Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

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...

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Autores principales:	Atocha Romero, Pilar Garre, Olivia Valentin, Julian Sanz, Pedro Pérez-Segura, Patricia Llovet, Eduardo Díaz-Rubio, Miguel de la Hoya, Trinidad Caldés
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c1bb200b181548ddadf730270d7d0024
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spelling	oai:doaj.org-article:c1bb200b181548ddadf730270d7d00242021-11-18T08:55:51ZFrequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.1932-620310.1371/journal.pone.0072195https://doaj.org/article/c1bb200b181548ddadf730270d7d00242013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24039744/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Large 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.Atocha RomeroPilar GarreOlivia ValentinJulian SanzPedro Pérez-SeguraPatricia LlovetEduardo Díaz-RubioMiguel de la HoyaTrinidad CaldésPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e72195 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atocha Romero Pilar Garre Olivia Valentin Julian Sanz Pedro Pérez-Segura Patricia Llovet Eduardo Díaz-Rubio Miguel de la Hoya Trinidad Caldés Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
description	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.
format	article
author	Atocha Romero Pilar Garre Olivia Valentin Julian Sanz Pedro Pérez-Segura Patricia Llovet Eduardo Díaz-Rubio Miguel de la Hoya Trinidad Caldés
author_facet	Atocha Romero Pilar Garre Olivia Valentin Julian Sanz Pedro Pérez-Segura Patricia Llovet Eduardo Díaz-Rubio Miguel de la Hoya Trinidad Caldés
author_sort	Atocha Romero
title	Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
title_short	Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
title_full	Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
title_fullStr	Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
title_full_unstemmed	Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.
title_sort	frequency and variability of genomic rearrangements on msh2 in spanish lynch syndrome families.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/c1bb200b181548ddadf730270d7d0024
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Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families.

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