Evidence of a founder BRCA1 mutation in Scotland

Liede, Alexander; Cohen, Brian; Black, D; Renwick, Andrew; Hoodfar, Elizabeth; Olopade, O. I.; Micek, Mark A.; Anderson, Vernon E.; Mey, R De; Fordyce, A.; Dann, Jamie L.; King, Mary Claire; Weber, Barbara; Narod, Steven A.; Steel, C. M.

doi:10.1054/bjoc.1999.0984

Cited by 32 publications

(22 citation statements)

References 21 publications

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“…Specific populations for which recurrent mutations in BRCA1 and BRCA2 have been described include Scotland, The Netherlands and Belgium, Iceland, Finland, Russia, as well as French-Canadian and Ashkenazi populations. 5,27,30,[33][34][35] Our study indicates that mutations 185delAG, 589delCT and Ala1708Glu may explain a significant fraction (63%) of BRCA1-related Spanish families. It may be recommendable to test the presence of these mutations as a first step of the screening protocol.…”

Section: Discussionmentioning

confidence: 99%

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Hoya

Osorio

Godino

et al. 2001

Intl Journal of Cancer

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Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2-from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics. © 2002 Wiley-Liss, Inc. Key words: BRCA1; BRCA2; logistic regression modelCancer of the breast is the most common malignancy among women in Western countries. In 5-10% of these patients, the disease can be attributed to an inherited predisposition. 1 A linkagebased study estimated that the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 account, respectively, for 52% and 32% of all hereditary breast and/or ovarian cancer families with at least 4 breast cancer cases. [2][3][4] Mutation-based studies indicated that defects in the 2 breast/ovarian cancer susceptibility genes account for a varying fraction of breast cancer families in different populations. 5 The risk of breast and ovarian cancer associated with mutations in these 2 genes has been estimated, 4 and other cancer types to which mutation carriers are predisposed have been identified. 6 -9 Today, many families with a moderate number of breast and/or ovarian cancer cases seek genetic testing in familial cancer clinics. Unfortunately, current laboratory methods are costly and timeconsuming due to the fact that BRCA1 and BRCA2 mutations are apparently randomly distributed over the large coding sequence of both genes. 10 A negative result does not indicate the absence of genetic predisposition in the family because PCR-based protocols do not detect genomic rearrangements and allele-specific transcription defects. Moreover, there is also evidence of other as yet unknown predisposing genes. 4 Management of these families does not defer either without testing or with a negative testing result. Ideally, one would prefer to t...

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Section: Discussionmentioning

confidence: 99%

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Hoya

Osorio

Godino

et al. 2001

Intl Journal of Cancer

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“…As controversy still exists and given that the population of Northern Ireland remains genetically homogenous [15,16], we decided to investigate the role of apolipoprotein E in a large cohort of AD patients from the Northern Irish population who were phenotyped using the Neuropsychiatric Inventory with Caregiver Distress (NPI-D), a validated tool for this research.…”

Section: Introductionmentioning

confidence: 99%

Association Analysis of Apolipoprotein E Genotype and Risk of Depressive Symptoms in Alzheimer’s Disease

Craig¹,

Hart²,

McIlroy³

et al. 2005

Dement Geriatr Cogn Disord

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Objectives: Behavioural and psychological symptoms of dementia (BPSD) are potent predictors of carer distress and admission to institutional care. In Alzheimer’s disease (AD), depressive symptoms are one of the most common complaints affecting around 50% of all patients. There is speculation these symptoms result from known genetic risk factors for AD, therefore we investigated the role of apolipoprotein E Ε4 in the aetiology of depression in AD. Methods: In this well-characterised cohort (n = 404) from the relatively genetically homogeneous Northern Ireland population, we tested the hypothesis that genetic variants of apolipoprotein E influence the risk for depressive symptoms in AD patients using the Neuropsychiatric Inventory (NPI-D) to determine the presence of depressive symptoms during the dementing illness. Results: A total of 55% of patients exhibited a history of depression/dysphoria during the course of the illness as gathered by the NPI-D questionnaire. Forty-six percent were suffering from depression/dysphoria when the analysis was restricted to the month prior to interview. No statistically significant association between genotypes or alleles of apolipoprotein E and depression/dysphoria in AD was observed, nor was any association noted between the presence of severe symptoms and genotypes/alleles of apolipoprotein E. Conclusions: These results suggest apolipoprotein E genotype creates no additional risk for depressive symptoms in AD.

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“…Most of these have been recorded many times in the BIC database and/or the Human Gene Mutation Database. Our earlier speculation (Liede et al, 2000) that BRCA1 2800 delAA may have originated in West-Central Scotland or in Ireland seems to be supported by the finding of three further cases, one from Glasgow and two from Belfast. BRCA2 6503 delTT has been found elsewhere in the UK as well as in Dutch, Swedish, Danish and Belgian families (BIC database).…”

Section: Discussionmentioning

confidence: 80%

“…Two are particularly frequent, BRCA1 2800 delAA and BRCA2 6503 delTT. The former has already been identified as a Scottish/Irish founder mutation (Liede et al, 2000), while the latter is also a recognised founder mutation, distributed throughout Europe and the USA (Mazoyer et al, 1996;Szabo and King, 1997;BIC database). In contrast to BRCA1 2800 delAA, the BRCA2 6503 delTT mutation is relatively frequent among families attending the Aberdeen and Dundee clinics (representing the North and East of Scotland), which may be in keeping with Scandinavian origin (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…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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Evidence of a founder BRCA1 mutation in Scotland

Cited by 32 publications

References 21 publications

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Association Analysis of Apolipoprotein E Genotype and Risk of Depressive Symptoms in Alzheimer’s Disease

BRCA1 and BRCA2 mutations in Scotland and Northern Ireland

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