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Milne R.L.,Genetic and Molecular Epidemiology Group | Antoniou A.C.,University of Cambridge
Annals of Oncology | Year: 2011

Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source


Lopez de Maturana E.,Genetic and Molecular Epidemiology Group
Human genetics | Year: 2014

The continuous advancement in genotyping technology has not been accompanied by the application of innovative statistical methods, such as multi-marker methods (MMM), to unravel genetic associations with complex traits. Although the performance of MMM has been widely explored in a prediction context, little is known on their behavior in the quantitative trait loci (QTL) detection under complex genetic architectures. We shed light on this still open question by applying Bayes A (BA) and Bayesian LASSO (BL) to simulated and real data. Both methods were compared to the single marker regression (SMR). Simulated data were generated in the context of six scenarios differing on effect size, minor allele frequency (MAF) and linkage disequilibrium (LD) between QTLs. These were based on real SNP genotypes in chromosome 21 from the Spanish Bladder Cancer Study. We show how the genetic architecture dramatically affects the behavior of the methods in terms of power, type I error and accuracy of estimates. Markers with high MAF are easier to detect by all methods, especially if they have a large effect on the phenotypic trait. A high LD between QTLs with either large or small effects differently affects the power of the methods: it impairs QTL detection with BA, irrespectively of the effect size, although boosts that of small effects with BL and SMR. We demonstrate the convenience of applying MMM rather than SMR because of their larger power and smaller type I error. Results from real data when applying MMM suggest novel associations not detected by SMR. Source


Malats N.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | Real F.X.,University Pompeu Fabra
Hematology/Oncology Clinics of North America | Year: 2015

Bladder cancer incidence is higher in old men, shows geographic variation, and is mostly an environmental disease. Cigarette smoking, occupational exposures, water arsenic, Schistosoma haematobium infestation, and some medications are the best established risk factors. Low-penetrance genetic factors also contribute to its origin, some through interaction with environmental factors. Bladder cancer has high prevalence and a low mortality, being largely a chronic disease. Data on environmental and genetic factors involved in the disease outcome are inconclusive. © 2015 Elsevier Inc. Source


Mocci E.,Genetic and Molecular Epidemiology Group | Milne R.L.,Genetic and Molecular Epidemiology Group | Milne R.L.,University of Melbourne | Mendez-Villamil E.Y.,Genetic and Molecular Epidemiology Group | And 7 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2013

Background: Increased risk of pancreatic cancer has been reported in breast cancer families carrying BRCA1and BRCA2 mutations; however, pancreatic cancer risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate pancreatic cancer risk in high-risk breast cancer families according to the BRCA mutation status. Methods: A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for pancreatic cancer. A total of 5,799 families with >1 breast cancer case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with >2 breast cancer diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4). Results: BRCA1 mutation carriers were at increased risk of pancreatic cancer [SIR = 4.11; 95% confidence interval (CI), 2.94-5.76] as were BRCA2 mutation carriers (SIR = 5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased pancreatic cancer risk, which did not appear to vary by number of members with early-onset breast cancer (SIR = 1.31; 95% CI, 1.06-1.63 for class 3 and SIR = 1.30; 95% CI, 1.13-1.49 for class 4). Conclusions: Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of pancreatic cancer. Members of BRCAX families are also at increased risk of pancreatic cancer, pointing to the existence of other genetic factors that increase the risk of both pancreatic cancer and breast cancer. Impact: This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, pancreatic cancer should be included in risk assessment in familial breast cancer counseling. Cancer Epidemiol Biomarkers Prev; 22(5); 803-11. © 2013 AACR. Source


Masson-Lecomte A.,Genetic and Molecular Epidemiology Group | Masson-Lecomte A.,French Institute of Health and Medical Research | Rava M.,Genetic and Molecular Epidemiology Group | Real F.X.,Epithelial Carcinogenesis Group | And 5 more authors.
European Urology | Year: 2014

Context Host immune response has an impact on tumour development and progression. There is interest in the use of inflammatory biomarkers (InfBMs) in cancer care. Although several studies assessing the potential prognostic value of InfBMs in cancer have been published in the past decades, they have had no impact on the management of patients with urothelial bladder carcinoma (UBC).Objective To review and summarise the scientific literature on the prognostic value of tumour, serum, urine, and germline DNA InfBMs on UBC. Evidence acquisition A systematic review of the literature was performed searching the Medline and Embase databases for original articles published between January 1975 and November 2013. The main inclusion criterion was the provision of a survival analysis (Kaplan-Meier and/or Cox) according to the Reporting Recommendations for Tumor Marker Prognostic Studies guidelines for the assessment of prognostic markers. We focused on markers assessed at least twice in the literature. Findings are reported following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Evidence synthesis Overall, 34 publications, mostly retrospective, fulfilled the main inclusion criterion. Main limitations of these studies were missing relevant information about design or analysis and heterogeneous methodology used. Inflammatory cells, costimulatory molecules in tumour cells, and serum cytokines showed prognostic significance, mainly in univariable analyses. High C-reactive protein values were consistently reported as an independent prognostic factor for mortality in invasive UBC.Conclusions There is a dearth of studies on InfBMs in UBC compared with other tumour types. Evidence suggests that InfBMs may have an impact on the management of patients with UBC. Currently, methodological drawbacks of the studies limit the translational potential of results.Patient summary In this review, we analysed studies evaluating the impact of inflammatory response on bladder cancer progression. Despite methodological limitations, some inflammatory biomarkers should be further analysed because they hold promise to improve patient care. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. Source

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