| 1. |
- Bergman, Annika, et al.
(författare)
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The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation
- 2001
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 9:10, s. 787-793
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Tidskriftsartikel (refereegranskat)abstract
- The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 3171ins5. In the western part of Sweden this mutation accounts for as much as 77% of identified mutations in these two genes. Our aim was to analyse in detail the haplotype and founder effects of the 3171ins5 and furthermore attempt to estimate the time of origin of the mutation. In the study we included eighteen apparently unrelated families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17.3 cΜ. We found several different haplotypes both for disease alleles and for the normal alleles. However, a conserved haplotype of 3.7 cΜ was observed in the 3171ins5 carriers spanning over four markers located within or very close to the BRCA1 gene. As this haplotype was not present in any of the normal controls it is highly likely that this is a mutation identical by descent, i.e. a true founder. The results from the haplotype analyses were used to estimate the age of the mutation. Estimations based on the Pexcess and linkage disequilibrium gives a first appearance of the mutation sometime around the 6th century, approximately 50 generations ago.
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| 2. |
- Einbeigi, Zakaria, 1962, et al.
(författare)
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Clustering of individuals with both breast and ovarian cancer--a possible indicator of BRCA founder mutations.
- 2002
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Ingår i: Acta oncologica (Stockholm, Sweden). - 0284-186X. ; 41:2, s. 153-7
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Tidskriftsartikel (refereegranskat)abstract
- In a cohort of 60436 women with a diagnosis of invasive breast carcinoma and known to reside in Sweden in 1960, 321 had a subsequent diagnosis of ovarian carcinoma. Assuming no correlation between the two cancers, one would expect that 191 women would develop ovarian cancer (standardized incidence ratio (SIR) 1.7; 95% confidence interval 1.5-1.9). Women with breast cancer before 40 years of age were at highest risk for developing ovarian cancer (SIR 4.5). Between 40 and 49 years of age, the SIR was 1.9, and at 50 years of age or older, the SIR was 1.3. Most of the excess in ovarian cancer occurred in southern Sweden. The geographic distribution of these cases coincided with the distribution of families with known BRCA1 and BRCA2 gene mutations. These results suggest that genetic factors account for the excess in ovarian cancer that occurs in breast cancer patients and that geographic clustering of patients who have both breast and ovarian cancer may indicate the presence of a BRCA founder mutation.
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| 3. |
- Einbeigi, Zakaria, 1962
(författare)
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Hereditary breast and ovarian cancer in western Sweden with a special focus on BRCA1 3171ins5 mutation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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