UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 from 1.60 (ATM) to 4.88 (MLH1), and mutation carrier rates in cases range from 0.06% (MSH2) to 2.01% (CHEK2).
UNASSIGNED: This study provides statistical evidence for association of previously reported genes and bladder cancer risk and has clinical utility for risk assessment and genetic counselling.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships.
We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher\'s exact tests focusing on mutation type and PTCH1 domains.
PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 × 10-6 ), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion-insertions (p = 4.0 × 10-4 ).
Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships.