Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome

Abstract

Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch‐like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. We report a family first classified as having LLS by Sanger sequencing analysis. Next‐generation sequencing (NGS) analysis identified an AluY5a insertion in MLH1 exon 6 that led to exon skipping. This splicing alteration inducing a pathogenic frameshift was found in patients who developed colorectal adenocarcinomas. Retroelement insertion might thus be an important but underestimated mechanism of cancer genetics that could be systematically tested in patients with a phenotype suggesting LS to accurately assess family risk and surveillance approaches.

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…However only this specific inversion is detected with these probes, and paracentric inversions involving other regions of MSH2 are not [196]. Insertions of Alu elements, such as the ones reported in the coding sequence of MSH2 [202] or MLH1 [188,203], are another type of SV that are not easily detected.…”

Identification and Characterization of New Alu Element Insertion in the BRCA1 Exon 14 Associated with Hereditary Breast and Ovarian Cancer

“…To our knowledge, this is the first report of an Alu insertion in exon 14 of BRCA1. Several cases of Alu insertion in cancer predisposition genes have been reported in the literature, most of which are pathogenic due to their effect on splicing [7,9,10]. Exons 11 of BRCA1 and BRCA2 showed a higher Alu insertion ratio than other cancer predisposition genes' exons, which may be explained by their large sequence sizes [8].…”

“…The detection of Alu insertion is difficult by sanger sequencing and often requires specific PCR conditions [9]. Recently, next generation sequencing (NGS) technologies with high coverage uniformity throughout the entire target region has emerged as a powerful tool to detect Alu insertion [10,11]. SOPHiA DDM ® platform incorporates an original bioinformatics module that is able to detect some complex variants such as long Indels, CNVs, and Alu insertions from NGS data generated by SOPHiA Genetics' Hereditary Cancer Solution (HCS) kit.…”

Insertion of an SVA element in MSH2 as a novel cause of Lynch syndrome

“…To date, 4015 unique mutations detected in the four MMR genes ( MLH1 , MSH2 , MSH6 , and PMS2 ) have been recorded in MMR genes in the Human Genome Mutation database (HGMD Professional 2020.4). Eleven (11) gross insertions larger than 20 base pairs (bp) have been reported, and five of these large insertions involved retrotransposons, four of which were Alu insertions with two in each of the MLH1 20,21 and MSH2 genes 22,23 and one was an SVA insertion in PMS2 9 . Up to now, no SVA insertion has been reported in MSH2 .…”