BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland

Abstract

Sixty-four Polish families with a history of breast and/or ovarian cancer were screened for mutations in the BRCA1/2 genes using a combination of denaturing high performance liquid chromatography (DHPLC) and sequencing. Two thirds (43/64; 67%) of the families were found to carry deleterious mutations, of which the most frequent were BRCA1 5382insC (n=22/43; 51%) and Cys61Gly (n=9/43; 20%). Two other recurrent mutations were BRCA1 185delAG (n=3) and 3819del5 (n=4), together accounting for 16% of the 43 mutation-positive cases. We also found three novel mutations (BRCA1 2991del5, BRCA2 6238ins2del21 and 8876delC) which combined with findings from our earlier study of 60 Northern Polish families. Moreover, screening of 43 BRCA1/2 negative families for the presence of large rearrangements by multiplex ligation-dependent probe amplification (MLPA) resulted in the finding of two additional BRCA1 mutations: a deletion of exons 1A, 1B and 2, and a deletion of exons 17-19, both present in single families. We conclude that the Polish population has a diverse mutation spectrum influenced by strong founder effects. However, families with strong breast/ovarian cancer history who are negative for these common mutations should be offered a complete BRCA gene screening, including MLPA analysis.

Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families

“…Our results indicate that 14% (47/324) of those from medium to high risk families in Malaysia carry cancer predisposing genomic deletions in BRCA1 or BRCA2 and that large genomic rearrangements constitute 8% (2/24) and 4% (1/23) of the total BRCA1 and BRCA2 mutations, respectively, in this cohort. Our results are consistent with previous studies in various European populations ( [14] and references therein; [15][16][17][18][19][20][21][22][23][24][25][26][27][28]) and in Singapore ( [4] and references therein) where large genomic rearrangements constitute 8 and 4% of the total BRCA1 and BRCA2 mutations, respectively. We would therefore suggest that large genomic rearrangements, though present at a low frequency, should nonetheless be included in the routine testing for BRCA1 and BRCA2.…”

Novel and common BRCA1 mutations in familial breast/ovarian cancer patients from Lithuania

“…We found pathogenic deletion in exon 15 not described elsewhere in the world and nonsense substitution previously was not reported in Eastern Baltic Sea region or neighboring populations. We did not yet found large rearrangements, but they are not so uncommon [6]. Secondly, mutations in BRCA1 gene are influenced by significant founder effect which is similar to that reported from Latvian (Baltic) population [1] and in our study were attributed to 78% of detected mutations.…”

Genetic testing and first presymptomatic diagnosis in Moroccan families at high risk for breast/ovarian cancer

“…Approximately 10% of cases of ovarian cancer and 3-5% of cases of breast cancer are known to be associated with germline mutations in BRCA1 and BRCA2 (2-4). The two genes are tumoursuppressor genes, and complete loss of their wild-type allele is a common mechanism of gene inactivation in tumourigenesis (5 (6). Mutations in BRCA genes lead to defects in DNA repair processes resulting in elevated genome instability and a predisposition to breast and ovarian cancers.…”