Author Response: Identifying metabolic features of colorectal cancer liability using Mendelian randomization
Year: 2023
Type: peer-review
Abstract: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development.
Authors: Caroline J. Bull, Emma Hazelwood, Joshua A. Bell, Vanessa Y. Tan, Andrei-Emil Constantinescu, Maria Carolina Borges, Danny N. Legge, Kimberly Burrows, Jeroen R. Huyghe, Hermann Brenner, Sergi Castellví-Bel, Andrew T Chan, Sun-Seog Kweon, Loic Le Marchand, Li Li, Iona Cheng, Rish K. Pai, Jane C. Figueiredo, Neil Murphy, Marc J. Gunter, Nicholas J. Timpson, Emma E. Vincent
Institutions: University of Bristol, MRC Integrative Epidemiology Unit, Fred Hutch Cancer Center, German Cancer Research Center, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Broad Institute, Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, Chonnam National University, Chonnam National University Hwasun Hospital, University of Hawaii Cancer Center, University of Virginia, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Mayo Clinic in Arizona, Cedars-Sinai Medical Center, Centre international de recherche sur le cancer, Imperial College London
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4387700527