A high proportion of founder BRCA1 mutations in Polish breast cancer families

Abstract

Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. Germline mutations in BRCA1 (MIM 113-705) and BRCA2 (MIM 600185) account for familial clustering in the majority of families with both breast and ovarian cancers and in approximately one-half of families with site-specific breast cancer. 1-3 Of the more than 1,000 BRCA mutations reported to the Breast Cancer Information Core (BIC) database, many are unique but there are also numerous examples of founder mutations. Founder mutations have been reported in genetic isolates such as Ashkenazi Jews 4,5 and the Icelandic, 6 Finnish, 7 Dutch 8,9 and French Canadian 10 populations. Founder mutations have also been noted in Slavic countries, including Poland. 11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. 11-17 Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of

Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients

“…In these centers, genetic testing is offered to all women with incident breast cancer. BRCA1 testing was conducted for the three founder mutations seen in Poland, according to a previously-described protocol [15]. For the purpose of this study, genetic testing was expedited; in most cases the test result was available within five days of diagnosis.…”

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

“…Extensive mutation analysis by direct sequencing of all exons encompassing both BRCA1 and BRCA2, including the intron exon boundaries was undertaken and failed to show any abnormality in either gene. 14 The age of patients ranged between 32-70 years. The breast surgery was carried out in 6 Polish Oncology hospitals in association with the cancer genetic services of the International Hereditary Cancer Center of Szczecin, Poland.…”

Breast cancer incidence and mortality in Lower Silesia (Poland) between 1984 and 2003 — trends and perspectives

“…Consequently, genetic testing for abnormalities in susceptibility genes and registries of families with breast cancer are being organized worldwide. Large genetic studies performed in Poland have revealed that at least three founder BRCA1 mutations are characteristic of the local population [13]. Our previous study demonstrated that these abnormalities are also present in the Lower Silesian population [14].…”