Abstract
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.
Highlights
About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes
Frequency of BRCA recurrent mutations Overall, following the mutational screening of 1114 eligible probands, different BRCA1/BRCA2 deleterious mutations were identified in 221 unrelated patients (18.9 %)
Thirty-five BRCA1 and 26 BRCA2 mutations were unique, while 15 BRCA1 and 19 BRCA2 mutations were recurrent in 2–18 families
Summary
About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Some populations present a wide spectrum of different mutations, while particular ethnic groups present high frequency of a single or a few recurrent mutations, usually due to a founder effect [3, 4]. Among the several well established founder mutations, the 3 mutations of the Ashkenazi Jews (AJ), i.e. BRCA1 c.68_69delAG and c.5266dupC, BRCA2 c.5946delT, are worthy of particular mention because overall they account for 6.7-11.7 % of all breast cancer patients and 59 % of patients from high-risk breast cancer families in this population [3]. Among the approximate 30.000 entries of the BIC database [5], these 3 mutations are at the head of both “top 20 mutation frequencies lists” This reflects in part their high recurrence in non-Jews Caucasian populations, because these mutations likely existed before the Jewish diaspora
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