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Search Results: 1 - 10 of 5534 matches for " Diana Eccles "
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Identification of personal risk of breast cancer: genetics
Diana M Eccles
Breast Cancer Research , 2008, DOI: 10.1186/bcr2172
Abstract: A second major breast cancer susceptibility gene, BRCA2, was mapped to chromosome 13q in 1994 shortly before the sequence of the BRCA1 gene was clarified and family-specific disease-causing mutations started to be reported [5,6]. The full BRCA2 gene sequence was reported in 1995 [7]. Families with mutations in the BRCA2 gene were noted to be more likely to contain a male breast cancer case than might be expected by chance (and more than had been seen in families due to BRCA1 mutations); ovarian and fallopian tube cancers still occurred with increased frequency but overall not as frequently as in BRCA1-associated families. With the discovery of the correct gene sequences for BRCA1 and BRCA2 it became possible to offer predictive genetic testing to members of families in which the causative gene mutation had been identified. Predictive testing for breast cancer susceptibility was introduced as a clinical service from the mid-1990s in some centres in the UK [8]. Families in which mutations were identified through research studies were the first to be informed [9]. Many of these families had been identified because of their high incidence of cancer, and so inevitably the estimated lifetime chance that a carrier of one of these genes would develop cancer was high [10,11].The BRCA1 and BRCA2 genes are very large, and mutation testing was either very expensive (in the USA) or very slow (in European countries) when it first became available. It soon became clear that mutations in these genes accounted for a relatively small proportion of all families with breast cancer clusters. Families with four or more cancer cases developing at young age, particularly those families in which ovarian cancers occurred, were more likely to yield pathogenic mutations when DNA from a cancer-affected family member was screened for mutations. Smaller clusters of later onset cancers, although clearly familial, were noted to have a much lower probability of harbouring a BRCA1 or BRCA2 mutation [
Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol
Diana Eccles, Sue Gerty, Peter Simmonds, Victoria Hammond, Sarah Ennis, Douglas G Altman, the POSH steering group
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-160
Abstract: The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period.Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward.Less than 5% of breast cancers diagnosed in the UK are diagnosed in women aged 40 years or younger although there is a rapid increase in the incidence from about 35 years of age[1].Published retrospective studies suggest that early age at onset of breast cancer (below 35 years) is a poor prognosis factor; high grade and oestrogen receptor (ER) negative tumours appear to be more frequent in younger women[2,3]. Breast cancer arising due to a high penetrance genetic predisposition gene such as BRCA1 or BRCA2 occurs at younger average age than breast cancer in the general population and a higher proportion of young onset cases will have a genetic predisposition than breast cancer cases in general. Family history is still the most important indicator of an underlying inherited predisposition [4]. However BRCA1 and BRCA2 may account for less than 40% of all familia
The DNMT3B C→T promoter polymorphism and risk of breast cancer in a British population: a case-control study
Karen G Montgomery, Mira CP Liu, Diana M Eccles, Ian G Campbell
Breast Cancer Research , 2004, DOI: 10.1186/bcr807
Abstract: To determine the role of this polymorphism in breast cancer, we genotyped 352 cases and 258 controls from a British population. The breast cancer cases were selected on the basis of either an age at onset of less than 40 years, a family history of breast cancer irrespective of age at onset, or bilateral breast cancer diagnosed after 39 years of age irrespective of family history.The C allele was found to be more common in case subjects than in control subjects (cases, 0.59; controls, 0.54) corresponding to a nominally significant increase in breast cancer risk to heterozygotes and CC homozygotes (odds ratio 1.51, 95% confidence interval 1.01–2.25) in the dominant inheritance model.Our findings contrast with those of a previous study, which showed that individuals carrying at least one T allele have a significantly increased risk of developing lung cancer. This discrepancy might be an artefact resulting from a chance variation, or it might point to differing influences of promoter hypermethylation in these cancer types.Genetic factors are increasingly being recognised as a major contributor to cancer risk [1,2]. Although genes with highly penetrant mutations, exemplified by BRCA1 and BRCA2, confer a high relative risk, they are rare in the general population and therefore the population attributable risk is low. It is now suspected that most of the population attributable genetic risk is due to relatively common 'low-penetrance' disease-associated allelic variants. Although these variants might confer a small absolute cancer risk, this is outweighed by the fact that they are very common in the general population [2]. Recognition of this fact has led to an explosion of epidemiological studies searching for common polymorphisms in genes that might represent susceptibility alleles [3,4]. Among the most promising candidates are genes involved in the maintenance of genomic integrity and DNA repair, which include genes such as BRCA1, BRCA2 and TP53 [5-8]. These and other f
Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer
Ian G Campbell, Simon W Baxter, Diana M Eccles, David YH Choong
Breast Cancer Research , 2002, DOI: 10.1186/bcr457
Abstract: We have investigated the possible influence of this MTHFR variant on breast cancer risk in a case-control study of 233 healthy women and 335 women who had breast cancer that occurred under the age of 40 years, bilateral breast cancer or a family history of breast cancer.A significant excess of the valine genotypes was observed among the cases (odds ratio 1.43, 95% confidence interval 1.02–2.00). The effect was more pronounced among the cases with a breast cancer diagnosis under the age of 40 years, with an odds ratio of 1.66 (95% confidence interval 1.12–2.41). A nonsignificant excess of the valine genotypes was observed among the cases with a family history of breast cancer or bilateral breast cancer.The low activity C677T (valine) genotype of MTHFR may increase the risk of early onset breast cancer.The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the carbon donor for de novo methionine synthesis and DNA methylation. Approximately 10% of Caucasian populations are homozygous for a common C→T substitution at nucleotide 677 of the MTHFR gene. This mutation converts an alanine to a valine at codon 225 and is associated with reduced enzyme activity and increased thermolability [1]. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair makes MTHFR an attractive candidate for a cancer predisposing gene [2,3].Deficiencies in thymidylate have been shown to increase the rate of misincorporation of uridylate into DNA and may in turn lead to an increased rate of DNA strand breaks and other chromosomal damage [4]. Consequently, reduced MTHFR activity, which leads to increased levels of cytosolic 5,10-methylenetetrahydrofolate available for thymidylate synthesis, may protect cells from DNA damage induced by uridylate misincorporation. Consistent with this model, several independent st
Support Vector Machine Classifier for Estrogen Receptor Positive and Negative Early-Onset Breast Cancer
Rosanna Upstill-Goddard, Diana Eccles, Sarah Ennis, Sajjad Rafiq, William Tapper, Joerg Fliege, Andrew Collins
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068606
Abstract: Two major breast cancer sub-types are defined by the expression of estrogen receptors on tumour cells. Cancers with large numbers of receptors are termed estrogen receptor positive and those with few are estrogen receptor negative. Using genome-wide single nucleotide polymorphism genotype data for a sample of early-onset breast cancer patients we developed a Support Vector Machine (SVM) classifier from 200 germline variants associated with estrogen receptor status (p<0.0005). Using a linear kernel Support Vector Machine, we achieved classification accuracy exceeding 93%. The model indicates that polygenic variation in more than 100 genes is likely to underlie the estrogen receptor phenotype in early-onset breast cancer. Functional classification of the genes involved identifies enrichment of functions linked to the immune system, which is consistent with the current understanding of the biological role of estrogen receptors in breast cancer.
Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers
Ellen R Copson, Helen E White, Jeremy P Blaydes, David O Robinson, Peter W Johnson, Diana M Eccles
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-80
Abstract: Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology? was used to determine the genotype at the MDM2 SNP309 locus.The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80).We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.Inheritance of a truncating mutation of the breast cancer predisposition gene BRCA1 has been reported to carry a lifetime risk of breast cancer of between 50 and 80%, with age at onset of first malignancy varying from the 2nd to the 8th decade [1,2]. Clinical studies indicate that BRCA1 mutation carriers can benefit significantly from preventative surgery, with prophylactic oophorectomy reducing breast cancer rates by up to 60% and ovarian cancer rates by 95%, and prophylactic double mastectomy reducing the incidence of breast cancer by up to 90% [3,4]. These two interventions are however major surgical procedures with potentially significant psychological and medical sequelae. The ability to predict whether a BRCA1 mutation carrier is likely to develop malignant disease early or late in life would facilitate the clinical management of these patients.No differences in penetrance have yet been documented for different BRCA1 truncating mutations [2]. Inter-individual variation in the speed at which BRCA1 mutation carriers develop cancer is likely to be influenced by environmental factors, but may also be affected by co-inheritance of othe
A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer
Ella Thompson, Rebecca L Dragovic, Sally-Anne Stephenson, Diana M Eccles, Ian G Campbell, Alexander Dobrovic
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-43
Abstract: We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer.The duplication allele had a frequency of 0.34 in the normal controls. There was a non-significant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours.The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer.Fanconi anaemia is a rare autosomal recessive disorder characterised by congenital abnormalities, progressive bone marrow failure, and predisposition to acute myelogenous leukemia and other malignancies. At the cellular level, the disease is characterised by an inability to repair cross-linked DNA [1]. There are multiple genes in which mutations can give rise to Fanconi anaemia.The FANCA gene is defective in more than 65% of Fanconi anaemia cases. FANCA and five other Fanconi anaemia genes code for components of a complex that is required for the ubiquitination of FANCD2 in response to DNA damage. Ubiquitinated FANCD2 is targeted to nuclear foci of DNA repair proteins including BRCA1 and RAD51 (reviewed in [2]). The complex also interacts directly with the FANCD1 protein [3]), now known to be the product of the breast and ovarian cancer predisposition gene, BRCA2 [4]. As individuals heterozygous for BRCA2 mutations have a high lifetime risk of acquiring breast and ovarian cancer, it is likely that alterations in other Fanconi anaemia genes might be associated with an increased risk of breast and ovarian cancer.In human breast and ovarian cancers, recurrent loss of heterozygosity has been shown t
Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis
Francesca Pigatto, Adrian Bateman, David Bunyan, Paul Strike, Esta Wilkins, Claire Curtis, Philippa Duncan, Denzil May, Karen Nugent, Diana Eccles
Hereditary Cancer in Clinical Practice , 2004, DOI: 10.1186/1897-4287-2-4-175
Abstract: 138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined.Clearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools.A cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection.Hereditary non-polyposis colorectal cancer (HNPCC) accounts for around 2-3% of all colorectal cancers and is an autosomal dominant cancer predisposition syndrome caused primarily by inactivating mutations in one of the genes involved in DNA mismatch repair (MMR), most commonly MLH1 and MSH2 [1-3]. HNPCC is characterised clinically by an early age of onset, a predominance of right-sided tumours and a high frequency of synchronous and metachronous cancers.It is important to diagnose HNPCC because colonoscopic surveillance with removal of adenomas and detection of early carcinomas reduces the colorectal cancer (CRC) rate and overall mortality in HNPCC mutation carriers [4].DNA analysis in many diagnostic laboratories has concentrated on the two most frequently affected genes, hMLH1 and hMSH2. Both are moderately large genes and mutations are scattered throughout making mutation searching expensive. The benefits of finding a pathogenic mutation are clear; co
The size of maximal systems of brick islands
Tom Eccles
Mathematics , 2010,
Abstract: For integers $m_1,...,m_d>0$ and a cuboid $M=[0,m_1]\times ... \times [0,m_d]\subset \mathbb{R}^d$, a brick of $M$ is a closed cuboid whose vertices have integer coordinates. A set $H$ of bricks in $M$ is a system of brick islands if for each pair of bricks in $H$ one contains the other or they are disjoint. Such a system is maximal if it cannot be extended to a larger system of brick islands. Extending the work of Lengv\'{a}rszky, we show that the minimum size of a maximal system of brick islands in $M$ is $\sum_{i=1}^d m_i - (d-1)$. Also, in a cube $C=[0,m]^d$ we define the corresponding notion of a system of cubic islands, and prove bounds on the sizes of maximal systems of cubic islands.
A stability result for the union-closed size problem
Tom Eccles
Mathematics , 2013, DOI: 10.1017/S0963548315000176
Abstract: A family of sets is called union-closed if whenever $A$ and $B$ are sets of the family, so is $A\cup B$. The long-standing union-closed conjecture states that if a family of subsets of $[n]$ is union-closed, some element appears in at least half the sets of the family. A natural weakening is that the union-closed conjecture holds for large families; that is, families consisting of at least $p_02^n$ sets for some constant $p_0$. The first result in this direction appears in a recent paper of Balla, Bollob\'as and Eccles \cite{BaBoEc}, who showed that union-closed families of at least $\frac{2}{3}2^n$ sets satisfy the conjecture --- they proved this by determining the minimum possible average size of a set in a union-closed family of given size. However, the methods used in that paper cannot prove a better constant than $\frac{2}{3}$. Here, we provide a stability result for the main theorem of \cite{BaBoEc}, and as a consequence we prove the union-closed conjecture for families of at least $(\frac{2}{3}-c)2^n$ sets, for a positive constant $c$.
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