2024

Sievänen, Tero

Lynch syndrome (LS) is the most common hereditary cancer syndrome. This thesis explored the associations between circulating microRNAs (c-miRs), lifestyle habits, and the incidence of LS cancer. By utilizing high-throughput sequencing and bioinformatic approaches, the aims of this thesis were to characterize the serum-based c-miR landscape of cancer-free LS carriers to inspect whether any of those c-miRs are potential indicators of upcoming colorectal cancer (CRC), and to determine whether they are associated with modifiable CRC risk factors, such as body mass index and physical activity. Furthermore, this thesis applied retrospective lifestyle questionnaire data to investigate whether longitudinal body weight gain and physical activity are associated with LS cancer risk. It was observed that cancer-free LS carriers (n = 101) displayed aberrant serum c-miR expression compared to the control group (n = 37), but not when compared to sporadic CRC patients (n = 24). A panel composed of these aberrantly expressed c-miRs, including hsa-miR-10b-5p, hsa-miR-19b-3p, hsa-miR-27b-3p, hsa-miR-200a-3p, and hsa-miR-3615, predicted CRC incidence in a prospective analysis. These findings indicated that c-miR profile mirrors early-stage carcinogenesis and may have risk stratification potential during surveillance. The CRC predictive c-miRs did not correlate with either body mass index or physical activity, suggesting that they are associated with LS CRC risk independently of lifestyle habits. However, in the retrospective analysis (n = 465), adulthood weight gain was seen as a cancer risk factor for males, whereas near-term weight was a protective factor for females. Longitudinal physical activity was associated with a decreased overall cancer risk in male LS carriers. Further research is required to validate these findings and to elucidate the complex factors underlying lifestyle and LS cancer.