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Search Results: 1 - 10 of 219619 matches for " Antonis C Antoniou "
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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
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
Familial relative risks for breast cancer by pathological subtype: a population-based cohort study
Nasim Mavaddat, Paul D Pharoah, Fiona Blows, Kristy E Driver, Elena Provenzano, Deborah Thompson, Robert J MacInnis, Mitul Shah, The SEARCH Team, Douglas F Easton, Antonis C Antoniou
Breast Cancer Research , 2010, DOI: 10.1186/bcr2476
Abstract: We computed breast cancer FRR for subtypes of breast cancer by comparing breast cancer incidence in relatives of breast cancer cases from a population-based series with known estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status with that expected from the general population. We estimated the contribution to the FRR of genetic variants associated with breast cancer susceptibility using subtype-specific genotypic relative risks and allele frequencies for each variant.At least one marker was measured for 4,590 breast cancer cases, who reported 9,014 affected and unaffected first-degree female relatives. There was no difference between the breast cancer FRR for relatives of patients with ER-negative (FRR = 1.78, 95% confidence intervals (CI): 1.44 to 2.11) and ER-positive disease (1.82, 95% CI: 1.67 to 1.98), P = 0.99. There was some suggestion that the breast cancer FRR for relatives of patients with ER-negative disease was higher than that for ER-positive disease for ages of the relative less than 50 years old (FRR = 2.96, 95% CI: 2.04 to 3.87; and 2.05, 95% CI: 1.70 to 2.40 respectively; P = 0.07), and that the breast cancer FRR for relatives of patients with ER-positive disease was higher than for ER-negative disease when the age of the relative was greater than 50 years (FRR = 1.76, 95% CI: 1.59 to 1.93; and 1.41, 95% CI: 1.08 to 1.74 respectively, P = 0.06). We estimated that mutations in BRCA1 and BRCA2 explain 32% of breast cancer FRR for relatives of patients with ER-negative and 9.4% of the breast cancer FRR for relatives of patients with ER-positive disease. Twelve recently identified common breast cancer susceptibility variants were estimated to explain 1.9% and 9.6% of the FRR to relatives of patients with ER-negative and ER-positive disease respectively.FRR for breast cancer was significantly increased for both ER-negative and ER-positive disease. Including receptor status in conjunction with genetic
The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers
Amanda B Spurdle, Antonis C Antoniou, David L Duffy, Nirmala Pandeya, Livia Kelemen, Xiaoqing Chen, Susan Peock, Margaret R Cook, Paula L Smith, David M Purdie, Beth Newman, Gillian S Dite, Carmel Apicella, Melissa C Southey, Graham G Giles, John L Hopper, kConFaB, EMBRACE Study Collaborators, ABCFS, AJBCS, Georgia Chenevix-Trench, Douglas F Easton
Breast Cancer Research , 2005, DOI: 10.1186/bcr971
Abstract: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size.There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers.The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.A CAG length polymorphism within exon 1 of the androgen receptor (AR) gene encodes a string of 9–32 glutamines. Even within this normal range, CAG repeat number is inversely associated with AR-mediated transcriptional activation in vitro [1,2]. Involvement of the AR in breast tumourigenesis is suggested by the existence of inactivating germline mutations in the hormone-binding domain in male breast cancer patients [3,4], and by splice variants that disrupt the transactivation domain in female breast tumours and tumour cell lines [5].There is evidence that suggests an association between longer AR CAG repeat length – representative of less active AR – and breast cancer risk at the population level (for review, see Lillie and coworkers [6]). Using slightly variable definitions of shorter and longer allele size across studies, one study reported a significant twofold increased risk for breast cancer, another three studies reported a slightly increased risk for breast ca
Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
Ana-Teresa Maia, Antonis C Antoniou, Martin O'Reilly, Shamith Samarajiwa, Mark Dunning, Christiana Kartsonaki, Suet-Feung Chin, Christina N Curtis, Lesley McGuffog, Susan M Domchek, EMBRACE, Douglas F Easton, Susan Peock, Debra Frost, D Evans, Ros Eeles, Louise Izatt, Julian Adlard, Diana Eccles, GEMO Study Collaborators, Olga M Sinilnikova, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Laurence Faivre, Laurence Venat-Bouvet, Capucine Delnatte, Heli Nevanlinna, Fergus J Couch, Andrew K Godwin
Breast Cancer Research , 2012, DOI: 10.1186/bcr3169
Abstract: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPα, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.Unequal expression of the alleles of autosomal genes is common in the human genome [1,2]. This differential allelic expression (DAE) is thought to play a major role in intra-species phenotypic variation as well as individual suscep
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
Antonis C Antoniou, Karoline B Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Andrew Lee, Daniel Barrowdale, Sue Healey, Olga M Sinilnikova, Maria A Caligo, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Richard Rosenquist, Per Karlsson, Kate Nathanson, Susan Domchek, Tim Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, El?bieta Z?owowcka-Per?owska, Ana Osorio, Mercedes Durán, Raquel Andrés, Javier Benítez, Ute Hamann
Breast Cancer Research , 2012, DOI: 10.1186/bcr3121
Abstract: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.Pathogenic mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancers [1,2]. Several lines of evidence suggest that these risks are modified by other genetic or environmental factors that cluster in families. Direct evidence for genetic modifiers of risk has been provided through studies that investigated the associations between common breast and ovarian cancer susceptibility variants, identified through genome-wide association studies (GWAS) or candidate gene studies in the general population, and cancer risk for BRCA1 and BRCA2 mutation carriers [
Two Different Secondary Metabolism Gene Clusters Occupied the Same Ancestral Locus in Fungal Dermatophytes of the Arthrodermataceae
Han Zhang, Antonis Rokas, Jason C. Slot
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041903
Abstract: Background Dermatophyte fungi of the family Arthrodermataceae (Eurotiomycetes) colonize keratinized tissue, such as skin, frequently causing superficial mycoses in humans and other mammals, reptiles, and birds. Competition with native microflora likely underlies the propensity of these dermatophytes to produce a diversity of antibiotics and compounds for scavenging iron, which is extremely scarce, as well as the presence of an unusually large number of putative secondary metabolism gene clusters, most of which contain non-ribosomal peptide synthetases (NRPS), in their genomes. To better understand the historical origins and diversification of NRPS-containing gene clusters we examined the evolution of a variable locus (VL) that exists in one of three alternative conformations among the genomes of seven dermatophyte species. Results The first conformation of the VL (termed VLA) contains only 539 base pairs of sequence and lacks protein-coding genes, whereas the other two conformations (termed VLB and VLC) span 36 Kb and 27 Kb and contain 12 and 10 genes, respectively. Interestingly, both VLB and VLC appear to contain distinct secondary metabolism gene clusters; VLB contains a NRPS gene as well as four porphyrin metabolism genes never found to be physically linked in the genomes of 128 other fungal species, whereas VLC also contains a NRPS gene as well as several others typically found associated with secondary metabolism gene clusters. Phylogenetic evidence suggests that the VL locus was present in the ancestor of all seven species achieving its present distribution through subsequent differential losses or retentions of specific conformations. Conclusions We propose that the existence of variable loci, similar to the one we studied, in fungal genomes could potentially explain the dramatic differences in secondary metabolic diversity between closely related species of filamentous fungi, and contribute to host adaptation and the generation of metabolic diversity.
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