Gene and pathway analysis of genome-wide genetic associations of bladder cancer

Abstract

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 enrichment 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 implicated 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 development 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.

Keywords

Bladder cancer / Genetic susceptibility / Genome-wide association studies / Functional annotation / Pathway analysis

Acknowledgments

We appreciate the National Human Genome Research Institute for making GWAS data publicly available and the TCGA working group for sharing genetic data of BCa patients. We also acknowledged the National Natural Science Foundation of China, the Natural Science Foundation of Hubei Province of China, and the Beijing Hospital Authority for the funding.

Statement of ethics

Not applicable.

Conflict of interest statement

No conflict of interest has been declared by the authors.

Funding source

XM is supported by National Natural Science Foundation of China (82303057), Natural Science Foundation of Hubei Province of China (2023AFB521), and “Chutian Scholars Program” of Hubei Province of China. MS was supported by the National Natural Science Foundation of China (82373436) and the Beijing Hospital Authority’s Youth Program (QML20230114).

Author contributions

XM, MS, XX, QW: Methodology;

XM, MS: Collection of the data, investigation;

XM: Code;

XM, MJS, XX: Writing—original draft preparation;

QW, MS: Writing—review and editing;

All authors have read and agreed to the published version of the manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

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