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Search Results: 1 - 10 of 149706 matches for " Douglas F. Easton "
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Familial risks of breast cancer
Douglas F Easton
Breast Cancer Research , 2002, DOI: 10.1186/bcr448
Abstract: The increased risk of breast cancer among women with a family history of the disease is one of the oldest established facts about the disease. This familial aggregation has been the inspiration for studies to identify breast cancer susceptibility genes that have borne fruit over the past decade, and has been the basis for defining high-risk groups for intervention studies (e.g. with tamoxifen). Yet despite the fact that questions about family history are asked in almost every epidemiological study of breast cancer, some important questions about the quantitative relationship between family history relationship have not been answered with precision. Among these questions are the magnitude of the risk according to the age of the women and the age of their affected relative(s), the precise effect of numbers and types of affected relatives, and the joint effects of family history and other known risk factors.Since only ~10–15% of women with breast cancer typically report a family history of breast cancer, individual epidemiological studies have not had the power to answer these questions precisely. The recent analysis by the Collaborative Group on Hormonal Factors in Breast Cancer [1] goes a long way toward resolving some of these uncertainties. This group has brought together data from 52 studies, originally to evaluate the effects of oral contraceptives and hormone replacement therapy. In the current overview, the group examine risks according to family history of breast cancer in a first-degree relative in over 58,000 cases and in nearly 102,000 controls.The main results from the overview [1] are straightforward to summarise. The results of the study are mainly expressed in terms of the risk ratio (or relative risk) of breast cancer associated with a family history; that is, the ratio of the incidence rate of breast cancer in relatives of breast cancer cases to the incidence in the relatives of controls. These risk ratios were estimated from the case-control studies
How many more breast cancer predisposition genes are there?
Douglas F Easton
Breast Cancer Research , 1999, DOI: 10.1186/bcr6
Abstract: Of the five genes that are, beyond any reasonable doubt, breast cancer predisposition genes, the BRCA1 and BRCA2 genes are the most important numerically (Table 1). Mutations in these genes, which cause high risks of breast and ovarian cancer, account for almost all the multiple case breast-ovarian cancer families, and probably around 2% of breast cancer cases overall [4,5]. Germline mutations in the TP53 gene predispose to a spectrum of cancers known as the Li-Fraumeni syndrome, including childhood sarcomas and brain tumours, as well as early-onset breast cancer [2]; and germline mutations in the PTEN gene are responsible for Cowdens syndrome, of which breast cancer is a major feature [6]. Mutations in a fifth gene, the androgen receptor gene, are known to pre-dispose to breast cancer in men [7].In addition to the five genes mentioned above, there is good, but not conclusive, evidence for two others. Female relatives of ataxia-telangiectasia patients have been shown in a number of studies [8,9] to be at increased risk of breast cancer (and perhaps of some other cancers), suggesting that heterozygous carriers of mutations in the ataxia-telangiectasia gene, ATM, are at increased risk of breast cancer. The results from different studies are reasonably consistent, and are confirmed by direct observation of haplotype sharing in breast cancer cases in relatives of ataxia-telangiectasia patients [10]. The residual doubt lies in the fact that, to date, no studies have demonstrated this association in breast cancer case-control studies [11]. There is also evidence that carriers of a certain class of rare alleles of the HRAS1 minisatellite locus are at increased risk of breast (and other) cancers, the relative risk being approximately two-fold [12]. The doubts that surround this association are that the typing of this locus is technically difficult, and has not been attempted on a sufficiently number of large case-control studies to be really convincing, and that the mechani
Clinical software development for the Web: lessons learned from the BOADICEA project
Alex P Cunningham, Antonis C Antoniou, Douglas F Easton
BMC Medical Informatics and Decision Making , 2012, DOI: 10.1186/1472-6947-12-30
Abstract: We developed the BOADICEA Web Application using an evolutionary software process. Our approach to Web implementation was conservative and we used conventional software engineering tools and techniques. The principal software development activities were: requirements, design, implementation, testing, documentation and maintenance. The BOADICEA Web Application has now been widely adopted by clinical geneticists and researchers. BOADICEA Web Application version 1 was released for general use in November 2007. By May 2010, we had > 1200 registered users based in the UK, USA, Canada, South America, Europe, Africa, Middle East, SE Asia, Australia and New Zealand.We found that an evolutionary software process was effective when we developed the BOADICEA Web Application. The key clinical software development issues identified during the BOADICEA Web Application project were: software reliability, Web security, clinical data protection and user feedback.
Incorporating tumour pathology information into breast cancer risk prediction algorithms
Nasim Mavaddat, Timothy R Rebbeck, Sunil R Lakhani, Douglas F Easton, Antonis C Antoniou
Breast Cancer Research , 2010, DOI: 10.1186/bcr2576
Abstract: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees.The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history.This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.Genetic testing for BRCA1 and BRCA2 has important clinical implications: individuals found to carry mutations in these genes can be carefully monitored and receive preventive therapies including oophorectomy or mastectomy [1-6]. As genetic testing is expensive and may be associated with adverse psy
BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families
Antonis C Antoniou, Francine Durocher, Paula Smith, Jacques Simard, INHERIT BRCAs program members, Douglas F Easton
Breast Cancer Research , 2005, DOI: 10.1186/bcr1365
Abstract: A total of 195 families with multiple affected individuals with breast or ovarian cancer were recruited through the INHERIT (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility) BRCAs research program. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BOADICEA and BRCAPRO models. The models were assessed using Brier scores, attributes diagrams and receiver operating characteristic curves. Log relative risks for breast and ovarian cancer in mutation carriers versus population risks were estimated by maximum likelihood, using a modified segregation analysis implemented in the computer program MENDEL. Twenty-five families were eligible for inclusion in the BRCA1 penetrance analysis and 27 families were eligible for the BRCA2 penetrance analysis.The BOADICEA model predicted accurately the number of BRCA1 and BRCA2 mutations for the various groups of families, and was found to discriminate well at the individual level between carriers and noncarriers. BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations. It significantly overestimated the carrier frequency for high predicted probabilities. However, it discriminated well between carriers and noncarriers. Receiver operating characteristic (ROC) curves indicate similar sensitivity and specificity for BRCAPRO and BOADICEA. The estimated risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers were consistent with previously published estimates.The BOADICEA model predicts accurately the carrier probabilities in French-Canadian families and may be used for counselling in this population. None of the penetrance estimates was significantly different from previous estimates, suggesting that previous estimates may be appropriate for counselling in this population.BRCA1 and BRCA2 are the most important breast cancer susceptibility genes identified to date. A rece
Cancer incidence in relatives of British Fanconi Anaemia patients
Marc Tischkowitz, Douglas F Easton, Jan Ball, Shirley V Hodgson, Christopher G Mathew
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-257
Abstract: Thirty-six families took part and data was collected on 575 individuals (276 males, 299 females), representing 18,136 person years. In this cohort, 25 males and 30 females were reported with cancer under the age of 85 years, and 36 cancers (65%) could be confirmed from death certificates, cancer registries or clinical records.A total of 55 cancers were reported in the FA families compared to an estimated incidence of 56.95 in a comparable general population cohort, and the relative risk of cancer was 0.97 (95% C.I. = 0.71–1.23, p = 0.62) for FA family members. Analysis of relative risk for individual cancer types in each carrier probability group did not reveal any significant differences with the possible exception of prostate cancer (RR = 3.089 (95% C.I. = 1.09 – 8.78; Χ2 = 4.767, p = 0.029).This study has not shown a significant difference in overall cancer risk in FA families.It has long been hypothesised that heterozygotes for autosomal recessive DNA repair disorders may have reduced efficiency of their DNA repair systems which could cause an increased risk of cancer [1]. This hypothesis has been upheld by molecular and epidemiological studies of cancer incidence in Ataxia Telangiectasia which have confirmed a two-fold increased risk of breast cancer in female ATM heterozygotes [2,3]. Fanconi anemia (FA) is an autosomal recessive bone marrow failure syndrome due to mutations in at least 13 different genes (FANCA, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M and N/PALB2) [4,5] and the incidences of acute myeloid leukaemia and certain solid tumours are all greatly increased in homozygotes [6]. Epidemiological studies of cancer risk in FA heterozygotes are conflicting: the initial study by Swift et al. analysed 102 deaths in the relatives of eight FA families and found a higher rate of leukaemia and gastric, colorectal and tongue cancer [7]. However, none of these was statistically significant and when the study was expanded to 25 families no overall or specific
Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk
Paul D. P Pharoah ,Jonathan Tyrer,Alison M Dunning,Douglas F Easton,Bruce A. J Ponder,SEARCH Investigators
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030042
Abstract: Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran–Armitage trend test (p-trend) and a two-degrees of freedom χ2 test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 10?5) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers
Antonis C Antoniou, Andrew Shenton, Eamonn R Maher, Emma Watson, Emma Woodward, Fiona Lalloo, Douglas F Easton, D Gareth Evans
Breast Cancer Research , 2006, DOI: 10.1186/bcr1630
Abstract: The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach.Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers.The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers.Deleterious mutations in the BRCA1 and BRCA2 genes are associated with high risks of breast and ovarian cancer [1]. However, there is evidence that these risks are modified by both genetic and environmental factors [1-4]. Breast cancer risk in the general population is closely related to reproductive history, and reproductive factors are therefore strong candidates for modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. In particular, increasing parity has been shown to be protective for breast cancer in the general population in many studies [5-7], but its effect among BRCA1 and BRCA2 mutation carriers is still under debate [8-14]. In this report we have used data from 810 BRCA1 and BRCA2 mutation carriers from the UK to assess the effect of parity on breast cancer risk.Families with breast and/or ovarian cancer have been tested for BRCA1/2 mutations since 1996 in the overlapping regions of North-West England and the West Midlands, covering about 10 million people. Women a
An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)
Georgia Chenevix-Trench, Roger L Milne, Antonis C Antoniou, Fergus J Couch, Douglas F Easton, David E Goldgar, CIMBA
Breast Cancer Research , 2007, DOI: 10.1186/bcr1670
Abstract: Female carriers of deleterious BRCA1 and BRCA2 mutations are predisposed to high lifetime risks of breast and ovarian cancer. Initial estimates indicated that around 80% of carriers of mutations in BRCA1 and BRCA2 from multiple-case families would develop breast cancer by age 70 [1,2], and genetic counseling is usually carried out on the assumption that penetrance estimates apply to all women. However, a later pooled analysis from population-based studies estimated an average risk by age 70 in this context of 66% in BRCA1 carriers and 45% in BRCA2 carriers [3]. It has also been reported that cancer risks vary by the age at diagnosis and the type of cancer in the index case [3,4]. Such observations are consistent with the more plausible hypothesis that cancer risks in mutation carriers are modified by genetic factors or other risk factors that cluster in families. Segregation analysis has also demonstrated that models that allow for other genes to have a modifying effect on the breast cancer risks conferred by BRCA1 and BRCA2 mutations fit significantly better than models without a modifying component [5]. Further evidence for genetic modifiers arises from studies of risk factors that are themselves influenced by genetic factors. For example, mammographic density that has a strong genetic component [6] has been recently shown in one study to modify the breast cancer risks in BRCA1 and BRCA2 mutation carriers [7].Although there has been considerable interest in finding genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers, the number of published studies is still fairly modest and has focused around genes involved in a limited number of pathways: detoxification of environmental carcinogens, DNA repair and steroidogenesis. Several studies have evaluated the CAG repeat length polymorphism in the androgen receptor (AR) gene as a modifier of breast cancer risk among mutation carriers. However, the data from different studies are contradictory and no firm c
Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design
Helen I Field, Serena A Scollen, Craig Luccarini, Caroline Baynes, Jonathan Morrison, Alison M Dunning, Douglas F Easton, Paul DP Pharoah
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-180
Abstract: We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design.The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5).Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation.Seq4SNPs is available as a service at http://moya.srl.cam.ac.uk/oncology/bio/s4shome.html webcite and http://moya.srl.cam.ac.uk/cgi-bin/oncology/srl/ncbi/seq4snp1.pl webcite, currently for human SNPs, but easily extended to include any species in dbSNP.A survey of single nucleotide polymorphism (SNP) and primer design software reveals several packages that align EST or genome sequences to discover SNPs [1-6]. SNP-VISTA visualizes SNPs from aligned genome sequences [7]. Other packages take a chromosome region then use recorded SNP genotypes, and additional information, to reduce the set of SNPs that need genotyping [[8,9] and references therein]. SNP i
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