A 3′ untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma

Abstract

Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.79-7.06] and XPC rs2228001 (OR = 2.38, 95% CI = 1.43-3.94) with UBC. In stratified analysis with respect to smoking status, OGG1 rs2304277 and XPC rs2228001 exhibited increased risk in smokers [(rs2304277 OR = 4.96, 95% CI = 1.51-16.30) (rs2228001 OR = 2.19, 95% CI = 1.02-4.72)] as well as nonsmokers [(rs2304277 OR = 2.95, 95% CI = 1.26-6.90) (rs2228001 OR = 2.57, 95% CI = 1.31-5.04)]. These polymorphisms were also associated with both low-grade [(rs2304277 OR = 3.73, 95% CI = 1.72-8.09) (rs2228001 OR = 2.18, 95% CI = 1.21-3.92)] and high-grade tumors [(rs2304277 OR = 3.45, 95% CI = 1.52-7.80) (rs2228001 OR = 2.81, 95% CI = 1.48-5.33)] as well as with non-muscle-invasive bladder cancer [(rs2304277 OR = 4.03, 95% CI = 1.87-8.67) (rs2228001 OR = 2.14, 95% CI = 1.20-3.81)] and muscle-invasive bladder cancer [(rs2304277 OR = 3.06, 95%CI = 1.31-7.13) (rs2228001 OR = 2.95, 95%CI = 1.51-5.75)]. This is the first study on DNA repair gene polymorphisms and UBC in the Pakistani population. It identifies OGG1 rs2304277 and replicates XPC rs2228001 as significant modulators of UBC susceptibility.

Systematic Review: Genetic Associations for Prognostic Factors of Urinary Bladder Cancer

“…For this review, 373 full-text articles were evaluated in depth, resulting in a final set of 112 articles for further summary (Figure 1). In total, 316 associations were extracted across all investigated outcomes as follows: age (N = 12 11-22 ), stage (N = 79 11,13,18,20,23-66 ), tumor size (N = 2 67,68 ), grade (N = 49 11,18,27,29,32,33,35…”

“…As for MIBC, most studies have defined the primary outcome as T2+ staged tumors. 11,20,23-32,34-57 However, some associations have been reported for a merged group of T2+ and T1 stages. 33,34…”

“…Broadly, we have differentiated between stages corresponding to NMIBC and MIBC cases. For studies reporting on NMIBC, the following endpoints were used: tumors of Tis, 61,65 T1, 37 Ta + T1, 13,18,36,39,54,58,[62][63][64]66 and Ta + T1 + Tis 32,59,60 (Supplementary Table 4). As for MIBC, most studies have defined the primary outcome as T2+ staged tum ors.…”

“…33,34 Most reports on grade can be roughly categorized into containing either low-or high-grade UBC cases. Low-grade UBC definitions were as follows: G1, 18,54,62,70 G2, 35,58,62,70 G1 + G2, 36 low-grade, 69,71 and G1 + G2 + papilloma. 32 High-grade UBC was usually defined as grade 3 UBC, 11,27,29,32,36,37,47,50,67,70,[72][73][74][75] a combination of G2 and G3 NMIBC, 54,66 and some studies have reported estimates for grade 4 tumors, without a reference for the grading system used (G3 + G4 42 and G2 + G3 + G4) 33 (Supplementary Table 5).…”

“…OGG1 was the most commonly reported gene, having been associated with patient age, 19 tumor stage, 54 grade, 54 recurrence, 40,78 and risk group. 40 Associations on OGG1 and UBC did not cluster within a clearly defined subgroup and instead showed relationships with various characteristics: increased age at diagnosis (>65 years) 19 and elevated risks of the following: non-muscle-invasive and invasive UBC, 54 low-and high-grade tumors, 54 rate of recurrence, 40,78 and high-risk tumors. 40 A set of 2 genes (TP53 and MDM2) have also been reported for multiple endpoints, specifically UBC grade, 42,69 stage, 25,41,42 recurrence, 25,69,101 survival, 101,117 and risk group.…”