Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, ON, Canada.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia.
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- University of Hawaii Cancer Center, Honolulu, HI, USA.
- Preventative Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Epidemiology, University of Washington, Seattle, WA, USA.
BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations.
METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines.
RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166.
CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
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