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- Antoniou, A, et al.
(författare)
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Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies
- 2003
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 72:5, s. 1117-1130
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
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| 2. |
- Antoniou, A C, et al.
(författare)
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Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies
- 2005
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 42:7, s. 602-603
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Tidskriftsartikel (refereegranskat)abstract
- A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
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| 4. |
- Antoniou, A. C., et al.
(författare)
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The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions
- 2008
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 98:8, s. 1457-1466
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Tidskriftsartikel (refereegranskat)abstract
- Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes ( polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families ( 301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920 - 1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in userfriendly Web-based program(http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home. html).
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| 7. |
- Johannsdottir, HK, et al.
(författare)
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Deletions on chromosome 4 in sporadic and BRCA mutated tumors and association with pathological variables
- 2004
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Ingår i: Anticancer research. - 1791-7530. ; 24:5A, s. 2681-2687
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chromosomal aberrations in breast tumors from BRCA1 and BRCA2 germ-line mutation carriers are considerably more frequent than what is seen in sporadic breast tumors. According to Comparative Genomic Hybridisation analysis (CGH), deletions on chromosome 4 are one of the most frequent events in BRCA1-associated tumors, suggesting inactivation of specific tumor suppressor genes. Materials and Methods: In the present study, 16 microsatellite markers covering chromosome 4 were used to map loss of heterozygosity (LOH) in tumors from BRCA1 (n =41) as well as in tumors from BRCA2 (n = 66) mutation carriers and in tumors from unselected cases of breast cancer (n = 68). Results: The frequency of LOH in these groups ranged from 16-73% in BRCA1-associated tumors, 13-42% in BRCA2-associated tumors and 8-33% in unselected tumors. LOH was significantly more frequent in BRCA1-associated tumors as compared to BRCA2-associated tumors and unselected tumors, and particularly high (over 70%) at 4q35.2. Pathological variables that were found significantly associated (pless than or equal to0.05) with LOH at specific markers were: high percentage of cells in S-phase, negative estrogen receptor status, young age at diagnosis and large tumors. Deletion mapping indicates the existence of seven non-overlapping regions at chromosome 4, which were identified in all three groups of tumors. Three of these seven regions, 4p16.3-p16.1, 4q27-q32.1 and 4q35.1-4qter, have not been reported in breast cancer previously. Conclusion: The results manifest the frequent alterations of chromosome 4 in BRCA1-associated breast tumors and indicate the location of several genes of potential importance in breast cancer development.
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| 10. |
- Tommiska, J, et al.
(författare)
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The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer
- 2008
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 27:17, s. 2501-6
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Tidskriftsartikel (refereegranskat)abstract
- The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.
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