Identification of the Lynch syndrome and Lynch-like syndrome specific somatic mutations in microsatellite instability-high colorectal cancer cases.

purposeLynch syndrome (LS), the most common hereditary colorectal cancer (CRC), is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite instability-high (MSI-H) tumors. Lynch-like syndrome (LL) exhibits MSI-H and MMR deficiency, but lacks identifiable germline MMR mutations. Although LS/LL CRCs share clinical and molecular features, they are distinct from sporadic MSI-H (SM) CRCs, emphasizing the need for refined molecular classification. This study investigated the somatic alterations that distinguish LS/LL CRC from SM CRC.

methodsWhole-exome sequencing (WES) was performed on 49 LS/LL CRC and 96 SM CRC samples. Tumor-normal paired data were analyzed using GATK and MuTect2 to detect somatic variants. Mutation frequencies were compared using Fisher's exact test (p < 0.005). Logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate the discriminatory performance.

resultsWe identified 11 gene regions that were significantly enriched in LS/LL CRC, including KRAS, ITGB3BP, CLEC16A, ARHGEF28, PIK3CA, and RBM26. A variant panel based on these alterations showed an area under the curve (AUC) of 0.85 and an Akaike information criterion of 129.81.

conclusionsThese findings support the utility of LS/LL-specific somatic variants in stratifying MSI-H CRCs and identifying hereditary cases for personalized management.