Whole-exome analysis of Lynch-like syndrome cases

Aim: to identify new genetic causes of lynch-like syndrome (LLS), a hereditary tumor syndrome characterized by the development of neoplasms with high microsatellite instability (MSI-H) and the absence of mutations in known Lynch syndrome genes.

Material and Methods. The study included 18 cases of MSI-H colorectal cancer (CRC), endometrial cancer (EC), and gastric cancer (GC) in young patients without mutations in the MLH1, MSH2 (EPCAM), MSH6, and PMS2 genes. Whole-exome sequencing was performed on DNA from patients’ peripheral blood samples.

Results. At least one pathogenic or potentially significant/candidate genetic variant was detected in all cases (77 variants total). Most patients carried a combination of several potentially significant variants. The most significant finding was the identification of a FAN1 gene variant of uncertain significance (VUS) co-occurring with an EXO1 gene mutation in a young patient with MSI-H CRC. Digenic inheritance involving these two functionally related genes had been previously proposed as a hypothetical mechanism for LLS. Another case of presumed digenic inheritance was identified: co-occurrence of two VUS in the TP63 and TP73 genes, both predicted to be functionally significant by bioinformatics tools. A number of VUS and pathogenic/ likely pathogenic (P/LP) variants were found in candidate CRC genes: LRP1 (n=2), HECW1, PSME4, APCDD1, HIC1, CDK18, SMAD6, ZNRF3, WIF1, WNK2, RBBP8NL, MAP1LC3A. Several new candidate CRC genes are proposed: ST6GALNAC1, TGFB1I1, TGFB1, PTPRD, NUDCD2, WIF1, STAG3, NFATC2, HNF4G. Seventeen out of 77 potentially significant variants were heterozygous VUS or P/ LP variants in DNA repair genes: ABRAXAS1 (P/LP), FANCD2, BLM (P/LP), CHEK2 (hypomorphic mutation), RECQL4, BRIP1, ERCC2, ERCC3, XPC (P/LP), MUTYH (P/LP), UNG, REV3L, PARP1, PARP3, LIG1.

Conclusion. Whole-exome sequencing enabled the detection of potentially significant genetic variants in the studied patients. Verification of the clinical significance of the candidate genes and variants will be possible as epidemiological data continues to accumulate.

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