Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility ...Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved.Materials and methods:In this 2-stage functional genomics study,we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics,followed by a meta-analysis of gene-level significance p values,to obtain a consensus gene ranking in terms of association with BCa.Subsequently,we performed preranked gene-set enrich-ment analysis to identify the functional pathways involved in BCa genetic susceptibility.Joint analysis with gene-set enrichment analysis,based on somatic alteration frequency,was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa.Results:Other than the well-known BCa genes(such as FGFR3,MYC,TERT,CCNE1,and TP63),we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development,including SETD2,a possible tumor suppressor gene involved in chromatin remodeling.We further demonstrated convergence between genetic associations and somatic alterations at both the gene(eg,FGFR3 and TERT)and pathway levels(eg,cell cycle and chromatin modification),as well as functional ontologies specifically impli-cated in germline predisposition to BCa(eg,CD8/TCR signaling,immune checkpoints,and cytokine signaling).Conclusions:We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the devel-opment of BCa by affecting antitumor immunity,response to toxic exposure,and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.展开更多
基金XM is supported by National Natural Science Foundation of China(82303057)Natural Science Foundation of Hubei Province of China(2023AFB521)+2 种基金“Chutian Scholars Program”of Hubei Province of ChinaMS was supported by the National Natural Science Foundation of China(82373436)the Beijing Hospital Authority’s Youth Program(QML20230114).
文摘Background:Although genetic variants associated with bladder cancer(BCa)risk have been identified through hypothesis-driven and genome-wide association studies,a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved.Materials and methods:In this 2-stage functional genomics study,we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics,followed by a meta-analysis of gene-level significance p values,to obtain a consensus gene ranking in terms of association with BCa.Subsequently,we performed preranked gene-set enrich-ment analysis to identify the functional pathways involved in BCa genetic susceptibility.Joint analysis with gene-set enrichment analysis,based on somatic alteration frequency,was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa.Results:Other than the well-known BCa genes(such as FGFR3,MYC,TERT,CCNE1,and TP63),we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development,including SETD2,a possible tumor suppressor gene involved in chromatin remodeling.We further demonstrated convergence between genetic associations and somatic alterations at both the gene(eg,FGFR3 and TERT)and pathway levels(eg,cell cycle and chromatin modification),as well as functional ontologies specifically impli-cated in germline predisposition to BCa(eg,CD8/TCR signaling,immune checkpoints,and cytokine signaling).Conclusions:We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the devel-opment of BCa by affecting antitumor immunity,response to toxic exposure,and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.
