BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer

Abstract

Germline mutations in the BRCA2 gene have been shown to be associated with familial female and male breast cancer. Mutations occur throughout the entire coding region of the gene, and there is considerable ethnic and geographical diversity in the deleterious mutations detected in different populations. No data exist on the role of the BRCA2 gene in the Cypriot population. In this study we present the results of characterizing mutations in the BRCA2 gene, in 26 Cypriot families with multiple cases of breast / ovarian cancer. The entire coding region, including splice sites, of BRCA2 were sequenced using cycle sequencing.In total 29 BRCA2 variants were detected which include 3 truncating mutations, 8 missense mutations, 6 polymorphisms and 12 intronic variants. The 3 truncating mutations are frameshift mutation 8984delG (exon 22), and two nonsense mutations, namely C1913X (exon 11) which is a novel mutation, and K3326X (exon 27). It is of interest that frameshift mutation 8984delG was the most frequent, since it was detected in 5 patients from three different families. Among the 6 polymorphisms detected, polymorphism T77T is novel and similarly 4 of the 12 intronic variants were also novel, namely IVS1+8G>A, IVS1-96insA, IVS4+36A>G and IVS11-51G>T. These results show that deleterious BRCA2 mutations, occur at the same frequency, about 20%, in Cypriot families, as that recorded in other European populations. We conclude that the BRCA2 gene plays a significant role in the familial breast cancer phenotype in the Cypriot population.© 2003 Wiley-Liss, Inc.KEY WORDS: BRCA2, germline mutations, breast cancer, Cyprus INTRODUCTIONBreast cancer is the leading malignancy in women and the second cause of cancer related deaths in Europe and the United States (Parkin et al., 1999). It has been estimated that approximately one in eight women in the Western developed countries will develop breast cancer (Kelsey and Ross 1993;Garfinkel et al., 1994). The identification of two tumor suppressor genes BRCA1 (MIM#113705) (Miki et al., 1994) and BRCA2 (MIM#600185) (Wooster et al., 1995), marked the first time that highly penetrant cancer predisposition genes, (Struewing et al., 1995;Friedman et al., 1995;Struewing et al., 1997;Thorlacius et al., 1996;Szabo and King, 1997) even among Mediterranean countries (DeBenedetti et al., 1998;Ottini et al., 2000;Blesa et al., 2000;Konstantopoulou et al., 2000).In Cyprus there are about 300 new cases of breast cancer diagnosed every year and the incidence, 46 per 100,000 is similar to Western European countries (Parkin et al., 1999). Previously, in a study on breast cancer genetics on the Cypriot population, it was shown that no truncating germline mutations were found in the BRCA1 gene, in 26 families with multiple cases of breast and/or ovarian cancer (Hadjisavvas et al., 2001). In view of these somewhat unexpected findings, we analysed the same families, for germline mutations in the BRCA2 gene and the results are presented in this report. Altogether 29 variants were detected in the BRCA2 gene...

Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy

“…1D). Although most known mutations (deletions) in donor splice sites affect one of the first two GT nucleotides of the consensus slice sequence, mutations affecting nucleotides located as far as +5, +8, or even +36 nucleotides from the donor site have been previously reported [Hadjisavvas et al, 2003;Buzin et al, 2003]. Analysis of the cDNA indicates that the intron 1 donor site was used instead of the nonfunctional intron 2 donor site causing the observed exon 2 skipping (Fig.…”

Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities

“…Monosomy 7 CD34 cells overexpressed several known oncogenes, including HOX9A, BRCA2, PRAME, BMI-1, and PLAB, aberrancies of which have been implicated in cell transformation in leukemias and solid tissue cancers, 35,37,[70][71][72][73][74][75][76][77] as well as poor responses to chemotherapy in hematologic malignancies. 78,79 Abnormal expression of 2 oncogenes, HOX9A and PLAB, has been useful in the classification of acute myeloid versus lymphoid leukemias and in monitoring minimal residual disease.…”

New sequence variants in BRCA1 and BRCA2 genes detected by high-resolution melting analysis in an elderly healthy female population in Croatia

“…The conserved BRC repeats region (Figure 4) is essential for the BRCA2 protein function in DNA repair and contains the ovarian cancer cluster region (OCCR, bounded by nucleotides 3059-4075 and 6503-6629) that is associated with ovarian cancer family history (41). Mutations in the BRC repeats are common in Japanese, Indian, German, Greek and Korean breast and ovarian cancer patients (26,27,36,(42)(43)(44). However, in this region we found 15 different variants in the healthy Croatian population, although most of them with low incidence (the exceptions were two synonymous variants).…”