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Search Results: 1 - 10 of 469856 matches for " Simon A Gayther "
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Ovarian Cancer: A Clinical Challenge That Needs Some Basic Answers
Kate Lawrenson,Simon A Gayther
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000025
Cancer Stem Cells and Epithelial Ovarian Cancer
Sheetal Dyall,Simon A. Gayther,Dimitra Dafou
Journal of Oncology , 2010, DOI: 10.1155/2010/105269
Abstract: The cancer stem cell hypothesis is becoming more widely accepted as a model for carcinogenesis. Tumours are heterogeneous both at the molecular and cellular level, containing a small population of cells that possess highly tumourigenic “stem-cell” properties. Cancer stem cells (CSCs), or tumour-initiating cells, have the ability to self-renew, generate xenografts reminiscent of the primary tumour that they were derived from, and are chemoresistant. The characterisation of the CSC population within a tumour that drives its growth could provide novel target therapeutics against these cells specifically, eradicating the cancer completely. There have been several reports describing the isolation of putative cancer stem cell populations in several cancers; however, no defined set of markers has been identified that conclusively characterises “stem-like” cancer cells. This paper highlights the current experimental approaches that have been used in the field and discusses their limitations, with specific emphasis on the identification and characterisation of the CSC population in epithelial ovarian cancer. 1. Introduction Ovarian cancer (OC) is the sixth most lethal malignancy in women in the western world. Over 90% of malignant tumours are epithelial. It has been hypothesised that tumours can arise either from a single layer of cells covering the ovary (the ovarian surface epithelium or OSE) or from the epithelial lining of the fimbrial end of the fallopian tube [1]. The aetiology of OC remains poorly understood. One proposed model is the incessant ovulation hypothesis, which postulates that continuous rupture of the OSE during ovulation and subsequent cell proliferation leading to repair make OSE cells more susceptible to malignant transformation. Approximately 70% of patients diagnosed with ovarian cancer have advanced stage disease, partly because symptoms are vague and can be confused with gastrointestinal complaints (e.g., bloating, constipation and mild abdominal pain) [2, 3]. Despite improvements in debulking surgery and initial good responses to platinum-based chemotherapies, survival rates for the disease remain poor due to the development of chemoresistant disease, and less than 60% of cases survive more than 5 years. Thus, the identification of molecular markers that target chemoresistance may represent suitable targets for new therapeutic approaches for epithelial ovarian cancers (EOC). The mechanisms underlying chemoresistance in cancer are not clear. One hypothesis is that cancers are driven by a subset of highly tumourigenic cells with stem
A Perl toolkit for LIMS development
James A Morris, Simon A Gayther, Ian J Jacobs, Christopher Jones
Source Code for Biology and Medicine , 2008, DOI: 10.1186/1751-0473-3-4
Abstract: We have developed ArrayPipeline, a Perl toolkit providing object oriented methods that facilitate the rapid development of bespoke LIMS applications. The toolkit includes Perl objects that encapsulate key components of a LIMS, providing methods for creating interactive web pages, interacting with databases, error tracking and reporting, and user and session management. The MT_Plate object provides methods for manipulation and management of microtitre plates, while a given LIMS can be encapsulated by extension of the core modules, providing system specific methods for database interaction and web page management.This important addition to the Perl developer's library will make the development of in house LIMS applications quicker and easier encouraging laboratories to create bespoke LIMS applications to meet their specific data management requirements.High throughput investigation techniques such as microarrays are now well established in scientific research. As the costs of these techniques fall, greater numbers of laboratories are adopting these approaches. High throughput techniques and the equipment associated with them provide researchers with a number of new challenges, one of which is the management and storage of the vast quantities of data they generate. Laboratory notebooks and computer spreadsheets still form the data management strategy for many research scientists, and this simple approach has advantages in the ease of storage and viewing of the data for low throughput approaches however this approach is inadequate for the amounts of data generated using the latest laboratory techniques.The solution to this data management challenge is the implementation of a Laboratory Information Management System (LIMS), a computer application designed to track samples, store data generated by laboratory equipment and experiments and report these data. There are numerous commercial LIMS applications available however these can be very costly and sometimes overly compl
An Epigenetic Signature in Peripheral Blood Predicts Active Ovarian Cancer
Andrew E. Teschendorff,Usha Menon,Aleksandra Gentry-Maharaj,Susan J. Ramus,Simon A. Gayther,Sophia Apostolidou,Allison Jones,Matthias Lechner,Stephan Beck,Ian J. Jacobs,Martin Widschwendter
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008274
Abstract: Recent studies have shown that DNA methylation (DNAm) markers in peripheral blood may hold promise as diagnostic or early detection/risk markers for epithelial cancers. However, to date no study has evaluated the diagnostic and predictive potential of such markers in a large case control cohort and on a genome-wide basis.
BRCA1 and BRCA2 mutations in a population-based study of male breast cancer
Victoria M Basham, Julian M Lipscombe, Joanna M Ward, Simon A Gayther, Bruce AJ Ponder, Douglas F Easton, Paul DP Pharoah
Breast Cancer Research , 2001, DOI: 10.1186/bcr419
Abstract: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk.Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives.These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found.Male breast cancer (MBC) is a rare disease and little is known about its aetiology. However, female first-degree relatives of MBC cases are at increased risk of breast cancer [1,2,3,4,5,6], which suggests that there is an inherited component to the disease. Several genes that are associated with a high lifetime risk of breast cancer in women have been identified during the past decade. One of these, BRCA2, has also been shown to confer a significant risk of breast cancer in men, and a recent study found the risk of breast cancer in male BRCA2 mutation carriers from multiple case breast/ovarian cancer families to be 80-fold higher than in the general population [7]. This equates to a 7% risk of breast cancer by age 80. The prevalence of BRCA2 mutations in MBC cases unselected for family history has been estimated in
Tagging Single Nucleotide Polymorphisms in the BRIP1 Gene and Susceptibility to Breast and Ovarian Cancer
Honglin Song, Susan J. Ramus, Susanne Krüger Kjaer, Estrid Hogdall, Richard A. DiCioccio, Alice S. Whittemore, Valerie McGuire, Claus Hogdall, Ian J. Jacobs, Douglas F. Easton, Bruce A.J. Ponder, Alison M. Dunning, Simon A. Gayther, Paul D.P. Pharoah
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000268
Abstract: Background BRIP1 interacts with BRCA1 and functions in regulating DNA double strand break repair pathways. Germline BRIP1 mutations are associated with breast cancer and Fanconi anemia. Thus, common variants in the BRIP1 are candidates for breast and ovarian cancer susceptibility. Methods We used a SNP tagging approach to evaluate the association between common variants (minor allele frequency≥0.05) in BRIP1 and the risks of breast cancer and invasive ovarian cancer. 12 tagging SNPs (tSNPs) in the gene were identified and genotyped in up to 2,270 breast cancer cases and 2,280 controls from the UK and up to 1,513 invasive ovarian cancer cases and 2,515 controls from the UK, Denmark and USA. Genotype frequencies in cases and controls were compared using logistic regression. Results Two tSNPs showed a marginal significant association with ovarian cancer: Carriers of the minor allele of rs2191249 were at reduced risk compared with the common homozygotes (Odds Ratio (OR) = 0.90 (95% CI, 0.82–1.0), P-trend = 0.045) and the minor allele of rs4988344 was associated with increased risk (OR = 1.15 (95%CI, 1.02–1.30), P-trend = 0.02). When the analyses were restricted to serous ovarian cancers, these effects became slightly stronger. These results were not significant at the 5% level after adjusting for multiple testing. None of the tSNPs was associated with breast cancer. Conclusions It is unlikely that common variants in BRIP1 contribute significantly to breast cancer susceptibility. The possible association of rs2191249 and rs4988344 with ovarian cancer risks warrant confirmation in independent case-control studies.
Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer
Lydia Quaye, Jonathan Tyrer, Susan J. Ramus, Honglin Song, Eva Wozniak, Richard A. DiCioccio, Valerie McGuire, Estrid H?gdall, Claus H?gdall, Jan Blaakaer, Ellen L. Goode, Joellen M. Schildkraut, Douglas F. Easton, Susanne Krüger-Kjaer, Alice S. Whittemore, Simon A. Gayther, Paul D. P. Pharoah
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005983
Abstract: Background Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. Methods We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. Results After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). Conclusion These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.
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).
A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival
Jyotsna Batra, Christina M Nagle, Tracy O'Mara, Melanie Higgins, Ying Dong, Olivia L Tan, Felicity Lose, Lene Skeie, Srilakshmi Srinivasan, Kelly L Bolton, Honglin Song, Susan J Ramus, Simon A Gayther, Paul DP Pharoah, Mary-Anne Kedda, Amanda B Spurdle, Judith A Clements
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-119
Abstract: In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site.We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.Ovarian cancer is an aggressive disease with high metastatic potential and is frequently diagnosed at an advanced stage [1,2]. In vitro studies show that malignant cells synthesize and secrete proteolytic enzymes which disrupt basement and extracellular membranes to allow malignant cells to invade neighboring tissues and metastasize [3]. Members of the Kallikrein-related (KLK) peptidase family are part of a proteolytic enzymatic cascade activated in aggressive forms of hormone-related cancers including ovarian cancer [4-6]. The KLKs are encoded by a 15-member gene family clustered together in a region of approximately 320 kb on chromosome 19q13.4 [5-7]. KLK15 (encoding for KLK15, previously reported as hK15, or prostinogen) is the most recently cloned member of the human kallikrein g
Inherited Variants in Regulatory T Cell Genes and Outcome of Ovarian Cancer
Ellen L. Goode, Melissa DeRycke, Kimberly R. Kalli, Ann L. Oberg, Julie M. Cunningham, Matthew J. Maurer, Brooke L. Fridley, Sebastian M. Armasu, Daniel J. Serie, Priya Ramar, Krista Goergen, Robert A. Vierkant, David N. Rider, Hugues Sicotte, Chen Wang, Boris Winterhoff, Catherine M. Phelan, Joellen M. Schildkraut, Rachel P. Weber, Ed Iversen, Andrew Berchuck, Rebecca Sutphen, Michael J. Birrer, Shalaka Hampras, Leah Preus, Simon A. Gayther, Susan J. Ramus, Nicolas Wentzensen, Hannah P. Yang, Montserrat Garcia-Closas, Honglin Song, Jonathan Tyrer, Paul P. D. Pharoah, Gottfried Konecny, Thomas A. Sellers, Roberta B. Ness, Lara E. Sucheston, Kunle Odunsi, Lynn C. Hartmann, Kirsten B. Moysich, Keith L. Knutson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053903
Abstract: Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10?5), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10?4, and rs3753348, p = 9.0×10?4, respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10?4). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10?4) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.
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