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EPCAM germline and somatic rearrangements in lynch syndrome: identification of a novel 3′ EPCAM deletion
Author(s) -
Spaepen Marijke,
Neven Esther,
Sagaert Xavier,
De Hertogh Gert,
Beert Eline,
Wimmer Katharina,
Matthijs Gert,
Legius Eric,
Brems Hilde
Publication year - 2013
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22080
Subject(s) - epithelial cell adhesion molecule , msh2 , lynch syndrome , germline mutation , biology , mlh1 , msh6 , genetics , microbiology and biotechnology , germline , cancer research , dna mismatch repair , mutation , colorectal cancer , gene , cancer
3′ EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3′ EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis . A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3′ EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556‐531_*872del) and one known EPCAM deletion (c.859‐689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM‐MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI‐high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM , MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM‐MSH2 region in the other tumor. This indicates that hemi‐ and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors. © 2013 Wiley Periodicals, Inc.