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

BMC Medical Genetics

Research Article

Riccardo Dolcetti¹  Alessio Fornasin²  Sara Bertok³  Antonio Amoroso⁴  Giuseppe Damante⁵  Angela Valentina D’Elia⁵  Giulia Cini⁶  Alessandra Viel⁶  Lara Della Puppa⁶  Roberta Maestro⁶  Massimo Mezzavilla⁷  Elisa Cupelli⁸  Gianmaria Miolo⁹  Paolo de Paoli^1,10 

[1] Cancer Bioimmunotherapy Unit, CRO Aviano National Cancer Institute, Aviano, PN, Italy;Department of Economics and Statistics, University of Udine, Udine, Italy;Department of Endocrinology; Diabetes and Metabolic Disease, Division of Pediatrics, University Medical Centre Ljubljana, Ljubljana, Slovenia;Department of Medical Sciences, University of Torino, Torino, Italy;Department of Medical and Biological Sciences, University of Udine, Udine, Italy;Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, PN, Italy;Institute for Maternal and Child Health, IRCCS “Burlo Garofalo”, Trieste, Italy;Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar;Institute of Hematology, Catholic University S. Cuore, Rome, Italy;Medical Oncology B, CRO Aviano National Cancer Institute, Aviano, PN, Italy;Scientific Directorate; CRO National Cancer Institute, Aviano, PN, Italy;

关键词: BRCA1;    BRCA2;    Founder mutation;    Breast cancer;    SNaPshot®;    Italian;   

DOI  :  10.1186/s12881-016-0274-6

 received in 2015-03-19, accepted in 2016-02-03,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundAbout 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.MethodsBRCA1 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.ResultsIn 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.ConclusionsProofs 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.

【 授权许可】

CC BY   
© Cini et al. 2016