The DNA in human cells is oxidatively damaged by various endogenous biochemical processes or exogenous stimuli. Base excision repair (BER) systems have important role for repairing oxidative DNA damage, and known to influence the carcinogenesis and the response to anti-cancer treatments. Although previous studies have shown that defective DNA repair is associated with an increased risk of hematologic malignancies including leukemia and lymphoma, it is unclear these polymorphisms alter the susceptibility and clinical outcome of multiple myeloma (MM) patients. The aim of this study was to evaluate the impact of polymorphisms in genes encoding four main proteins of BER system: OGG1 Ser326Cys, XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His on the risk and survival of MM.
We examined 93 patients [age range, 35–83 years; male/female44/49; Durie and Salmon stage I (n=8), stage II (n=22), stage III (n=61), unknown (n=2); Intenational staging system (ISS) 1 (n=21), 2 (n=21), 3 (n=29), unknown (n=22); IgG (n=55), IgA (n=15), IgD (n=2), non-secretory (n=3), Bence Jones (n=18)] with MM and 192 healthy controls. Genomic DNA was isolated from peripheral blood using the DNA extraction kit. Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Allele and genotype frequencies were calculated by direct counting. Genotype and allele frequencies were compared between patients group and control group by using Χ2-test. The characteristics and laboratory features of MM patients with each polymorphisms were compared using Χ2-tests and student t-tests. The Kaplan-Meier method was used in the calculation of overall survival (OS). Difference between the survival curves by genotypes was compared using the generalized Wilcoxon test. For the multivariate survival analyses, cox proportional hazard models were used to define the prognostic factors for OS. Probability values <0.05 were considered statistically significant. All patients and healthy controls received written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital.
The frequencies of genotypes of BER gene polymorphism in patients with MM were as follows: Ser/Ser 35.9%, Ser/Cys 34.8%, and Cys/Cys 29.3% for OGG1; Gln/Gln 22.6%, Gln/His 49.5%, and His/His 28% for MUTYH; Arg/Arg 57%, Arg/Gln 38.7% and Gln/Gln 4.3% for XRCC1; Asp/Asp 35.5%, Asp/Glu 41.9%, and Glu/Glu 22.6% for APE1. These results showed the OGG1 Cys/Cys genotype (low DNA repair type) compared with OGG1 non-Cys/Cys genotype increases the risk of MM (OR 1.86, 95% CI 1.04–3.31, p<0.05). Furthermore, the Ser/Cys genotype compared with OGG1 non-Ser/Cys genotype strongly reduces the risk of MM (OR 0.39; 95% CI 0.24–0.06, p<0.0005). In contrast, there was no statistically significant difference about the risk of MM in the allele and genotype frequencies of the XRCC1 Arg399Gln, APE1 Asp148Glu, and MUTYH Gln324His polymorphisms between the control group and the patients with MM. When comparing OS according to APE1 Asp148Glu polymorphism, the group with APE1 Glu/Glu (low DNA repair type) showed inferior OS (median OS 3.07 years vs.5.63 years, p=0.02). In a multivariate analysis using stepwise selection, APE Glu/Glu (low DNA repair type) (p=0.02), MUTYH His/His (low DNA repair type) (p=0.0001), ISS 3 (p=0.003), and Hb<10 g/dl (p=0.03) were independent prognostic factors significantly associated with shorter survival.
According to our data, BER gene polymorphisms may affect the carcinogenesis and prognosis of MM. It is suspected that low BER activity gave rise to high DNA damage, and induced malignant transformation of plasma cell and progression to aggressive myeloma. The BER gene polymorphisms may be one of useful prognostic markers of MM and require further verification as predictive biomarkers in a larger study population.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.