title: Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
abstract: Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.
authors.affiliation: Molecular Oncology Laboratory, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
authors.forename: Atocha
authors.initials: A
authors.lastname: Romero
authors.forename: Pilar
authors.initials: P
authors.lastname: Garre
authors.forename: Olivia
authors.initials: O
authors.lastname: Valentin
authors.forename: Julian
authors.initials: J
authors.lastname: Sanz
authors.forename: Pedro
authors.initials: P
authors.lastname: Pérez-Segura
authors.forename: Patricia
authors.initials: P
authors.lastname: Llovet
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D056905:Chromosome Breakpoints; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013030:Spain; D014178:Translocation, Genetic
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
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