Unique circulating miRNAome signatures captured with distinct molecular states in Lynch syndrome and sporadic colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC), usually termed Lynch syndrome (LS), is the most prevalent hereditary colorectal cancer syndrome, yet molecular biomarkers to differentiate nonmalignant from malignant LS cases remain limited. We performed a secondary analysis of the circulating miRNAome in 155 individuals, including healthy controls (CTRL), nonmalignant LS (H‐LS), cancer‐associated LS (C‐LS), and sporadic colorectal cancer (CRC). We observed that LS variant heterozygotes, especially those without overt cancer, exhibit a transitional miRNAomic architecture distinct from both healthy controls and CRC patients in different age groups. Age‐stratified differential expression and miRNA‐mRNA network analyses revealed distinct regulatory hubs across groups. Group‐specific miRNAs targeted oncogenic, immune, and DNA repair pathways. The analysis suggested that nonmalignant LS variant heterozygotes occupy a circulating miRNAome state distinct from both healthy controls and overt CRC, whereas C‐LS and sporadic CRC shared selected malignant‐associated miRNA features. To assess external concordance, we performed orthogonal validation of a prespecified six‐miRNA panel in the independent GSE30454 primary colorectal tissue cohort, comprising normal, LS, sporadic MSI, and MSS samples. The composite panel preserved disease‐axis structure across the external cohort, with strongest discrimination in biologically relevant mismatch repair‐related contrasts. These findings suggest candidate circulating miRNA molecular states across LS and sporadic colorectal cancer.