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Clare Turnbull,
Sheila Seal,
Anthony Renwick,
Margaret Warren-Perry,
Deborah Hughes,
Anna Elliott,
David Pernet,
Susan Peock,
Julian W Adlard,
Julian Barwell, [......],
Mark T Rogers,
Susan Shanley,
Lisa Walker, Munaza Ahmed,
Diana Eccles,
D Gareth Evans,
Peter Donnelly,
Douglas F Easton,
Michael R Stratton,
Nazneen Rahman
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ABSTRACT: There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.
Human Molecular Genetics 11/2011; 21(4):958-62. · 7.64 Impact Factor
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ABSTRACT: Previous publications and utilisation of risk models for BRCA1 and BRCA2 mutation identification suggests that multiple primary disease in an individual is a strong predictor of a BRCA1/2 mutation and that this is more predictive than the same cancers occurring in close relatives.
This study assessed the pathological mutation detection rates for BRCA1, BRCA2 and the CHEK2c.1100 delC mutation in 2022 women with breast cancer, including 100 with breast/ovary double primary and 255 with bilateral breast cancer.
Although detection rates for mutations in BRCA1/2 are high at 49% for breast/ovarian double primary and 34% for bilateral breast cancer, the differential effect of multiple primaries in an individual appears to have been overestimated, particularly in those families with only a few malignancies. Nonetheless, bilateral breast cancer does differentially enhance detection rates in strong familial aggregations. CHEK2 1100 DelC mutation rates were lower in bilateral than for unilateral cases at 0.8% compared to 2%. The detected mutation rates for isolated double primary breast and ovarian cancer was 14% (3/22) compared to 17% (17/99) for the same two primaries in two close relatives in families with no other cases of breast/ovarian cancer. Risk models may need to be adjusted if further studies corroborate these findings.
Journal of Medical Genetics 08/2010; 47(8):561-6. · 6.36 Impact Factor
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ABSTRACT: It has been evident for some time that individuals from some families exhibit a genetic predisposition to breast cancer. Since the discovery of the first breast cancer susceptibility gene, BRCA1 in the 1990s, much work has been carried out to identify further breast cancer susceptibility genes. This has led to the identification of another high-penetrance gene, BRCA2, a number of moderate-penetrance genes and, more recently, common low-penetrance genes and loci. The clinical benefit of the identification of such susceptibility genes and loci is in allowing an estimate of the risk of developing breast cancer in carriers. Ultimately, it is hoped that knowledge of an individual's genetic profile in relation to these genes may allow the use of targeted therapies to maximize efficacy in the treatment of breast cancer.
Expert Review of Anti-infective Therapy 09/2009; 9(8):1103-13. · 2.65 Impact Factor
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Sheila Seal,
Deborah Thompson,
Anthony Renwick,
Anna Elliott,
Patrick Kelly,
Rita Barfoot,
Tasnim Chagtai,
Hiran Jayatilake, Munaza Ahmed,
Katarina Spanova,
Bernard North,
Lesley McGuffog,
D Gareth Evans,
Diana Eccles,
Douglas F Easton,
Michael R Stratton,
Nazneen Rahman
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ABSTRACT: We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.
Nature Genetics 12/2006; 38(11):1239-41. · 35.53 Impact Factor
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Anthony Renwick,
Deborah Thompson,
Sheila Seal,
Patrick Kelly,
Tasnim Chagtai, Munaza Ahmed,
Bernard North,
Hiran Jayatilake,
Rita Barfoot,
Katarina Spanova,
Lesley McGuffog,
D Gareth Evans,
Diana Eccles,
Douglas F Easton,
Michael R Stratton,
Nazneen Rahman
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ABSTRACT: We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.
Nature Genetics 09/2006; 38(8):873-5. · 35.53 Impact Factor
