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3 results on '"Duerst, M."'

1. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author

Glubb, DM, Johnatty, SE, Quinn, MCJ, O'Mara, TA, Tyrer, JP, Gao, B, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Edwards, DRV, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Thompson, PJ, Doerk, T, Duerst, M, Modungo, F, Moysich, K, Heitz, F, du Bois, A, Pfisterer, J, Hillemanns, P, Karlan, BY, Lester, J, Goode, EL, Cunningham, JM, Winham, SJ, Larson, MC, McCauley, BM, Kjaer, SK, Jensen, A, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Salvesen, HB, Bjorge, L, Webb, PM, Grant, P, Pejovic, T, Moffitt, M, Hogdall, CK, Hogdall, E, Paul, J, Glasspool, R, Bernardini, M, Tone, A, Huntsman, D, Woo, M, deFazio, A, Kennedy, CJ, Pharoah, PDP, MacGregor, S, Chenevix-Trench, G, Grp, AGOS, Grp, AOCS, Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
meta-analysis, genetic association, Oncology and Carcinogenesis, AGO Study Group, ovarian cancer outcome, gene regulation, health care economics and organizations
Abstract

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p

Published
2017
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2. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author

Painter, J.N., O'Mara, T.A., Batra, J., Cheng, T., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Kaufmann, S., Hillman, K.M., Walpole, C., Moya, L., Pollock, P., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Magdalena Echeverry De Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Santos, E., Teixeira, M.R., Carvajal-Carmona, L., Shu, X-O., Long, J., Zheng, W., Xiang, Y-B., Montgomery, G.W., Webb, P.M., Scott, R.J., McEvoy, M., Attia, J., Holliday, E., Martin, N.G., Nyholt, D.R., Henders, A.K., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Ashton, K., Proietto, T., Otton, G., Tzortzatos, G., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., French, J.D., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Edwards, S.L., Thompson, D.J., Spurdle, A.B., Canc, N.S.E., Consortium, CHIBCHA, Canc, ANE, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository

Subjects
Genotype, Chromosome Mapping, Computational Biology, Genetic Variation, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Endometrial Neoplasms, Epigenesis, Genetic, Haplotypes, Genetic Loci, Risk Factors, Case-Control Studies, Cell Line, Tumor, Databases, Genetic, Humans, Female, RNA, Messenger, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. ispartof: Human Molecular Genetics vol:24 issue:5 pages:1478-92 ispartof: location:England status: published

Published
2015

3. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N.., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Pooley, K., Beesley, J., Cheng, T., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Wentzensen, N., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Scott, R.J., Ashton, K., Proietto, T., Otton, G., Wersaell, O., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A.-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Spurdle, A.B., Thompson, D.J., NSECG, ANECS, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
National Study of Endometrial Cancer Genetics Group, Australian Ovarian Cancer Study, Polymorphism, Single Nucleotide, Chromosomes, Promoter Regions, Paediatrics and Reproductive Medicine, Databases, Uterine Cancer, Genetic, Complementary and Alternative Medicine, Risk Factors, Models, Australian National Endometrial Cancer Study Group, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Testing, Aetiology, Polymorphism, Promoter Regions, Genetic, Telomerase, Cancer, Genetics & Heredity, Neoplastic, Models, Genetic, Nucleic Acid, RENDOCAS, Prevention, Human Genome, Membrane Proteins, Single Nucleotide, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Haplotypes, Genetic Loci, Chromosomes, Human, Pair 5, Female, GENICA Network, Pair 5, Databases, Nucleic Acid, Human
Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. ispartof: Human Genetics vol:134 issue:2 pages:231-45 ispartof: location:Germany status: published

Published
2015

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