title: Frequency of rearrangements in Lynch syndrome cases associated with MSH2: characterization of a new deletion involving both EPCAM and the 5' part of MSH2.
abstract: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3' end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation-dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3' end region of EPCAM to the 5' initial sequences of the MSH2 (c.859-1860_MSH2:646-254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome.
authors.affiliation: Cancer Genetics Laboratory, Instituto de Biología y Genética Molecular, University of Valladolid, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pérez-Cabornero
authors.forename: Mar
authors.initials: M
authors.lastname: Infante Sanz
authors.forename: Eladio
authors.initials: E
authors.lastname: Velasco Sampedro
authors.forename: Enrique
authors.initials: E
authors.lastname: Lastra Aras
authors.forename: Alberto
authors.initials: A
authors.lastname: Acedo Becares
authors.forename: Cristina
authors.initials: C
authors.lastname: Miner Pino
authors.forename: Mercedes
authors.initials: M
authors.lastname: Durán Domínguez
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D056905:Chromosome Breakpoints; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D015321:Gene Rearrangement; D018095:Germ-Line Mutation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D012333:RNA, Messenger; D004247:DNA; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein