Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

Abstract

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as MUTYH and ATM. Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene POLN and other cancer-related genes such as PPARG, CTC1, DCC and ALPK1. Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.

Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome

“…Whole exome sequencing identified germline pathogenic/likely pathogenic variants in DNA repair genes, such as MCM8 , MCM9, WRN , MCPH1, BARD1 , REV3L , EXO1, POLD1 , RFC1 , RPA1, ATM, and MLH3 . In addition, other cancer-related genes, such as PPARG , CTC1 , DCC and ALPK, were identified as candidate genes for LLS [ 13 , 37 – 39 ].…”

Bacterial ADP-heptose initiates a revival stem cell program in the intestinal epithelium

“…Indeed, genotoxic microorganisms (including colibactin-expressing Escherichia coli 19 and Fusobacterium nucleatum 20 ) are frequently found within the class of Gram-negative bacteria that produce ADP-Hep. Interestingly, mutations in ALPK1 were associated with Lynch-like syndrome, in which patients meet the clinical criteria for Lynch syndrome (the most common cause of hereditary colorectal cancer (CRC)) but do not present with typical mutations in DNA mismatch repair genes 21 . Moreover, ALPK1 expression was found to be reduced in CRC tumours as compared to normal adjacent tissue, suggesting that it acts as a tumour suppressor in CRC 22 .…”

The Role of Microbiota-Derived Metabolites in Colorectal Cancer

“…In host cells, ADP-heptose is recognized by the cytosolic alpha-kinase 1 (ALPK1) receptor, which initiates a signaling cascade via TIFA and TRAF2/6 to activate the pro-inflammatory transcription factor NF-κB [130]. In addition to pro-inflammatory signaling, ALPK1 activation and mutations have also been linked to the development of tumors [133][134][135][136][137]. For example, F. nucleatum abundance is correlated with ALPK1 expression in CRC tissues, which is further correlated with lower survival rates in these patients [133].…”