Sex-Based Differences in Circulating microRNA and Metabolite Signatures Associated with Physical Activity in Lynch Syndrome Carriers

Lynch syndrome (LS) carriers face a high cancer risk, especially colorectal cancer. Although physical activity (PA) is known to reduce cancer risk in LS, it remains unclear whether this protective effect varies by sex and which molecular mechanisms underlie it. This study aimed to use an integrated omics approach to examine molecular mechanisms associated with PA in LS, focusing on sex-specific differences and links to cancer-related processes. We profiled serum sample-based circulating microRNAs (c-miRNA) by Illumina sequencing and quantified metabolites using targeted nuclear magnetic resonance-based metabolomics from 93 Finnish LS carriers. PA levels were assessed by questionnaire. Bioinformatics approaches, such as principal coordinates analysis, weighted correlation network analysis, and overrepresentation analysis, identified molecular mechanisms associated with PA and links to cancer-related mechanisms. In addition, a short submaximal exercise bout was conducted to examine acute miRNA responses. We observed sex-based differences in PA-associated c-miRNAs and metabolites. In females, PA was linked to lipid metabolism. In males, miRNAs negatively correlated with PA are associated with distinct cancers, regulating pathways involved in cell growth, apoptosis, transcription, senescence, and the cell cycle. Four PA-associated miRNAs (hsa-miR-885-3p, hsa-miR-483-5p, hsa-miR-374a-5p, and hsa-miR-301a-3p) strongly correlated with metabolites related to lipid and fatty acid metabolism and inflammation, with correlation patterns differing by sex. The expression of these miRNAs changed after acute exercise. Our findings highlight the importance of considering sex as a biological factor in PA-based cancer prevention strategies for LS and provide novel insights into underlying molecular mechanisms. PREVENTION RELEVANCE: Understanding how protective lifestyle factors, particularly PA, shape molecular responses in LS carriers may reveal new avenues for cancer risk reduction.