Hereditary breast and ovarian cancer in western Sweden with a special focus on BRCA1 3171ins5 mutation

Abstract: Aims: To describe the phenotype and geographic distribution of the western Swedish founder mutation BRCA1 3171ins5, evaluate the reliability of mutation analysis of this mutation on archival material, analyse the haplotype for founder effects in families with BRCA1 3171ins5 mutation, estimate the age of this mutation and evaluate whether the occurrence of both breast and ovarian cancers in the same women may be a marker of a BRCA gene mutation. Materials and methods: The first study was based on 16 families with BRCA1 3171ins5 mutation and the second study was based on 18 families with the same mutation. All affected families were selected from the cancer genetic counselling unit. Subjects for the third and fourth studies were selected from the Swedish Cancer Registry. Study III included a total of 60,436 women with a diagnosis of invasive adenocarcinoma of the breast who were identified in the Swedish Cancer Registry from 1960 to 1997. The women were born between 1920 and 1960 and information regarding their place of residence was available from the 1960 census.All women with both breast and ovarian tumours in western Sweden who had at least one of the diagnoses after 1970 were included in Study IV.Results: Paper I: There were 47 breast cancers in 39 women and 25 women developed ovarian cancer at a median 44 years and 52 years, respectively. Nine women had both breast and ovarian cancer. The penetrance of breast or ovarian cancer by age 70 was estimated to 59-93%. No differences in survival were found between these patients and matched controls. There was complete agreement between results obtained from blood and results from archival tissues. All families with this mutation originated from western Sweden.Paper II: Families with BRCA1 3171ins5 mutations shared a common haplotype, which indicates that BRCA1 3171in5 is a true founder mutation. The best estimate of the age of the mutation was 50 generations or approximately 1500 years.Paper III-IV: The standardized incidence ratio, SIR, for ovarian cancer among breast cancer patients in Sweden was 1.7. As the regions with highest risks seemed to coincide with the distribution of known BRCA1 and BRCA2 gene mutations geographic clustering may indicate the presence of BRCA gene mutations. The founder mutation in the western region could explain the excess of ovarian cancer there compared to the neighbouring regions. The frequency of BRCA gene mutations was estimated to be about 25%among women with both breast and ovarian cancer. It is sufficiently high to offer BRCA mutation screening in this group. The precision of the histopathology diagnosis is too low to be used as an exclusion criterion for mutation screening.