Baudi et al.1 described the first example of a founder BRCA1 (MIM 113705) mutation specific to the Italian population. They studied 24 patients from unrelated breast/ovarian cancer families from the southern region of Calabria and found the 5083del19 mutation to be present four times. This single mutation accounted for four of the six BRCA1 mutations detected in the study. Haplotype analysis confirms the 5083del19 mutation to be a founder mutation. Here we present data on Italian breast/ovarian cancer families in North America, and ask whether or not this mutation is observed in these families.

Founder mutations in BRCA1 and BRCA2 (MIM 600185) have been described in several Western European countries, but, to date, no population has demonstrated founder effects as striking as those observed for Icelandic and the Ashkenazi Jewish groups.2,3,4 Table 1 summarises the different BRCA1 or BRCA2 mutations that have been reported in more than one family from various studies and regions of Italy. To date, only the BRCA1 5083del19 mutation is recurrent and specific to individuals of Italian descent; most mutations are also found in other European countries.

Table 1 BRCA1 and BRCA2 mutations reported in two or more Italian families
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At the Sunnybrook & Women's College Health Sciences Centre in Toronto, Canada, we evaluated DNA samples for germline mutations in BRCA1 and BRCA2 from 116 women with primary cancers of the breast or ovary, and with at least one parent with Italian ancestry. The 116 women participated in genetic studies for either clinical (high-risk families) or research (unselected patients) purposes. A variety of methods were employed for mutation analysis. All samples were tested for deleterious mutations in exons 10 and 11 of BRCA2 and exons 2, 5, 11, 16, 20 and exon 13 duplication of BRCA1. This testing covered the majority of mutations described previously for Italian patients (Table 1), revealing 29 of the 39 mutations (Table 2). Subsequent testing by direct sequencing (by Myriad Genetic Laboratories) revealed ten additional mutations in other exons.

Table 2 Characteristics of 23 BRCA1 and 16 BRCA2 families of Italian ancestry
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Thirty-nine BRCA1 or BRCA2 mutations were identified among the 116 families (33.6%); 23 in BRCA1 and 16 in BRCA2 (Table 2). In total, 19 of the 39 mutations (48.7%) were present in more than one family. Of particular significance was the detection of the BRCA1 exon 16 5083del19 in five families. Three of these five families, who provided specific information about their ancestry, indicated that they originated from Calabria. The 5083del19 mutation accounted for 21.7% of all BRCA1 mutations. Seven other mutations were identified in two families each, including the BRCA1 3875del4, 5382insC and the BRCA2 6696delTC previously described in Italian studies. We did not detect two BRCA1 mutations reported in multiple families in Italy (T300G (C61G) and 1499insA).

In a recent study of 649 unselected ovarian cancer patients in Canada, Risch et al.5 reported that the highest BRCA mutation frequency (24.1%) was among women of Italian ancestry (for non-Jewish subjects). In our study of 116 women of Italian ancestry diagnosed with breast or ovarian cancer, one-third were carriers of mutations in BRCA1 or BRCA2; this mutation frequency is likely an underestimate, as we did not screen all patients for all possible mutations in these genes. In the past, research centres have focused on the exon 11 region of the BRCA1 gene, and interestingly 16 of the 23 BRCA1 mutations identified in Italian families were outside of exon 11. Our data confirms the BRCA1 exon 16 5083del19 mutation to be a founder mutation in the Italian population (from Calabria), in North America as well as in Italy. It may be prudent to screen for recurrent mutations prior to undertaking a full genetic screen in families of Italian origin.

Electronic Database Information

Accession numbers and URLs for data in this article are as follows:

Online Mendelian Inheritance in Man (OMIM), http://www3.ncbi.nlm.nih.gov/Omim/, for inherited breast cancer type 1 and ovarian cancer [MIM 113705] and for inherited breast cancer type 2 [MIM 600185].

Breast Cancer Information Core Database (BIC), http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/, for information on sequence alterations in BRCA1 and BRCA2.