Identification of a founder BRCA2 mutation in Sardinia

Abstract

Breast cancer is the most common malignancy in women, with an incidence that varies between 40 and 90 per 100 000 (standardized rate) worldwide. Breast cancer is the most frequent female tumour in Italy, representing about 25% of all female tumours as reported in Italian registries (Zanetti et al, 1997).A positive family history is known to be a high risk factor for developing the disease: 5-10% of all breast cancers arise in individuals carrying a germline mutation and are usually considered hereditary forms (Claus et al, 1991). Two major breast cancersusceptibility genes, BRCA1 and BRCA2, have been cloned (Miki et al, 1994;Wooster et al, 1995) and both are thought to account for 30-60% of hereditary breast cancer (Serova et al, 1997;Szabo et al, 1997;Vehmanen et al, 1997aVehmanen et al, , 1997b. However, large-scale mutation analyses conducted in several populations suggest the existence of additional breast cancer-susceptibility gene(s). BRCA1 mutations are responsible for the majority of familial breast cancer associated with ovarian carcinoma, for about 50% of cases with breast cancer alone and for very few male breast cancer cases (Easton et al, 1993;Stratton et al, 1994;Narod et al, 1995). It has been estimated that women carrying a germline mutation in BRCA1 have a risk ranging from 80 to 90% for developing breast cancer and from 44 to 63% for developing ovarian cancer (Easton et al, 1993(Easton et al, , 1995Ford et al, 1994; Miki et al, 1994;Wooster et al, 1994). BRCA2 mutations account for a similar proportion of inherited breast cancer and are frequently associated with male breast cancer (Wooster et al, 1995). Breast cancer risk in females carrying BRCA2 mutations is calculated to be similar to that conferred by BRCA1 mutations (Easton et al, 1993Ford et al, 1994; Miki et al, 1994;Wooster et al, 1994). BRCA1 and particularly BRCA2 families are often affected by other tumours such as prostate, liver, pancreas, lung, stomach and colorectum (Wooster et al, 1995;Gudmundsson et al, 1996;Phelan et al, 1996;Thorlacius et al, 1996;Vehmanen et al, 1997b;Tonin et al, 1998). Except for higher incidences of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 of BRCA2 (the so-called ovarian cancer cluster region [OCCR]; Gayther et al, 1997), no other significant association between genotype and phenotype was described. BRCA1 and BRCA2 mutations are for the most part frame-shifts due to small deletions leading to premature translation termination (Wooster et al, 1995;Phelan et al, 1996;Tavtigian et al, 1996;Gayther et al, 1997).Some of these mutations are prevalent in genetically homogeneous populations as a consequence of a founder effect. A single BRCA2 mutation accounts for the majority of hereditary breast cancer in Iceland Thorlacius et al, 1996) and for 40% of male breast cancer cases , whereas three different founder mutations (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2) have a high frequency in Ashkenazi Jews (Roa et al, 1996). Although at different rates, BRCA1 and BRCA2 f...

Concerns of Gonadal Dysfunction Following Radioactive Iodine (RAI131) Treatment for Thyroid Cancer

“…The proportion of breast cancer families attributable to BRCA1 and BRCA2 mutations in this study is relatively lower when compared to many studies [25][26][27][28][29][30][31][32][33][34][35][36][37][38]. However, the finding of only one of seventeen breast families with BRCA1 mutations is less than has been reported elsewhere.…”

Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital‐based screening

“…Most of these mutations (13 mutations; 86.7%) were found in BRCA2, and only small numbers (2 mutations; 13.3%) were found in BRCA1. The mutation BRCA2-8765delAG, which we described previously as a frameshift mutation with founder effect in North Sardinia, 29 remained the only recurrent mutation among families from our series (prevalence, 12 of 102 families; 11.8%) ( Table 2). The distribution of familial members carrying the BRCA2-8765delAG variation and originating from different villages in North Sardinia further confirmed the founder effect of this germline mutation in such a geographic area (Fig.…”

“…30 Haplotype analysis of some Sardinian and French-Canadian families, as we reported previously, 29 demonstrated that the BRCA2-8765delAG mutation is associated with different haplotypes in 2 such populations (DNA samples of French-Canadian BRCA2-8765delAG carriers kindly were provided by Dr. Tonin). These results support the hypothesis that the AG-rich sequence in which the BRCA2-8765delAG mutation occurs may be a mutational hot-spot.…”

Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases

“…Genomic DNA was extracted from formalin-fixed paraffin-embedded samples after microdissection separating tumour tissue from adjacent stroma by light microscopy. DNA was isolated according to previously described protocols (Pisano et al, 2000). Control DNA was obtained from normal adjacent skin of the corresponding patients.…”