Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort

Abstract

Objectives: To evaluate which of previously reported monogenic genes are associated with increased bladder cancer risk, we reviewed published papers on associations of genes and bladder cancer risk and performed a confirmation study of these genes in a large population-based cohort. Subjects and methods:A systematic review of published papers prior to June 2022 was performed first to identify all genes where germline mutations were associated with bladder cancer risk. The associations of these candidate genes with bladder cancer risk were then tested among 1695 bladder cancer cases and 186 271 controls in the UK Biobank (UKB). The robust SKAT-O, a gene-based analysis that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, smoking status, and genetic background.Results: The systematic review identified nine genes that were significantly associated with bladder cancer risk in at least one study (p < 0.05), including MUTYH, MSH2, MSH6, MLH1, ATM, BRCA2, ERCC5, TGFB1 and CHEK2. When pathogenic/ likely pathogenic mutations were aggregated within each gene, the association was confirmed for three genes in the UKB at p < 0.0056 (Bonferroni correction for nine tests), including CHEK2, ATM and BRCA2, all also known to be associated with hereditary breast cancer. Suggestive evidence of association was found for two other genes, including MLH1 (p = 0.006) and MSH2 (p = 0.007), both known to be associated with Lynch syndrome. Among these five genes, the bladder cancer risks range Abrar Mian and Jun Wei contributed equally to this work.

Metabolic changes preceding bladder cancer occurrence among Korean men: a nested case-control study from the KCPS-II cohort

“…It was challenging to undertake replication analysis utilizing the UK Biobank (UKBB), a representative European ethnic cohort, in the current study. A review of papers on BLCA biomarkers using the UKBB [ 46 – 48 ] revealed no matching results on SNP identified in our investigation, and no BLCA-metabolome studies based on UKBB were found. Consequently, our findings could be confined to this population; further studies on other races are needed.…”

Incidental Pathogenic Variants in Renal Cell and Urothelial Carcinoma: Is It Time for Universal Screening?

“…It is important to note that this is not a population-based study, and the homogenous nature of the patients affects the generalizability of the results. Mian et al 16 took this analysis further by identifying the PVs significantly associated with bladder cancer risk. In their results, CHEK2, ATM, and BRCA2 were most frequently implicated, as well as MLH1 and MSH2.…”

“…In their results, CHEK2, ATM, and BRCA2 were most frequently implicated, as well as MLH1 and MSH2. 16 In a similar study by Carlo et al, 17 586 patients with advanced UC were prospectively sequenced to identify PVs. A total of 80 patients (14%) showed moderate to high-penetrance actionable PV in BRCA2 (n 5 9), MSH2 (n 5 8), BRCA1 (n 5 8), CHEK2 (n 5 6), ERCC3 (n 5 4), and NBN and RAD50 (n 5 3).…”