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Search Results: 1 - 10 of 461901 matches for " Rosalind A Eeles "
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Future possibilities in the prevention of breast cancer: Intervention strategies in BRCA1 and BRCA2 mutation carriers
Rosalind A Eeles
Breast Cancer Research , 2000, DOI: 10.1186/bcr70
Abstract: About 5-10% of breast and ovarian cancers occur as a result of highly penetrant germline mutations in cancer predisposing genes [1,2]. Half of these are due to mutations in BRCA1 or BRCA2 [3]. BRCA1 on chromosome 17q encodes a protein of 1863 amino acids [4*] and BRCA2 on 13q is about twice the size of BRCA1 [5*]. Although deleterious mutations in both genes predispose to earlier onset and an increased risk for female breast cancer, the risk of cancers at other sites and the risk profile differs for the two genes.Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have combined data from numerous families with germline mutations in BRCA1 and BRCA2 worldwide to determine penetrance estimates and risks for other cancers in BRCA1 and BRCA2 mutation carriers. These have shown that both genes confer an increased risk for female breast cancer of 80-85% by the age of 80 years [6,7**], although the penetrance curve for BRCA1 starts to rise slightly earlier than that for BRCA2 (Figs 1 and 2). Both genes confer an increased risk for ovarian cancer, but the lifetime risks are higher for BRCA1 (60% by age 80 years) than for BRCA2 (27% by age 80 years; the population risk is just under 1%), and the penetrance curve also starts to rise earlier (late 30s) for BRCA1 than for BRCA2 (mid 40s; Figs 1 and 2) [7**].It is now clear that both genes confer an increased risk for prostate cancer, which is threefold for BRCA1 mutations [8*] and threefold to sevenfold for BRCA2 mutations [9,10], equating to an absolute risk of 6-14% by age 74 years; the population risk by this age is 2%. Mutations in BRCA1 are also thought to increase the risk of colon cancer to about 6% by age 70 years [8*], but carriers of mutations in BRCA2 do not appear to be predisposed to colon cancer.A recent analysis of the risk of other cancers in BRCA2 carriers [10] reported a significantly increased risk for cancer of the prostate, stomach, pancreas, male breast, head and neck, ocular melanoma, cuta
Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls
Imogen Locke, Zsofia Kote-Jarai, Mary Jo Fackler, Elizabeth Bancroft, Peter Osin, Ashutosh Nerurkar, Louise Izatt, Gabriella Pichert, Gerald PH Gui, Rosalind A Eeles
Breast Cancer Research , 2007, DOI: 10.1186/bcr1657
Abstract: The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-β, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid.Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls(p = 0.13).We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers.Women carrying pathogenic gene mutations in either BRCA1 or BRCA2 are at significantly increased lifetime risk of up to 80% for developing breast cancer [1]. A significant proportion of this risk occurs in women under the age of 50 years. Current surveillance recommendations include mammographic screening and clinical breast examination [2]. It is well recognised that mammograms are less sensitive in younger women, who have more radiodense breast tissue, and although alternative imaging modalities such as magnetic resonance imaging have shown promise there is still a clear need for better risk assessment and earlier breast cancer detection in this high-risk group [3,4]. Ductal lavage (DL) is a novel method for repeated minimally invasive sampling of brea
A population-based audit of ethnicity and breast cancer risk in one general practice catchment area in North London, UK: implications for practice
Michelle Ferris, Douglas F Easton, Rebecca J Doherty, Brian HJ Briggs, Michelle Newman, Ifthikhar M Saraf, Sarah Scambler, Lyndon Wagman, Michael T Wyndham, Ann Ward, Rosalind A Eeles
Hereditary Cancer in Clinical Practice , 2007, DOI: 10.1186/1897-4287-5-3-157
Abstract: Population-based cohort study.A single general practice catchment area in North London.1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer.Incidence of breast cancer, ethnicity.This study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer.This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.General practice offers the doctor the privilege of caring for individuals and their families over many episodes and sometimes for many years, allowing doctors a unique insight into the impact of health and illness on individuals' physical and psychosocial wellbeing. This study was undertaken in a GP practice in a multi-ethnic catchment area in North-West London with a high proportion of Jewish families. Within this practice there was an apparent cluster of breast cancer diagnoses in young Jewish women under 45 years, a diagnosis which had obvious medical and psychosocial consequences for both the women themselves and their young families. This also had a presumed extended impact upon the close-knit Jewish
Ductal approaches to assessment and management of women at high risk for developing breast cancer
Imogen Locke, Gillian Mitchell, Rosalind Eeles
Breast Cancer Research , 2004, DOI: 10.1186/bcr759
Abstract: In the adult nonpregnant, nonlactating breast, fluid is secreted into the ducts and may contain exfoliated ductal epithelial cells along with foam cells, lymphocytes and neutrophils. Foam cells, thought to be of macrophage lineage, are the most abundant cells found within ductal fluid. They demonstrate CD68 macrophage-specific antibody staining and are usually negative for cytokeratin markers [1,2].The intraduct approach is an umbrella term for several different techniques, including nipple aspiration (NA), ductal lavage (DL) and duct endoscopy (DE), that allow sampling of breast fluid and exfoliated epithelial cells – the cells at risk for malignant transformation. DE also permits direct visualization of the epithelial lining of the milk ducts. NA and DL are minimally invasive techniques, whereas DE involves the cannulation of the mammary duct system by a fibreoptic ductoscope with an outer diameter typically less than 1 mm. Women may be at significantly increased lifetime risk for developing breast cancer because they have a significant family history of breast or ovarian cancer or a number of personal history factors. They may also be at heightened risk because of carriage of a known deleterious mutation in a highly penetrant breast cancer predisposition gene such as BRCA1 or BRCA2, or other mutations in rarer susceptibility alleles in genes including TP53, PTEN and the recently described lower penetrance 1100delC mutation in the cell cycle checkpoint kinase gene (CHEK 2) [3-6]. Carriers of mutations in BRCA1/2 have a lifetime risk for developing breast cancer of 60–85%, whereas germ-line mutations in TP53 confer a lifetime risk for breast cancer as high as 90% [7-9].Currently, women who carry mutations in high-risk breast cancer predisposition genes must make a difficult choice between regular surveillance, risk-reducing surgery, or taking part in trials of chemopreventive agents. The effectiveness of surveillance is uncertain and there are concerns about the hi
The Clinical Genetics of Prostate Cancer
Sashi Kommu, Stephen Edwards, Rosalind Eeles
Hereditary Cancer in Clinical Practice , 2004, DOI: 10.1186/1897-4287-2-3-111
Abstract: This article explores the current evidence that there is a genetic component to the aetiology of prostate cancer and attempts to put into context the diverse findings that have been shown to be possibly associated with the development of hereditary prostate cancer. Linkage searches over the last decade are summarised. It explores issues as to why understanding the genetics of prostate cancer has been so difficult and why despite this, it is still a major focus of research. Finally, current and future management strategies of men with Hereditary Prostate Cancer (HPC) are discussed.Prostate cancer is the most common cancer in men and the second highest cause of cancer-related mortality in the U.K. Family history is the strongest risk factor for prostate cancer. A man with one close relative (such as a father or a brother) with prostate cancer has twice the risk of developing prostate cancer as a man with no family history. If two close male relatives (such as a brother and a father) are affected, a man's lifetime risk of developing prostate cancer is increased fivefold. The degree of relative risk and the increase in its magnitude can be explained by a genetic effect in, at least, a component of the predisposing factors to this disease. It is now becoming clear that the identification of mutations in candidate prostate cancer predisposition genes is proving more difficult to be made than the identification of susceptibility genes for some other common cancers such as breast, ovary, and colon cancer.This difficulty of prostate cancer predisposition gene identification could be for several reasons. Firstly, prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation. This makes linkage in large pedigrees difficult. Secondly, the presence within high-risk pedigrees of phenocopies (those with prostate cancer, but without the genetic alteration) weakens the linkage results. Finally,
Developments in Clinical Practice: Follow up Clinic for BRCA Mutation Carriers: a Case Study Highlighting the "Virtual Clinic"
Audrey Ardern-Jones, Rosalind Eeles
Hereditary Cancer in Clinical Practice , 2004, DOI: 10.1186/1897-4287-2-2-77
Abstract: Families who harbour deleterious genetic alterations in a BRCA gene react differently according to their situation. Health professionals provide time and understanding within the genetic testing programme to help individuals consider their options before proceeding to genetic testing. Once the test result is confirmed, the affected person may consider new prevention options to reduce the risk of another cancer developing. These options may be discussed with the medical team who are trained in oncology and genetics. Patients who are gene mutation carriers and who have developed cancer have a risk to develop further primaries. Gene carriers who have developed cancer are managed under different units with specialists who may not have an in-depth understanding of the BRCA syndrome.The BRCA gene mutation carrier clinic of the Royal Marsden Hospital/Institute of Cancer Research has a threefold purpose [1]:1. Ongoing support of gene carrier families and patients. Annual appointments are made for these patients as well as access to a ''virtual telephone clinic''. The latter clinic is run by the nursing team who are trained in oncology and genetics and who probably know the family well.2. Clinical management issues: Discussions related to further surgical prevention procedures i.e. mastectomy, prophylactic oophorectomy. All information is given in the light of the current research.3. The opportunity for family members to participate in research. Within the Carrier Clinic of the Royal Marsden Hospital/Institute of Cancer Research there are several ongoing collaborative studies (as shown in Figure 1) and patients have the options to be involved in studies after full informed consent.There are nearly 200 patients who have BRCA gene mutations who are participating in this clinic. For some people, years later, the effort of attending a clinic diminishes its attraction, especially if they are unaffected and have chosen prophylactic surgery as an option. A ''virtual'' clinic has th
Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status
Emma Killick, Malgorzata Tymrakiewicz, Clara Cieza-Borrella, Paula Smith, Deborah J. Thompson, Karen A. Pooley, Doug F. Easton, Elizabeth Bancroft, Elizabeth Page, Daniel Leongamornlert, The IMPACT collaborators , Zsofia Kote-Jarai, Rosalind A. Eeles
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086659
Abstract: This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.
Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci
Dennis J. Hazelett ,Suhn Kyong Rhie,Malaina Gaddis,Chunli Yan,Daniel L. Lakeland,Simon G. Coetzee,Ellipse/GAME-ON consortium ?,Practical consortium ?,Brian E. Henderson,Houtan Noushmehr,Wendy Cozen,Zsofia Kote-Jarai,Rosalind A. Eeles,Douglas F. Easton,Christopher A. Haiman,Wange Lu,Peggy J. Farnham,Gerhard A. Coetzee
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004102
Abstract: Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations— we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at . 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium () with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.
Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer: the UK MARIBS study
Deborah J Thompson, Martin O Leach, Gek Kwan-Lim, Simon A Gayther, Susan J Ramus, Iqbal Warsi, Fiona Lennard, Michael Khazen, Emilie Bryant, Sadie Reed, Caroline RM Boggis, D Gareth Evans, Rosalind A Eeles, Douglas F Easton, Ruth ML Warren, The UK study of MRI screening for breast cancer in women at high risk (MARIBS)
Breast Cancer Research , 2009, DOI: 10.1186/bcr2447
Abstract: The analyses were based on MRI (n = 655) and mammography (n = 607) images obtained in the course of the UK multicentre magnetic resonance imaging breast screening (MARIBS) study of asymptomatic women aged 31 to 49 years who were at high genetic risk of breast cancer. The MRI percent and absolute dense volumes were estimated using our novel algorithm (MRIBview) while mammographic percent and absolute dense area were estimated using the Cumulus thresholding algorithm and also using a 21-point Visual Assessment scale for one medio-lateral oblique image per woman. We assessed the relationships of the MRI and mammographic measures to one another, to standard anthropometric and hormonal factors, to BRCA1/2 genetic status, and to breast cancer risk (60 cases) using linear and Poisson regression.MRI percent dense volume is well correlated with mammographic percent dense area (R = 0.76) but overall gives estimates 8.1 percentage points lower (P < 0.0001). Both show strong associations with established anthropometric and hormonal factors. Mammographic percent dense area, and to a lesser extent MRI percent dense volume were lower in BRCA1 carriers (P = 0.001, P = 0.010 respectively) but there was no association with BRCA2 carrier status. The study was underpowered to detect expected associations between percent density and breast cancer, but women with absolute MRI dense volume in the upper half of the distribution had double the risk of those in the lower half (P = 0.009).The MRIBview estimates of volumetric breast density are highly correlated with mammographic dense area but are not equivalent measures; the MRI absolute dense volume shows potential as a predictor of breast cancer risk that merits further investigation.Mammographic breast density is usually defined as the proportion of a mammographic image occupied by radiodense tissue (largely stromal and epithelial tissues, appearing as white regions) as opposed to nondense, fatty tissue (the darker regions of the image).
Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives
Audrey Ardern-Jones, Regina Kenen, Elly Lynch, Rebecca Doherty, Rosalind Eeles
Hereditary Cancer in Clinical Practice , 2010, DOI: 10.1186/1897-4287-8-1
Abstract: We conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive BRCA1/2 genetic diagnostic test (where no mutations or unclassified variants were identified). We arranged three focus groups for affected women and their close female relatives - 13 women took part. We also interviewed 12 health professionals who were involved in the care of these women.The majority of the women had a good grasp of the meaning of their own or a family member's inconclusive result, but a few indicated some misunderstanding. Most of the women in this study underwent the test for the benefit of others in the family and none mentioned that they were having the test purely for themselves. A difficult issue for sisters of affected women was whether or not to undertake prophylactic breast surgery. The professionals were sensitive to the difficulties in explaining an inconclusive result. Some felt frustrated that technology had not as yet provided them with a better tool for prediction of risk.Some of the women were left with the dilemma of what decision to make regarding medical management of their cancer risk. For the most part, the professionals believed that the women should be supported in whatever management decisions they considered best, provided these decisions were based on a complete and accurate understanding of the genetic test that had taken place in the family.In an investigation of psychosocial aspects of genetic counselling and testing, Vadaparampil et al (2004) concluded that a key area deserving research and clinical attention was the area of inconclusive test results [1]. Members of hereditary breast/ovarian cancer (HBOC) families who have been affected by cancer are offered testing for mutations in the BRCA1 and BRCA2 cancer predisposition genes with the hope of identifying the cause of the family's cancers. This can then provide information for others in the family about their own individual ri
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