BRCA1 mutations in southern England

Eccles, Diana M.; Englefield, P.; Soulby, M A; Campbell, Ian

doi:10.1038/bjc.1998.366

Cited by 28 publications

(30 citation statements)

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“…It thus seems on solid biochemical grounds to assume that BRCA1 and BRCA2 mutations predispose towards the development of bilateral breast cancer via their impairment of DNA repair. On the other hand, the first population-based studies of a limited number of BRCA1 and BRCA2 gene mutations have revealed mutations only in a small minority of patients with bilateral disease, and most of these also had an early onset at first primary (Eccles et al, 1998;Gershoni-Baruch et al, 1999).To gain more insight into the proportion of bilateral breast cancer that can be explained by BRCA1 and BRCA2 mutations in a hospital setting, we analysed the whole BRCA1 and BRCA2 coding region in 75 consecutive patients with bilateral breast cancer not selected for age or family history. Somewhat unexpectedly, only 5 unrelated carriers of a truncating mutation were identified.…”

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confidence: 99%

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

et al. 2001

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Summary Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations. 850-858 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2016 of the patients. After written informed consent had been obtained, blood samples were collected from 1000 participating patients. 75 patients had developed bilateral breast cancer and took part in this study. This proportion of 7.5% of cases with bilateral disease was the same as has been previously reported in another series of over 500 German breast cancer patients (Mose et al, 1995), indicating that our cohort is representative for a hospital-based cancer population in Germany. As a comparison group for mutation frequency determination, we selected 75 patients with unilateral breast cancer from the total cohort who were pairwise matched with respect to age and family history at the time of treatment.Clinical data of the patients with bilateral breast cancer were collected and compared with data of the whole series of 1000 breast cancer patients. In 29 patients, bilateral breast cancer occurred simultaneously. In the other 46 patients, contralateral breast cancer developed with a median time interval of 7.2 years (range 1 to 40 years). A time interval of at least 3 years was observed in 37 patients. The median age at diagnosis of the first breast cancer was 54 years, compared with 57 years in the total cohort. 22 patients (29.3%) were younger than 50 years and 9 patients (12%) younger than 40 years at first diagnosis. Selfreported fam...

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confidence: 99%

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

et al. 2001

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“…It was the most frequently recurring BRCA2 mutation (four examples) among 25 recorded by Gayther et al (1997) from 'the United Kingdom and Eire' but no further breakdown by geographical region was provided. BRCA1 4184 del4 was identified as a recurring mutation in that survey and also in separate reports of families from Wales and the South of England (Lancaster et al, 1998;Eccles et al, 1998). In the last-mentioned study, BRCA1 3875 was found five times in a total series of 17 mutations.…”

Section: Discussionmentioning

confidence: 78%

“…For BRCA1, two studies published in 1995 indicated that the relative risk of ovarian cancer was substantially higher for mutations occurring in the 5 0 two-thirds of the gene Shattuck-Eidens et al, 1995) but this was not confirmed in three other reports Couch et al, 1997;Frank et al, 1998) and is not apparent in a fourth (Eccles et al, 1998), where the data are presented but not discussed in detail. Taking the 3 0 end of exon 11 as the potential 'change point', we found a highly significant difference in the relative proportions of breast and ovarian cancers 'upstream' and 'downstream' of this position.…”

Section: Discussionmentioning

confidence: 92%

“…In several populations or ethnic groups, distinctive founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies (Levy-Lahad et al, 1997;Peelen et al, 1997;Thorlacius et al, 1997;Moller et al, 2001). In the UK, there has been only limited evidence to date of founder mutations (Gayther et al, , 1997Eccles et al, 1998;Lancaster et al, 1998;Peto et al, 1999), the most clear-cut example being BRCA1 2800 delAA, probably originating from the West of Scotland or Ireland (Liede et al, 2000). Since the present day populations of Scotland and Northern Ireland remain relatively homogeneous, and distinct from those of other parts of the UK (Bodmer et al, 1987;Liede et al, 2000), we have collated information on all BRCA1 and BRCA2 mutations recorded among families attending breast cancer genetics clinics in Aberdeen, Belfast, Dundee, Edinburgh or Glasgow.…”

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confidence: 99%

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BRCA1 and BRCA2 mutations in Scotland and Northern Ireland

2003

Br J Cancer

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BRCA1 and BRCA2 mutations have been identified in 107 families in Scotland and Northern Ireland. Ninety-seven of these families had been referred to regional cancer genetics centres and a further 10 were identified from a sequential series of male breast cancers treated in Edinburgh. Fifty-nine of the families had a mutation in BRCA1 and 46 in BRCA2. Two families had both. Family trees were extended and cancer diagnoses verified by means of the unusually complete and accessible Scottish and Northern Irish records. Ten specific recurring mutations (five in each gene) accounted for almost half of the total detected, and almost one-quarter were accounted for by just two (BRCA1 2800 delAA and BRCA2 6503 delTT). The prevalence of breast cancer is similar for BRCA1 and BRCA2 mutation families (average 3.7 and 3.6 per family), but the former have a much greater risk of ovarian cancer (average 1.5 and 0.6 per family, respectively). For breast cancer, age of onset tended to be younger in BRCA1 mutation carriers but, for ovarian cancer, there was no difference between BRCA1 and BRCA2 families in mean age at diagnosis. Mutations within the 5 0 two-thirds of BRCA1 carry a significantly higher relative risk of ovarian cancer and the same is true for mutations within the central portion of BRCA2 (the 'OCCR'). In the former case, this appears to be because of differences in absolute risk for both ovarian and breast cancer, while, in the latter, only ovarian cancer risk varies significantly. The findings confirm that founder mutations are present within the Scottish/ Northern Irish population and have implications for the organisation of molecular screening services.

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“…As there is uncertainty about many of the parameters associated with genetic breast cancer (Easton et al, 1993Ford et al, 1995;Couch et al, 1997;Serova et al, 1997;Stoppa-Lyonnet et al, 1997;Struewing et al, 1997;Whittemore et al, 1997;Eccles et al, 1998;Grann et al, 1999b), the uncertainty was accounted for by conducting one-way and multi-way sensitivity analysis upon the following model parameters:…”

Section: Sensitivity Analysismentioning

confidence: 99%

Estimating the survival benefits gained from providing national cancer genetic services to women with a family history of breast cancer

et al. 2004

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The aim of this paper is to compare a service offering genetic testing and presymptomatic surveillance to women at increased risk of developing breast cancer with its predecessor of no service at all in terms of survival and quality-adjusted survival (QALYs) by means of a Markov cohort chain simulation model. Genetic assessment and presymptomatic care provided between 0.07 -1.61 mean additional life years and 0.05 -1.67 mean QALYs over no services. Prophylactic surgery and surveillance extended mean life expectancy by 0.41 -1.61 and 0.32 -0.99 years, respectively over no services for high-risk women. Model outcomes were sensitive to all the parameters varied in the sensitivity analysis. Providing cancer genetic services increase survival and as long as services do not induce adverse psychological effects they also provide more QALYs. The greatest survival and QALY benefits were found for women with identified mutations. As more cancer genes are identified, the survival and cost-effectiveness of genetic services will improve. Although mastectomy provided most additional life years, when quality of life was accounted for oophorectomy was the optimal strategy. Delayed entry into coordinated genetic services was found to diminish the average survival and QALY gains for a woman utilising these services. Despite the recognition by clinicians for over a century that a hereditary predisposition to cancer exists in certain families, the possibility of utilising this information to help these patients has only become available in the 1990s with the discovery of cancer susceptibility genes (Steel et al, 1999). Two of the first common cancer genes to be mapped and cloned were the breast and ovarian cancer susceptibility genes BRCA1 (Miki et al, 1994) and BRCA2 (Wooster et al, 1995). It is estimated that BRCA1 and BRCA2 are responsible for 5 -10% of breast cancer cases (King et al, 1993;Eeles, 1996) and 10% of ovarian cancer cases (Easton et al, 1993;Couch and Weber, 1998;Landis et al, 1999;Risch et al, 2001). Women with a BRCA1 mutation and multiple cases of BRCA1 mutations in their families can have a lifetime risk in excess of 80% of developing breast cancer, a 40 -60% chance of developing ovarian cancer and possibly an increased risk of developing colorectal cancer (Ford et al, 1994).As a consequence of increased awareness of genetic issues and the technology to test for mutations there has been demand for genetic assessment services (Evans et al, 1994;Campbell et al, 1995; Priority Areas Cancer Team, 1998;Ponder, 1999), demand that is likely to increase (Ponder, 1999). However, as cancer mutations have only been isolated in the last decade, clinical trials, cancer registry and observational studies will take years to collect data, establishing long-term costs, and assess the efficacy of surveillance and prophylactic interventions in preventing cancer and prolonging life. In the mean time, researchers have begun to look at these long-term outcomes by means of mathematical modelling. Studies assessing the potential costs ...

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BRCA1 mutations in southern England

Cited by 28 publications

References 14 publications

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

BRCA1 and BRCA2 mutations in Scotland and Northern Ireland

Estimating the survival benefits gained from providing national cancer genetic services to women with a family history of breast cancer

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