Affiliation: | 1. Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland;2. Department of Education and Research, Central Finland Health Care District, Jyväskylä, Finland;3. Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland;4. Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland;5. Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland;6. Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;7. Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland;8. Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland Applied Tumor Genomics Research Program, University of Helsinki, Helsinki, Finland |
Abstract: | Circulating microRNAs (c-miRs) are small noncoding RNA molecules that migrate throughout the body and regulate gene expression. Global c-miR expression patterns (c-miRnomes) change with sporadic carcinogenesis and have predictive potential in early detection of cancers. However, there are no studies that have assessed whether c-miRnomes display similar potential in carriers of inherited pathogenic mismatch-repair gene variants (path_MMR), known as Lynch syndrome (LS), who are predisposed to highly increased cancer risk. Using high-throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c-miRnomes of path_MMR carriers, sporadic rectal cancer patients and non-LS controls. We showed for the first time that cancer-free path_MMR carriers have a systemic c-miRnome of 40 differentially expressed c-miRs that can distinguish them from non-LS controls. The systemic c-miRnome of cancer-free path_MMR carriers also resembles the systemic c-miRnomes of cancer patients with or without path_MMR. Our pathway analysis linked the found differentially expressed c-miRs to carcinogenesis. A total of 508 putative target genes were identified for 32 out of 40 differentially expressed c-miRs, and 238 of them were enriched in cancer-related pathways. The most enriched c-miR-target genes include well-known oncogenes and tumor suppressor genes such as BCL2, AKT3, PIK3CA, KRAS, NRAS, CDKN1A and PIK3R1. Taken together, our findings suggest that LS and sporadic carcinogenesis share common biological pathways and alterations in these pathways can produce a c-miR signature which can track potential oncogenic stress in cancer-free path_MMR carriers. Therefore, c-miRs hold potential in monitoring the LS risk stratification patterns during clinical surveillance or cancer management. |