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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2016

Open Access 01-12-2016 | Research article

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

Authors: Giulia Cini, Massimo Mezzavilla, Lara Della Puppa, Elisa Cupelli, Alessio Fornasin, Angela Valentina D’Elia, Riccardo Dolcetti, Giuseppe Damante, Sara Bertok, Gianmaria Miolo, Roberta Maestro, Paolo de Paoli, Antonio Amoroso, Alessandra Viel

Published in: BMC Medical Genetics | Issue 1/2016

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Abstract

Background

About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions. In some populations, especially if relatively isolated, a few number of recurrent mutations is reported, sometimes caused by founder effect.

Methods

BRCA1 and BRCA2 screening for mutations was carried out on 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing. Haplotype analysis was performed on the probands carrying recurrent mutations and their relatives, using two sets of microsatellite markers covering the BRCA1 (D17S588, D17S806, D17S902, D17S1325, D17S855, D17S1328, D17S800, and D17S250) and BRCA2 (D13S220, D13S267, D13S171, D13S1701, D13S1698, D13S260, D13S290, D13S1246) loci. The DMLE + 2.2 software was used to estimate the age of BRCA1 c.676delT and BRCA2 c.7806-2A > G. A multiplex PCR and two different primer extension assays were optimized and used for genotyping the recurrent mutations of the two genes.

Results

In the time frame of almost 20 years of genetic testing, we have found that five BRCA1 and three BRCA2 mutations are recurrent in a substantial subset of carriers from North-East Italy and neighboring Istria, where they represent more than 50 % of all mutations. Microsatellite analyses identified a common haplotype of different length for each mutation. Age estimation of BRCA1 c.676delT and BRCA2 c.7806-2A > G mutations revealed that they arose in the Friuli Venezia Giulia area about 86 and 94 generations ago, respectively. Suggestion of an association between BRCA2 c.7806-2A > G and risk of breast cancer in males has emerged. Finally, we developed a simple and efficient pre-screeening test, performing an in-house primer extension SNaPshot® assay for the rapid identification of the eight recurrent mutations.

Conclusions

Proofs of common ancestry has been obtained for the eight recurrent mutations. The observed genotype-phenotype correlation and the proposed rapid mutation detection strategy could improve the clinical management of breast and ovarian patients in North-East of Italy and neighboring geographic areas.
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Metadata
Title
Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy
Authors
Giulia Cini
Massimo Mezzavilla
Lara Della Puppa
Elisa Cupelli
Alessio Fornasin
Angela Valentina D’Elia
Riccardo Dolcetti
Giuseppe Damante
Sara Bertok
Gianmaria Miolo
Roberta Maestro
Paolo de Paoli
Antonio Amoroso
Alessandra Viel
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2016
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-016-0274-6

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