Dataset Information

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.

ABSTRACT: 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. 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. 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. 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.

SUBMITTER: Caputo SM

PROVIDER: S-EPMC8268747 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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5' Region Large Genomic Rearrangements in the <i>BRCA1</i> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints.

Caputo Sandrine M SM Telly Dominique D Briaux Adrien A Sesen Julie J Ceppi Maurizio M Bonnet Françoise F Bourdon Violaine V Coulet Florence F Castera Laurent L Delnatte Capucine C Hardouin Agnès A Mazoyer Sylvie S Schultz Inès I Sevenet Nicolas N Uhrhammer Nancy N Bonnet Céline C Tilkin-Mariamé Anne-Françoise AF Houdayer Claude C Moncoutier Virginie V Andrieu Catherine C French Covar Group Collaborators Bièche Ivan I Stern Marc-Henri MH Stoppa-Lyonnet Dominique D Lidereau Rosette R Toulas Christine C Rouleau Etienne E

Cancers 20210625 13

<h4>Background</h4>Large genomic rearrangements (LGR) in <i>BRCA1</i> 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.<h4>Methods</h4>DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridi ...[more]

PMID: 34202044

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Project description:BackgroundBoth recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations. The current study was aimed at establishing the mutation spectrum of BRCA1/2 in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families.MethodsThe original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the BRCA1/2 screening were: (i) probands with at least two first degree relatives with breast and ovarian cancer; (ii) probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii) individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family.ResultsProbands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A BRCA1/2 mutation was found in 56 (39%). Two novel large deletions covering consecutive exons of BRCA1 were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the BRCA1 gene and IVS16-2A>G in the BRCA2 gene). The IVS16-2A>G in the BRCA2 gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the BRCA1/2 positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of the cryptic cysteine residues of the BRCA1 Ring Finger domain.ConclusionA high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate BRCA1/2 mutation screening in Slovenian families.

Dataset Information

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.

Publications

5' Region Large Genomic Rearrangements in the <i>BRCA1</i> Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints.

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