scholarly journals Large genomic rearrangements and germline epimutations in Lynch syndrome

2009 ◽  
Vol 124 (10) ◽  
pp. 2333-2340 ◽  
Author(s):  
Annette Gylling ◽  
Maaret Ridanpää ◽  
Outi Vierimaa ◽  
Kristiina Aittomäki ◽  
Kristiina Avela ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Genomic Rearrangements ◽  
Large Genomic Rearrangements

scholarly journals Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Francesca Duraturo ◽  
Angela Cavallo ◽  
Raffaella Liccardo ◽  
Bianca Cudia ◽  
Marina De Rosa ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Germ Line ◽  
Point Mutations ◽  
Low Frequency ◽  
Genomic Rearrangements ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Large Genomic Rearrangements ◽  
Large Deletions ◽  
Long Range Pcr

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainlyMLH1andMSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in theMLH1andMSH2genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in theMLH1,MSH2, andMSH6genes. We identified a large novel deletion in theMSH2gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement withinMSH2gene and showed that large deletions or duplications inMLH1andMSH2genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

scholarly journals 5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3171
Author(s):  
Sandrine M. Caputo ◽  
Dominique Telly ◽  
Adrien Briaux ◽  
Julie Sesen ◽  
Maurizio Ceppi ◽  
...  
Keyword(s):  
Brca1 Gene ◽  
Genomic Rearrangements ◽  
Comparative Genomic ◽  
Homologous Region ◽  
Exon 2 ◽  
Large Genomic Rearrangements ◽  
Causality Score ◽  
Frequent Site ◽  
First Time ◽  
Intron 2

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

Novel BRCA1 Large Genomic Rearrangements in Italian Breast/Ovarian Cancer Patients

2018 ◽  
Vol 23 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Roberta Rizza ◽  
Karl Hackmann ◽  
Ida Paris ◽  
Angelo Minucci ◽  
Rossella De Leo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Genomic Rearrangements ◽  
Large Genomic Rearrangements

scholarly journals Simultaneous detection of BRCA mutations and large genomic rearrangements in germline DNA and FFPE tumor samples

Oncotarget ◽  
2016 ◽  
Vol 7 (38) ◽  
pp. 61845-61859 ◽  
Author(s):  
Márton Zsolt Enyedi ◽  
Gábor Jaksa ◽  
Lajos Pintér ◽  
Farkas Sükösd ◽  
Zoltán Gyuris ◽  
...  
Keyword(s):  
Simultaneous Detection ◽  
Genomic Rearrangements ◽  
Brca Mutations ◽  
Large Genomic Rearrangements ◽  
Ffpe Tumor

Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome

2020 ◽  
Vol 57 (7) ◽  
pp. 487-499
Author(s):  
Qing Wang ◽  
Julie Leclerc ◽  
Gaëlle Bougeard ◽  
Sylviane Olschwang ◽  
Stéphanie Vasseur ◽  
...  
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Founder Effect ◽  
Predictive Value ◽  
Haplotype Analysis ◽  
Genomic Rearrangements ◽  
Colorectal Cancers ◽  
Amsterdam Criteria ◽  
Insight Into

BackgroundHeterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.MethodsWe report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.ResultsGenomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.ConclusionOur results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

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