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Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype.
Cancer Prev Res (Phila). 2011 Oct; 4(10):1546-55.CP

Abstract

It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.

Authors+Show Affiliations

Cancer Genetics Laboratory, IBGM-CSIC, University of Valladolid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21778331

Citation

Pérez-Cabornero, Lucia, et al. "Characterization of New Founder Alu-mediated Rearrangements in MSH2 Gene Associated With a Lynch Syndrome Phenotype." Cancer Prevention Research (Philadelphia, Pa.), vol. 4, no. 10, 2011, pp. 1546-55.
Pérez-Cabornero L, Borrás Flores E, Infante Sanz M, et al. Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype. Cancer Prev Res (Phila). 2011;4(10):1546-55.
Pérez-Cabornero, L., Borrás Flores, E., Infante Sanz, M., Velasco Sampedro, E., Acedo Becares, A., Lastra Aras, E., Cuevas González, J., Pineda Riu, M., Ramón y Cajal Asensio, T., Capellá Munar, G., Miner Pino, C., & Durán Domínguez, M. (2011). Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype. Cancer Prevention Research (Philadelphia, Pa.), 4(10), 1546-55. https://doi.org/10.1158/1940-6207.CAPR-11-0227
Pérez-Cabornero L, et al. Characterization of New Founder Alu-mediated Rearrangements in MSH2 Gene Associated With a Lynch Syndrome Phenotype. Cancer Prev Res (Phila). 2011;4(10):1546-55. PubMed PMID: 21778331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype. AU - Pérez-Cabornero,Lucia, AU - Borrás Flores,Ester, AU - Infante Sanz,Mar, AU - Velasco Sampedro,Eladio, AU - Acedo Becares,Alberto, AU - Lastra Aras,Enrique, AU - Cuevas González,Jorge, AU - Pineda Riu,Marta, AU - Ramón y Cajal Asensio,Teresa, AU - Capellá Munar,Gabriel, AU - Miner Pino,Cristina, AU - Durán Domínguez,Mercedes, Y1 - 2011/07/21/ PY - 2011/7/23/entrez PY - 2011/7/23/pubmed PY - 2012/2/3/medline SP - 1546 EP - 55 JF - Cancer prevention research (Philadelphia, Pa.) JO - Cancer Prev Res (Phila) VL - 4 IS - 10 N2 - It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns. SN - 1940-6215 UR - https://www.unboundmedicine.com/medline/citation/21778331/Characterization_of_new_founder_Alu_mediated_rearrangements_in_MSH2_gene_associated_with_a_Lynch_syndrome_phenotype_ L2 - http://cancerpreventionresearch.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21778331 DB - PRIME DP - Unbound Medicine ER -