 £ 1013) and intermediate (p < 0.001, OR=2.54 £ 1013).Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnicdifferences and regional influences in pathogenesis and prognosis of MDS.