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Search Results: 1 - 10 of 402483 matches for " Alison M Dunning "
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Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk
Paul D. P Pharoah ,Jonathan Tyrer,Alison M Dunning,Douglas F Easton,Bruce A. J Ponder,SEARCH Investigators
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030042
Abstract: Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran–Armitage trend test (p-trend) and a two-degrees of freedom χ2 test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 10?5) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case–control study
Patrick R Benusiglio, Fabienne Lesueur, Craig Luccarini, Donald M Conroy, Mitul Shah, Douglas F Easton, Nick E Day, Alison M Dunning, Paul D Pharoah, Bruce AJ Ponder
Breast Cancer Research , 2005, DOI: 10.1186/bcr982
Abstract: We aimed to determine if common polymorphisms (frequency ≥ 5%) in ERBB2 were associated with breast cancer risk in a white British population. Five single-nucleotide polymorphisms (SNPs) were selected for study: SNP 1 near the promoter, SNP 2 in intron 1, SNP 3 in intron 4, SNP 4 in exon 17 (I655V), and SNP 5 in exon 27 (A1170P). We tested their association with breast cancer in a large case–control study (n = 2192 cases and 2257 controls).There were no differences in genotype frequencies between cases and controls for any of the SNPs examined. To investigate the possibility that a common polymorphism not included in our study might be involved in breast cancer predisposition, we also constructed multilocus haplotypes. Our set of SNPs generated all existing (n = 6) common haplotypes and no differences were seen in haplotype frequencies between cases and controls (P = 0.44).In our population, common ERBB2 polymorphisms are not involved in predisposition to breast cancer.Breast cancer is the most common cause of cancer in women in the United Kingdom and is, after lung cancer, the most common cause of cancer death (Office for National Statistics). Positive family history is a well-established risk factor for the disease: the risk to first-degree relatives of a breast cancer case is about twice the population risk [1]. Most of the excess familial risk associated with breast cancer is likely to be genetic in origin [2,3]. However, only about a third of this risk is accounted for by known genes, the most important being BRCA1 and BRCA2, while the remainder might be explained by a combination of weakly predisposing alleles [2-4]. A gene thought to be involved in low-level susceptibility to breast cancer is ERBB2 (HER2). This gene is located on chromosome 17q12–q21, spans 38 kilobases, and comprises 27 coding exons. It is a member of the ERBB family, a family of protein tyrosine kinases involved in cell division, migration, adhesion, differentiation, and apoptosis and consi
Saliva samples are a viable alternative to blood samples as a source of DNA for high throughput genotyping
Jean E Abraham, Mel J Maranian, Inmaculada Spiteri, Roslin Russell, Susan Ingle, Craig Luccarini, Helena M Earl, Paul DP Pharoah, Alison M Dunning, Carlos Caldas
BMC Medical Genomics , 2012, DOI: 10.1186/1755-8794-5-19
Abstract: Patients were recruited from the Pharmacogenetics of Breast Cancer Chemotherapy (PGSNPS) study. Paired blood and saliva samples were collected from 79 study participants. The Oragene DNA Self-Collection kit (DNAgenotek?) was used to collect and extract DNA from saliva. DNA from EDTA blood samples (median volume 8 ml) was extracted by Gen-Probe, Livingstone, UK. DNA yields, standard measures of DNA quality, genotype call rates and genotype concordance between paired, duplicated samples were assessed.Total DNA yields were lower from saliva (mean 24 μg, range 0.2–52 μg) than from blood (mean 210 μg, range 58–577 μg) and a 2-fold difference remained after adjusting for the volume of biological material collected. Protein contamination and DNA fragmentation measures were greater in saliva DNA. 78/79 saliva samples yielded sufficient DNA for use on Illumina Beadchip arrays and using Taqman assays. Four samples were randomly selected for genotyping in duplicate on the Illumina Beadchip arrays. All samples were genotyped using Taqman assays. DNA quality, as assessed by genotype call rates and genotype concordance between matched pairs of DNA was high (>97%) for each measure in both blood and saliva-derived DNA.We conclude that DNA from saliva and blood samples is comparable when genotyping using either Taqman assays or genome-wide chip arrays. Saliva sampling has the potential to increase participant recruitment within clinical trials, as well as reducing the resources and organisation required for multicentre sample collection.
Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis
Hongxia Ma,Ziyuan Zhou,Sheng Wei,Zhensheng Liu,Karen A. Pooley,Alison M. Dunning,Ulrika Svenson,G?ran Roos,H. Dean Hosgood III,Min Shen,Qingyi Wei
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020466
Abstract: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting.
Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design
Helen I Field, Serena A Scollen, Craig Luccarini, Caroline Baynes, Jonathan Morrison, Alison M Dunning, Douglas F Easton, Paul DP Pharoah
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-180
Abstract: We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design.The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5).Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation.Seq4SNPs is available as a service at http://moya.srl.cam.ac.uk/oncology/bio/s4shome.html webcite and http://moya.srl.cam.ac.uk/cgi-bin/oncology/srl/ncbi/seq4snp1.pl webcite, currently for human SNPs, but easily extended to include any species in dbSNP.A survey of single nucleotide polymorphism (SNP) and primer design software reveals several packages that align EST or genome sequences to discover SNPs [1-6]. SNP-VISTA visualizes SNPs from aligned genome sequences [7]. Other packages take a chromosome region then use recorded SNP genotypes, and additional information, to reduce the set of SNPs that need genotyping [[8,9] and references therein]. SNP i
CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen
Jean E Abraham, Mel J Maranian, Kristy E Driver, Radka Platte, Bolot Kalmyrzaev, Caroline Baynes, Craig Luccarini, Mitul Shah, Susan Ingle, David Greenberg, Helena M Earl, Alison M Dunning, Paul DP Pharoah, Carlos Caldas
Breast Cancer Research , 2010, DOI: 10.1186/bcr2629
Abstract: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis.In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups.CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.Tamoxifen has been the standard treatment for oestrogen receptor (ER)-positive breast cancer for more than three decades. Indications for its use [1] include: metastatic disease in women (pre- and post-menopausal) and men; adjuvant therapy in pre- and post-menopausal women with breast cancer (lymph node positive and negative); preventative therapy in women at high risk of breast cancer; ductal carcinoma in situ post-resection; and for the prevention of contra-lateral breast cancer. There are proven benefits ass
Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk
Caroline Baynes, Catherine S Healey, Karen A Pooley, Serena Scollen, Robert N Luben, Deborah J Thompson, Paul DP Pharoah, Douglas F Easton, Bruce AJ Ponder, Alison M Dunning, the SEARCH breast cancer study
Breast Cancer Research , 2007, DOI: 10.1186/bcr1669
Abstract: We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.No significant breast cancer associations were detected with any individual or combination of tag SNPs.It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.Four of the genes which lie in the DNA damage-recognition and repair pathway, ATM, BRCA1, BRCA2 and TP53, have mutations that are recognised to increase breast cancer susceptibility with moderate to high penetrance. Such mutations are very rare, and most probably of recent origin. A fifth gene, CHEK2, in the same pathway, has a deletion (1100delC) that reaches polymorphic frequencies (>0.01) in some European countries and doubles the risk of breast cancer in female carriers [1]. Together these mutations account for only a small proportion (2% to 5%) of all breast cancer incidences [2,3]. Breast cancer is, however, a common disease and genetic epidemiological data suggest that there is a low-penetrance genetic contribution to most cases [4,5]. It is likely that at least a part of breast cancer aetiology will fit the common disease-common variant hypothesis, which states that patients with a common, complex disease are likely to share some common, low-penetrance alleles that increase their susceptibility to that disease. This raises the question of whether such common, polymorphic susceptibility alleles exist within these five genes in addition t
Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies
Linda E Kelemen, Fergus J Couch, Shahana Ahmed, Alison M Dunning, Paul DP Pharoah, Douglas F Easton, Zachary S Fredericksen, Robert A Vierkant, V Shane Pankratz, Ellen L Goode, Christopher G Scott, David N Rider, Xianshu Wang, James R Cerhan, Celine M Vachon
Breast Cancer Research , 2008, DOI: 10.1186/bcr2201
Abstract: We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)).In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (Ptrend ≤ 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes.Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer.Stromal changes are well documented in breast tumors [1,2] and in preinvasive breast lesions [2
Genetic Variants in ER Cofactor Genes and Endometrial Cancer Risk
Yuqing Li, Hui-Qi Low, Jia Nee Foo, Hatef Darabi, Kristjana Einarsd?ttir, Keith Humphreys, Amanda Spurdle, ANECS Group , Douglas F. Easton, Deborah J. Thompson, Alison M. Dunning, Paul D. P. Pharoah, Kamila Czene, Kee Seng Chia, Per Hall, Jianjun Liu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042445
Abstract: Given that the transcriptional regulatory activity of estrogen receptor (ER) is modulated by its biochemical cofactors, genetic variation within the ER cofactor genes may alter cellular response to estrogen exposure and consequently modify the risk for endometrial cancer. We genotyped 685 tagging SNPs within 60 ER cofactor genes in 564 endometrial cancer cases and 1,510 controls from Sweden, and tested their associations with the risk of endometrial cancer. We investigated the associations of individual SNPs by using a trend test as well as multiple SNPs within a gene or gene complex by using multi-variant association analysis. No significant association was observed for any individual SNPs or genes, but a marginal association of the cumulative genetic variation of the NCOA2 complex as a whole (NCOA2, CARM1, CREBBP, PRMT1 and EP300) with endometrial cancer risk was observed (Padjusted = 0.033). However, the association failed to be replicated in an independent European dataset of 1265 cases and 5190 controls (P = 0.71). The results indicate that common genetic variants within ER cofactor genes are unlikely to play a significant role in endometrial cancer risk in European population.
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.
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