Ber Gene Polymorphisms Associated With Key Molecular Events in Bladder Cancer

Abstract

Aim: Base excision repair (BER) gene polymorphisms are known to play an independent role in predisposition to developing different cancers as well as to be associated with clinicopathological traits of the disease modifying its clinical outcomes. One of the underlying mechanisms is presumed to include interplay between BER gene polymorphisms and key mutational, epigenetic and chromosomal events in tumor tissues. The present study was aimed at elucidating potential gene-gene interaction and assessing their mutual effects in bladder cancer (BC). Materials and Methods: The earlier obtained data on genotyping patients with verified diagnosis of BC for OGG1 rs1052133 (Ser326Cys) and XRCC1 rs25487 (Arg399Gln) polymorphisms were used for this study. The tumor tissue samples from the same patients were analyzed for mutations, epigenetic variations and losses of heterozygosity in some key genes involved in divergent pathogenic pathways of BC. Results: It was shown that the OGG1 (326 codon) heterozygous genotype as well as the minor 326Cys allele can intensify a mutational response of the RAS locus in urothelial carcinomas in the total cohort of patients simultaneously decreasing the mutation rates in the PIK3CA locus in smokers. The XRCC1 (399 codon) heterozygous genotype as well as the minor 399Gln allele reduced the frequency of LOH in the PTEN and TNKS genes, but did not affect the mutational variability in any locus tested. Both polymorphisms influenced the methylation status, carriers of OGG1 326Ser/Cys or Ser/Cys+Cys/Cys genotypes demonstrating increased frequency of methylated RUNX3 and ISL1 genes whereas the similar effect of XRCC1 polymorphism concerning methylation of p16 and TIMP3 genes. When dividing the total cohort into groups based on the extent of tumor spread, the observed associations were characteristic of non-muscle invasive BC. Conclusion: The BER gene polymorphisms contributed to modification of key molecular events in urothelial carcinomas. Their mutual effects mainly manifested in non-muscle invasive BC. The underlying mechanisms as well as possible clinical outcomes need to be further explored to propose novel prognostic biomarkers for BC.

New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps

“…Indeed, the frequency of the oncogenic phosphatidylinositol 3-kinase (PIK3CA) mutations was reduced in smokers of heterozygous genotype (Ser/Cys) and minor allele (Cys) carriers. On the contrary, the same polymorphism correlated with an increased frequency of mutations in the RAS loci and affected the levels of runt-related transcription factor 3 (RUNX3) and ISL LIM homeobox 1 (ISL1) methylation (277). In addition, it has been shown that OGG1 Ser326Cys homozygous genotype (Cys/Cys) represents a risk factor for childhood leukaemia ( 278).…”

“…BER polymorphism can affect the methylation status of some tumour suppressor genes, as previously mentioned. For instance, focusing on XRCC1, in a study which considered a cohort of patients with bladder cancer, the XRCC1 Arg399Gln (rs25487) heterozygous (Arg/Gln) genotype increased the frequency of p16 and TIMP3 methylation (277).…”

Link between Base Excision Repair (BER), Reactive Oxygen Species (ROS), and Cancer

“…Similarly, Tayyaba et al showed that such a variant contributes to urothelial bladder carcinoma [44]. In parallel, rs1052133 OGG1 variant was linked to various cancers as breast, colon, stomach, kidney, orolaryngeal, bladder, colorectal cancers, and leukemia [45][46][47][48][49][50]. Rs113561019 OGG1 was suggested as a low penetrance contributor to colorectal cancer [51].…”

The prevalence of DNA base excision repair gene variants among the indigenous Abkhazian population

“…С полиморфизмом в гене OGG1 связывают риски развития многих заболеваний: рака легкого [2], поджелудочной железы [3], молочной железы [4], яичника [5], колоректального рака [6], рака желудка [7], мочевого пузыря [8], щитовидной железы [9], простаты [10], а также нейродегенеративных процессов в мозге, болезни Альцгеймера [11], острой [12] и хронической миелоидной лейкемии [13], диабета 2-го типа [14], рассеянного склероза [15], возрастной катаракты [16], прогрессирования первичной открытоугольной глаукомы [17], мужской инфертильности [18], повышенной смертности от кардиоваскулярных заболеваний [19], тяжести отравления пестицидами [20].…”