未经证实:为了评估先前报道的单基因基因与膀胱癌风险增加相关,我们回顾了有关基因与膀胱癌风险关联的已发表论文,并在一个基于人群的大型队列中对这些基因进行了确证研究.
UNASSIGNED:首先对2022年6月之前发表的论文进行了系统评价,以确定种系突变与膀胱癌风险相关的所有基因。然后在英国生物库(UKB)的1695例膀胱癌病例和186271例对照中测试了这些候选基因与膀胱癌风险的关联。强大的SKAT-O,一种基于基因的分析,可以正确控制由于病例对照比例不平衡而导致的I型错误率,用于在招募时调整年龄的关联测试,性别,吸烟状况,和遗传背景。
UNASSIGNED:系统评价在至少一项研究中确定了与膀胱癌风险显着相关的9个基因(p<0.05),包括MUTYH,MSH2,MSH6,MLH1,ATM,BRCA2、ERCC5、TGFB1和CHEK2。当致病性/可能的致病性突变聚集在每个基因中时,在p<0.0056时,UKB中的三个基因的相关性得到了证实(9个测试的Bonferroni校正),包括CHEK2,ATM和BRCA2,都已知与遗传性乳腺癌有关。发现了另外两个基因的关联证据,包括MLH1(p=0.006)和MSH2(p=0.007),两者都与Lynch综合征有关.在这五个基因中,膀胱癌的风险范围从1.60(ATM)到4.88(MLH1),病例中的突变携带者率为0.06%(MSH2)至2.01%(CHEK2)。
UNASSIGNED:这项研究为以前报道的基因与膀胱癌风险的关联提供了统计证据,并在风险评估和遗传咨询方面具有临床实用性。
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.