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

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-30
DOI
https://doi.org/10.1038/s41467-025-60275-6
Citations
3
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
4.41

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article

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

Dylan M. Glubb, Andrei‐Emil Constantinescu, Tom G. Richardson, Matthew A. Lee et al.
3 citations
Nature Communications
Genetic factors in colorectal cancer
4.41
article

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

Dylan M. Glubb, Andrei‐Emil Constantinescu, Tom G. Richardson, Matthew A. Lee, Jane C. Figueiredo, Pik Fang Kho, Jeroen R. Huyghe, Michael O. Woods, Loı̈c Le Marchand, Rish K. Pai, Neil Murphy, Xue Min Wang, Andrew T. Chan, Stephen B. Gruber, Daffodil M. Canson, Stephanie L. Schmit, Marc J. Gunter, Tracy A. O’Mara, Jochen Hampe, Emma E. Vincent, Vicki Whitehall, Emma Hazelwood, Danny Legge, Wei Zheng, D. Timothy Bishop, Benedita Deslandes
article en
3 citations

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.

Nature CommunicationsVol. 16(1)
Broad Institute (US), University of Hawaiʻi at Mānoa (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), City Of Hope National Medical Center (US), Queensland Health (AU), Memorial University of Newfoundland (CA), University of Leeds (GB), Cleveland Clinic (US), University of Hawaii System (US), Harvard University (US), The University of Queensland (AU), QIMR Berghofer Medical Research Institute (AU), University of Bristol (GB), Cleveland Clinic Lerner College of Medicine (US), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), Cancer Center of Hawaii (US), Mayo Clinic in Arizona (US), MRC Epidemiology Unit (GB), Centre international de recherche sur le cancer (FR), University of Hawaii Cancer Center, Imperial College London (GB), Technische Universität Dresden (DE), Vanderbilt University Medical Center (US), Stanford University (US)
U.S. Department of Health and Human Services, European Association for Cancer Research, Wellcome, Fred Hutchinson Cancer Research Center, Wellcome Trust, Cancer Research UK, Harold Hyam Wingate Foundation, University of Bristol, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, Office of Research Infrastructure Programs, National Institutes of Health
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Openalex Percentile: Top 6%
Genetic factors in colorectal cancer
4.41
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