Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes

Emma Hazelwood, Daffodil M. Canson, Benedita Deslandes, Xuemin Wang, Pik Fang Kho, Danny Legge, Andrei-Emil Constantinescu, Matthew A. Lee, D. Timothy Bishop, Andrew T. Chan, Stephen B. Gruber, Jochen Hampe, Loic Marchand, Michael O. Woods, Rish K. Pai, Stephanie L. Schmit, Jane C. Figueiredo, Wei Zheng, Jeroen R. Huyghe, Neil Murphy, Marc J. Gunter, Tom G. Richardson, Vicki L. J. Whitehall, Emma E. Vincent, Dylan M. Glubb and Tracy A. O’Mara ()
Additional contact information
Emma Hazelwood: University of Bristol
Daffodil M. Canson: QIMR Berghofer
Benedita Deslandes: University of Bristol
Xuemin Wang: QIMR Berghofer
Pik Fang Kho: Stanford University School of Medicine
Danny Legge: University of Bristol
Andrei-Emil Constantinescu: University of Bristol
Matthew A. Lee: WHO
D. Timothy Bishop: University of Leeds
Andrew T. Chan: Massachusetts General Hospital and Harvard Medical School
Stephen B. Gruber: City of Hope National Medical Center
Jochen Hampe: Technische Universität Dresden (TU Dresden)
Loic Marchand: University of Hawaii Cancer Center
Michael O. Woods: Discipline of Genetics
Rish K. Pai: Arizona
Stephanie L. Schmit: Cleveland Clinic
Jane C. Figueiredo: Cedars-Sinai Medical Center
Wei Zheng: Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center
Jeroen R. Huyghe: Fred Hutchinson Cancer Center
Neil Murphy: WHO
Marc J. Gunter: WHO
Tom G. Richardson: University of Bristol
Vicki L. J. Whitehall: QIMR Berghofer Medical Research Institute
Emma E. Vincent: University of Bristol
Dylan M. Glubb: QIMR Berghofer
Tracy A. O’Mara: QIMR Berghofer

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS. Most likely causal genes with evidence of cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. Notably, SEMA4D, encoding a protein targeted by an investigational CRC therapy, emerges as a key risk gene. We also identify a female-specific association with CRC risk for CCM2 expression and subsite-specific associations, including LAMC1 with rectal cancer risk. These findings offer valuable insights into CRC molecular mechanisms and support promising therapeutic avenues.

Date: 2025
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DOI: 10.1038/s41467-025-60275-6

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