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

Autor: Solassol J; Department of Pathology and Oncobiology, Montpellier University Hospital, Montpellier, France.; IRCM Inserm, Montpellier University, Montpellier, France., Larrieux M; Department of Pathology and Oncobiology, Montpellier University Hospital, Montpellier, France., Leclerc J; Department of Biochemistry and Molecular Biology, and Inserm UMR-S, Lille University Hospital, JPA Research Center, Lille University, Lille, France., Ducros V; Department of Pathology and Oncobiology, Montpellier University Hospital, Montpellier, France., Corsini C; Department of Genetics, Montpellier University Hospital, Montpellier, France., Chiésa J; Department of Cytogenetics, Nimes University Hospital, Nîmes, France., Pujol P; Department of Genetics, Montpellier University Hospital, Montpellier, France.; Montpellier University, Montpellier, France., Rey JM; Department of Pathology and Oncobiology, Montpellier University Hospital, Montpellier, France.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2019 Jun; Vol. 40 (6), pp. 716-720.
DOI: 10.1002/humu.23725
Abstrakt: 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.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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