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1. CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Author: Thompson, Deborah J, O'Mara, Tracy A, Glubb, Dylan M, Painter, Jodie N, Cheng, Timothy, Folkerd, Elizabeth, Doody, Deborah, Dennis, Joe, Webb, Penelope M, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley, Michailidou, Kyriaki, Tyrer, Jonathan P, Maranian, Mel J, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Zhao, Hui, Depreeuw, Jeroen, Schrauwen, Stefanie, Amant, Frederic, Goode, Ellen L, Fridley, Brooke L, Dowdy, Sean C, Winham, Stacey J, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Carvajal-Carmona, Luis, Tham, Emma, Liu, Tao, Mints, Miriam, Scott, Rodney J, McEvoy, Mark, Attia, John, Holliday, Elizabeth G, Montgomery, Grant W, Martin, Nicholas G, Nyholt, Dale R, Henders, Anjali K, Hopper, John L, Traficante, Nadia, Ruebner, Matthias, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Lambrechts, Diether, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Bolla, Manjeet K, Wang, Qin, Bojesen, Stig E, Shah, Mitul, Luben, Robert, Khaw, Kay-Tee, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Dowsett, Mitch, Easton, Douglas F, and Spurdle, Amanda B
Subjects: Uterine Cancer, Genetics, Cancer, Prevention, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Age Factors, Alleles, Aromatase, Body Mass Index, Case-Control Studies, Endometrial Neoplasms, Estradiol, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, endometrial cancer, CYP19A1, estradiol, Australian National Endometrial Cancer Study Group, National Study of Endometrial Cancer Genetics Group, for RENDOCAS, AOCS Group, Biological Sciences, Medical and Health Sciences, Oncology & Carcinogenesis
Abstract: Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Published: 2016

2. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

Author: Cheng, Timothy HT, Thompson, Deborah, Painter, Jodie, O'Mara, Tracy, Gorman, Maggie, Martin, Lynn, Palles, Claire, Jones, Angela, Buchanan, Daniel D, Win, Aung Ko, Hopper, John, Jenkins, Mark, Lindor, Noralane M, Newcomb, Polly A, Gallinger, Steve, Conti, David, Schumacher, Fred, Casey, Graham, Giles, Graham G, Pharoah, Paul, Peto, Julian, Cox, Angela, Swerdlow, Anthony, Couch, Fergus, Cunningham, Julie M, Goode, Ellen L, Winham, Stacey J, Lambrechts, Diether, Fasching, Peter, Burwinkel, Barbara, Brenner, Hermann, Brauch, Hiltrud, Chang-Claude, Jenny, Salvesen, Helga B, Kristensen, Vessela, Darabi, Hatef, Li, Jingmei, Liu, Tao, Lindblom, Annika, Hall, Per, de Polanco, Magdalena Echeverry, Sans, Monica, Carracedo, Angel, Castellvi-Bel, Sergi, Rojas-Martinez, Augusto, Aguiar Jnr, Samuel, Teixeira, Manuel R, Dunning, Alison M, Dennis, Joe, Otton, Geoffrey, Proietto, Tony, Holliday, Elizabeth, Attia, John, Ashton, Katie, Scott, Rodney J, McEvoy, Mark, Dowdy, Sean C, Fridley, Brooke L, Werner, Henrica MJ, Trovik, Jone, Njolstad, Tormund S, Tham, Emma, Mints, Miriam, Runnebaum, Ingo, Hillemanns, Peter, Dörk, Thilo, Amant, Frederic, Schrauwen, Stefanie, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif, Czene, Kamila, Meindl, Alfons, Bolla, Manjeet K, Michailidou, Kyriaki, Tyrer, Jonathan P, Wang, Qin, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Annibali, Daniela, Depreeuw, Jeroen, Al-Tassan, Nada A, Harris, Rebecca, Meyer, Brian F, Whiffin, Nicola, Hosking, Fay J, Kinnersley, Ben, Farrington, Susan M, Timofeeva, Maria, Tenesa, Albert, Campbell, Harry, Haile, Robert W, Hodgson, Shirley, Carvajal-Carmona, Luis, Cheadle, Jeremy P, Easton, Douglas, Dunlop, Malcolm, Houlston, Richard, and Spurdle, Amanda
Subjects: Humans, Colorectal Neoplasms, Endometrial Neoplasms, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Proteins, Homeodomain Proteins, Neoplasm Proteins, Polymorphism, Genetic, Alleles, Female, Male, Genome-Wide Association Study, Polymorphism, Genetic
Abstract: High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.
Published: 2015

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

Author: Painter, Jodie N, O'Mara, Tracy A, Batra, Jyotsna, Cheng, Timothy, Lose, Felicity A, Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P, Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S, Kaufmann, Susanne, Hillman, Kristine M, Walpole, Carina, Moya, Leire, Pollock, Pamela, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, De Polanco, Ma Magdalena Echeverry, Sans, Monica, Carracedo, Angel, Castellvi-Bel, Sergi, Rojas-Martinez, Augusto, Santos, Erika, Teixeira, Manuel R, Carvajal-Carmona, Luis, Shu, Xiao-Ou, Long, Jirong, Zheng, Wei, Xiang, Yong-Bing, Montgomery, Grant W, Webb, Penelope M, Scott, Rodney J, McEvoy, Mark, Attia, John, Holliday, Elizabeth, Martin, Nicholas G, Nyholt, Dale R, Henders, Anjali K, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Renner, Stefan P, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C, Goode, Ellen L, Teoman, Attila, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Tzortzatos, Gerasimos, Mints, Miriam, Tham, Emma, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L, Southey, Melissa C, Ekici, Arif B, Ruebner, Matthias, Johnson, Nicola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Bruinsma, Fiona, Cunningham, Julie M, Fridley, Brooke L, Børresen-Dale, Anne-Lise, Kristensen, Vessela N, Cox, Angela, Swerdlow, Anthony J, and Orr, Nicholas
Subjects: Cancer, Biotechnology, Human Genome, Prevention, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alleles, Case-Control Studies, Cell Line, Tumor, Chromosome Mapping, Computational Biology, Databases, Genetic, Endometrial Neoplasms, Epigenesis, Genetic, Female, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Hepatocyte Nuclear Factor 1-beta, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger, Risk Factors, White People, National Study of Endometrial Cancer Genetics Group, CHIBCHA Consortium, Australian National Endometrial Cancer Study Group, RENDOCAS, Australian Ovarian Cancer Study, GENICA Network, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
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 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 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 tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium 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.
Published: 2015

4. 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, Luis G, O’Mara, Tracy A, Painter, Jodie N, Lose, Felicity A, Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P, Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S, Pooley, Karen, Beesley, Jonathan, Cheng, Timothy, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, National Study of Endometrial Cancer Genetics Group (NSECG), The Australian National Endometrial Cancer Study Group (ANECS), Wentzensen, Nicholas, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Renner, Stefan P, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C, Goode, Ellen L, Teoman, Attila, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Scott, Rodney J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Wersäll, Ofra, Mints, Miriam, Tham, Emma, RENDOCAS, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L, Southey, Melissa C, Australian Ovarian Cancer Study (AOCS), Ekici, Arif B, Ruebner, Matthias, Johnson, Nichola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K, Meindl, Alfons, Brauch, Hiltrud, The GENICA Network, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Bruinsma, Fiona, Cunningham, Julie M, Fridley, Brooke L, Børresen-Dale, Anne-Lise, Kristensen, Vessela N, Cox, Angela, Swerdlow, Anthony J, Orr, Nicholas, Bolla, Manjeet K, Wang, Qin, Weber, Rachel Palmieri, Chen, Zhihua, Shah, Mitul, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, and Thompson, Deborah J
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Genetic Testing, Human Genome, Prevention, Cancer, Uterine Cancer, 2.1 Biological and endogenous factors, Aetiology, Chromosomes, Human, Pair 5, Databases, Nucleic Acid, Female, Gene Expression Regulation, Neoplastic, Genetic Loci, Haplotypes, Humans, Membrane Proteins, Models, Genetic, Neoplasm Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Telomerase, National Study of Endometrial Cancer Genetics Group, Australian National Endometrial Cancer Study Group, RENDOCAS, Australian Ovarian Cancer Study, GENICA Network, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
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.
Published: 2015

5. Establishment and characterization of uterine sarcoma and carcinosarcoma patient-derived xenograft models

Author: Cuppens, Tine, Depreeuw, Jeroen, Annibali, Daniela, Thomas, Debby, Hermans, Els, Gommé, Ellen, Trinh, Xuan Bich, Debruyne, David, Moerman, Philippe, Lambrechts, Diether, and Amant, Frédéric
Published: 2017
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6. Supplementary Table 4. Association of 47 waist-hip ratio (WHR) SNPs with endometrial cancer risk from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., primary, Marquart, Louise, primary, Webb, Penelope M., primary, Attia, John, primary, Medland, Sarah E., primary, Cheng, Timothy, primary, Dennis, Joe, primary, Holliday, Elizabeth G., primary, McEvoy, Mark, primary, Scott, Rodney J., primary, Ahmed, Shahana, primary, Healey, Catherine S., primary, Shah, Mitul, primary, Gorman, Maggie, primary, Martin, Lynn, primary, Hodgson, Shirley V., primary, Beckmann, Matthias W., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Hein, Alexander, primary, Rübner, Matthias, primary, Czene, Kamila, primary, Darabi, Hatef, primary, Hall, Per, primary, Li, Jingmei, primary, Dörk, Thilo, primary, Dürst, Matthias, primary, Hillemanns, Peter, primary, Runnebaum, Ingo B., primary, Amant, Frederic, primary, Annibali, Daniela, primary, Depreeuw, Jeroen, primary, Lambrechts, Diether, primary, Neven, Patrick, primary, Cunningham, Julie M., primary, Dowdy, Sean C., primary, Goode, Ellen L., primary, Fridley, Brooke L., primary, Winham, Stacey J., primary, Njølstad, Tormund S., primary, Salvesen, Helga B., primary, Trovik, Jone, primary, Werner, Henrica M.J., primary, Ashton, Katie A., primary, Otton, Geoffrey, primary, Proietto, Anthony, primary, Mints, Miriam, primary, Tham, Emma, primary, Bolla, Manjeet K., primary, Michailidou, Kyriaki, primary, Wang, Qin, primary, Tyrer, Jonathan P., primary, Hopper, John L., primary, Peto, Julian, primary, Swerdlow, Anthony J., primary, Burwinkel, Barbara, primary, Brenner, Hermann, primary, Meindl, Alfons, primary, Brauch, Hiltrud, primary, Lindblom, Annika, primary, Chang-Claude, Jenny, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Kristensen, Vessela N., primary, Cox, Angela, primary, Pharoah, Paul D.P., primary, Tomlinson, Ian, primary, Dunning, Alison M., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, and Spurdle, Amanda B., primary
Published: 2023
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7. Supplementary Table 3: Association of 77 body mass index (BMI) SNPs with endometrial cancer risk and BMI in the endometrial cancer dataset from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., primary, Marquart, Louise, primary, Webb, Penelope M., primary, Attia, John, primary, Medland, Sarah E., primary, Cheng, Timothy, primary, Dennis, Joe, primary, Holliday, Elizabeth G., primary, McEvoy, Mark, primary, Scott, Rodney J., primary, Ahmed, Shahana, primary, Healey, Catherine S., primary, Shah, Mitul, primary, Gorman, Maggie, primary, Martin, Lynn, primary, Hodgson, Shirley V., primary, Beckmann, Matthias W., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Hein, Alexander, primary, Rübner, Matthias, primary, Czene, Kamila, primary, Darabi, Hatef, primary, Hall, Per, primary, Li, Jingmei, primary, Dörk, Thilo, primary, Dürst, Matthias, primary, Hillemanns, Peter, primary, Runnebaum, Ingo B., primary, Amant, Frederic, primary, Annibali, Daniela, primary, Depreeuw, Jeroen, primary, Lambrechts, Diether, primary, Neven, Patrick, primary, Cunningham, Julie M., primary, Dowdy, Sean C., primary, Goode, Ellen L., primary, Fridley, Brooke L., primary, Winham, Stacey J., primary, Njølstad, Tormund S., primary, Salvesen, Helga B., primary, Trovik, Jone, primary, Werner, Henrica M.J., primary, Ashton, Katie A., primary, Otton, Geoffrey, primary, Proietto, Anthony, primary, Mints, Miriam, primary, Tham, Emma, primary, Bolla, Manjeet K., primary, Michailidou, Kyriaki, primary, Wang, Qin, primary, Tyrer, Jonathan P., primary, Hopper, John L., primary, Peto, Julian, primary, Swerdlow, Anthony J., primary, Burwinkel, Barbara, primary, Brenner, Hermann, primary, Meindl, Alfons, primary, Brauch, Hiltrud, primary, Lindblom, Annika, primary, Chang-Claude, Jenny, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Kristensen, Vessela N., primary, Cox, Angela, primary, Pharoah, Paul D.P., primary, Tomlinson, Ian, primary, Dunning, Alison M., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, and Spurdle, Amanda B., primary
Published: 2023
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8. Figure S4 from Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma

Author: Depreeuw, Jeroen, primary, Stelloo, Ellen, primary, Osse, Elisabeth M., primary, Creutzberg, Carien L., primary, Nout, Remi A., primary, Moisse, Matthieu, primary, Garcia-Dios, Diego A., primary, Dewaele, Michael, primary, Willekens, Karen, primary, Marine, Jean-Christophe, primary, Matias-Guiu, Xavier, primary, Amant, Frédéric, primary, Lambrechts, Diether, primary, and Bosse, Tjalling, primary
Published: 2023
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9. Supplemental Table 1. Details of cases and controls included in the endometrial cancer analyses from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., primary, Marquart, Louise, primary, Webb, Penelope M., primary, Attia, John, primary, Medland, Sarah E., primary, Cheng, Timothy, primary, Dennis, Joe, primary, Holliday, Elizabeth G., primary, McEvoy, Mark, primary, Scott, Rodney J., primary, Ahmed, Shahana, primary, Healey, Catherine S., primary, Shah, Mitul, primary, Gorman, Maggie, primary, Martin, Lynn, primary, Hodgson, Shirley V., primary, Beckmann, Matthias W., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Hein, Alexander, primary, Rübner, Matthias, primary, Czene, Kamila, primary, Darabi, Hatef, primary, Hall, Per, primary, Li, Jingmei, primary, Dörk, Thilo, primary, Dürst, Matthias, primary, Hillemanns, Peter, primary, Runnebaum, Ingo B., primary, Amant, Frederic, primary, Annibali, Daniela, primary, Depreeuw, Jeroen, primary, Lambrechts, Diether, primary, Neven, Patrick, primary, Cunningham, Julie M., primary, Dowdy, Sean C., primary, Goode, Ellen L., primary, Fridley, Brooke L., primary, Winham, Stacey J., primary, Njølstad, Tormund S., primary, Salvesen, Helga B., primary, Trovik, Jone, primary, Werner, Henrica M.J., primary, Ashton, Katie A., primary, Otton, Geoffrey, primary, Proietto, Anthony, primary, Mints, Miriam, primary, Tham, Emma, primary, Bolla, Manjeet K., primary, Michailidou, Kyriaki, primary, Wang, Qin, primary, Tyrer, Jonathan P., primary, Hopper, John L., primary, Peto, Julian, primary, Swerdlow, Anthony J., primary, Burwinkel, Barbara, primary, Brenner, Hermann, primary, Meindl, Alfons, primary, Brauch, Hiltrud, primary, Lindblom, Annika, primary, Chang-Claude, Jenny, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Kristensen, Vessela N., primary, Cox, Angela, primary, Pharoah, Paul D.P., primary, Tomlinson, Ian, primary, Dunning, Alison M., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, and Spurdle, Amanda B., primary
Published: 2023
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10. Supplemental Table 2. Average BMIs in the ANECS, SEARCH and iCOGS endometrial cancer datasets. from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., primary, Marquart, Louise, primary, Webb, Penelope M., primary, Attia, John, primary, Medland, Sarah E., primary, Cheng, Timothy, primary, Dennis, Joe, primary, Holliday, Elizabeth G., primary, McEvoy, Mark, primary, Scott, Rodney J., primary, Ahmed, Shahana, primary, Healey, Catherine S., primary, Shah, Mitul, primary, Gorman, Maggie, primary, Martin, Lynn, primary, Hodgson, Shirley V., primary, Beckmann, Matthias W., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Hein, Alexander, primary, Rübner, Matthias, primary, Czene, Kamila, primary, Darabi, Hatef, primary, Hall, Per, primary, Li, Jingmei, primary, Dörk, Thilo, primary, Dürst, Matthias, primary, Hillemanns, Peter, primary, Runnebaum, Ingo B., primary, Amant, Frederic, primary, Annibali, Daniela, primary, Depreeuw, Jeroen, primary, Lambrechts, Diether, primary, Neven, Patrick, primary, Cunningham, Julie M., primary, Dowdy, Sean C., primary, Goode, Ellen L., primary, Fridley, Brooke L., primary, Winham, Stacey J., primary, Njølstad, Tormund S., primary, Salvesen, Helga B., primary, Trovik, Jone, primary, Werner, Henrica M.J., primary, Ashton, Katie A., primary, Otton, Geoffrey, primary, Proietto, Anthony, primary, Mints, Miriam, primary, Tham, Emma, primary, Bolla, Manjeet K., primary, Michailidou, Kyriaki, primary, Wang, Qin, primary, Tyrer, Jonathan P., primary, Hopper, John L., primary, Peto, Julian, primary, Swerdlow, Anthony J., primary, Burwinkel, Barbara, primary, Brenner, Hermann, primary, Meindl, Alfons, primary, Brauch, Hiltrud, primary, Lindblom, Annika, primary, Chang-Claude, Jenny, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Kristensen, Vessela N., primary, Cox, Angela, primary, Pharoah, Paul D.P., primary, Tomlinson, Ian, primary, Dunning, Alison M., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, and Spurdle, Amanda B., primary
Published: 2023
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11. Supplementary Text for: Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., primary, Marquart, Louise, primary, Webb, Penelope M., primary, Attia, John, primary, Medland, Sarah E., primary, Cheng, Timothy, primary, Dennis, Joe, primary, Holliday, Elizabeth G., primary, McEvoy, Mark, primary, Scott, Rodney J., primary, Ahmed, Shahana, primary, Healey, Catherine S., primary, Shah, Mitul, primary, Gorman, Maggie, primary, Martin, Lynn, primary, Hodgson, Shirley V., primary, Beckmann, Matthias W., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Hein, Alexander, primary, Rübner, Matthias, primary, Czene, Kamila, primary, Darabi, Hatef, primary, Hall, Per, primary, Li, Jingmei, primary, Dörk, Thilo, primary, Dürst, Matthias, primary, Hillemanns, Peter, primary, Runnebaum, Ingo B., primary, Amant, Frederic, primary, Annibali, Daniela, primary, Depreeuw, Jeroen, primary, Lambrechts, Diether, primary, Neven, Patrick, primary, Cunningham, Julie M., primary, Dowdy, Sean C., primary, Goode, Ellen L., primary, Fridley, Brooke L., primary, Winham, Stacey J., primary, Njølstad, Tormund S., primary, Salvesen, Helga B., primary, Trovik, Jone, primary, Werner, Henrica M.J., primary, Ashton, Katie A., primary, Otton, Geoffrey, primary, Proietto, Anthony, primary, Mints, Miriam, primary, Tham, Emma, primary, Bolla, Manjeet K., primary, Michailidou, Kyriaki, primary, Wang, Qin, primary, Tyrer, Jonathan P., primary, Hopper, John L., primary, Peto, Julian, primary, Swerdlow, Anthony J., primary, Burwinkel, Barbara, primary, Brenner, Hermann, primary, Meindl, Alfons, primary, Brauch, Hiltrud, primary, Lindblom, Annika, primary, Chang-Claude, Jenny, primary, Couch, Fergus J., primary, Giles, Graham G., primary, Kristensen, Vessela N., primary, Cox, Angela, primary, Pharoah, Paul D.P., primary, Tomlinson, Ian, primary, Dunning, Alison M., primary, Easton, Douglas F., primary, Thompson, Deborah J., primary, and Spurdle, Amanda B., primary
Published: 2023
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12. Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies

Author: Depreeuw, Jeroen, Hermans, Els, Schrauwen, Stefanie, Annibali, Daniela, Coenegrachts, Lieve, Thomas, Debby, Luyckx, Mathieu, Gutierrez-Roelens, Ilse, Debruyne, David, Konings, Katrien, Moerman, Philippe, Vergote, Ignace, Lambrechts, Diether, and Amant, Frédéric
Published: 2015
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13. Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

Author: Schrauwen, Stefanie, Depreeuw, Jeroen, Coenegrachts, Lieve, Hermans, Els, Lambrechts, Diether, and Amant, Frédéric
Published: 2015
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14. Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Author: Cuppens, Tine, Moisse, Matthieu, Depreeuw, Jeroen, Annibali, Daniela, Colas, Eva, Gil‐Moreno, Antonio, Huvila, Jutta, Carpén, Olli, Zikán, Michal, Matias‐Guiu, Xavier, Moerman, Philippe, Croce, Sabrina, Lambrechts, Diether, and Amant, Frédéric
Published: 2018
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15. Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

Author: Smeets, Dominiek, Miller, Ian S., O’Connor, Darran P., Das, Sudipto, Moran, Bruce, Boeckx, Bram, Gaiser, Timo, Betge, Johannes, Barat, Ana, Klinger, Rut, van Grieken, Nicole C. T., Cremolini, Chiara, Prenen, Hans, Mazzone, Massimiliano, Depreeuw, Jeroen, Bacon, Orna, Fender, Bozena, Brady, Joseph, Hennessy, Bryan T., McNamara, Deborah A., Kay, Elaine, Verheul, Henk M., Maarten, Neerincx, Gallagher, William M., Murphy, Verena, Prehn, Jochen H. M., Koopman, Miriam, Punt, Cornelis J. A., Loupakis, Fotios, Ebert, Matthias P. A., Ylstra, Bauke, Lambrechts, Diether, and Byrne, Annette T.
Published: 2018
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16. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer

Author: Church, David N., Stelloo, Ellen, Nout, Remi A., Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P. M., Wild, Peter J., Lambrechts, Diether, Jürgenliemk-Schulz, Ina M., Jobsen, Jan J., Smit, Vincent T. H. B. M., Creutzberg, Carien L., and Bosse, Tjalling
Published: 2015
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17. The tumor suppressor protein PTEN undergoes amyloid-like aggregation in tumor cells

Author: Claes, Filip, primary, Maritschnegg, Elisabeth, additional, De Baets, Greet, additional, Siekierska, Aleksandra, additional, Rubio, Mirian Saiz, additional, Ramakers, Meine, additional, Michiels, Emiel, additional, De Smet, Frederik, additional, Depreeuw, Jeroen, additional, Vergote, Ignace, additional, Vanderstichele, Adriaan, additional, Van den Broeck, Annick, additional, Olbrecht, Siel, additional, Hermans, Els, additional, Amant, Frédéric, additional, Lambrechts, Diether, additional, Nilsson, K. Peter R., additional, Rousseau, Frederic, additional, and Schymkowitz, Joost, additional
Published: 2020
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18. Identification of nine new susceptibility loci for endometrial cancer.

Author: O'Mara, Tracy A, Glubb, Dylan M, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L, Beckmann, Matthias W, Black, Amanda, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Buchanan, Daniel D, Burwinkel, Barbara, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Chen, Maxine M, Cheng, Timothy H T, Clarke, Christine L, Clendenning, Mark, Cook, Linda S, Couch, Fergus J, Cox, Angela, Crous-Bous, Marta, Czene, Kamila, Day, Felix, Dennis, Joe, Depreeuw, Jeroen, Doherty, Jennifer Anne, Dörk, Thilo, Dowdy, Sean C, Dürst, Matthias, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Friedenreich, Christine M, Fritschi, Lin, Fung, Jenny, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goode, Ellen L, Gorman, Maggie, Haiman, Christopher A, Hall, Per, Hankison, Susan E, Healey, Catherine S, Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A, Holliday, Elizabeth G, Hopper, John L, Hunter, David J, Jones, Angela, Krakstad, Camilla, Kristensen, Vessela N, Lambrechts, Diether, Marchand, Loic Le, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, Meindl, Alfons, Michailidou, Kyriaki, Milne, Roger L, Mints, Miriam, Montgomery, Grant W, Nassir, Rami, Olsson, Håkan, Orlow, Irene, Otton, Geoffrey, Palles, Claire, Perry, John R B, Peto, Julian, Pooler, Loreall, Prescott, Jennifer, Proietto, Tony, Rebbeck, Timothy R, Risch, Harvey A, Rogers, Peter A W, Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E, Schumacher, Fredrick, Scott, Rodney J, Setiawan, V Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony J, Tham, Emma, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P, Vachon, Celine, VanDen Berg, David, Vanderstichele, Adriaan, Wang, Zhaoming, Webb, Penelope M, Wentzensen, Nicolas, Werner, Henrica M J, Winham, Stacey J, Wolk, Alicja, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Pharoah, Paul D P, Dunning, Alison M, Kraft, Peter, De Vivo, Immaculata, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Glubb, Dylan M, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L, Beckmann, Matthias W, Black, Amanda, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Buchanan, Daniel D, Burwinkel, Barbara, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Chen, Maxine M, Cheng, Timothy H T, Clarke, Christine L, Clendenning, Mark, Cook, Linda S, Couch, Fergus J, Cox, Angela, Crous-Bous, Marta, Czene, Kamila, Day, Felix, Dennis, Joe, Depreeuw, Jeroen, Doherty, Jennifer Anne, Dörk, Thilo, Dowdy, Sean C, Dürst, Matthias, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Friedenreich, Christine M, Fritschi, Lin, Fung, Jenny, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goode, Ellen L, Gorman, Maggie, Haiman, Christopher A, Hall, Per, Hankison, Susan E, Healey, Catherine S, Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A, Holliday, Elizabeth G, Hopper, John L, Hunter, David J, Jones, Angela, Krakstad, Camilla, Kristensen, Vessela N, Lambrechts, Diether, Marchand, Loic Le, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, Meindl, Alfons, Michailidou, Kyriaki, Milne, Roger L, Mints, Miriam, Montgomery, Grant W, Nassir, Rami, Olsson, Håkan, Orlow, Irene, Otton, Geoffrey, Palles, Claire, Perry, John R B, Peto, Julian, Pooler, Loreall, Prescott, Jennifer, Proietto, Tony, Rebbeck, Timothy R, Risch, Harvey A, Rogers, Peter A W, Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E, Schumacher, Fredrick, Scott, Rodney J, Setiawan, V Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony J, Tham, Emma, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P, Vachon, Celine, VanDen Berg, David, Vanderstichele, Adriaan, Wang, Zhaoming, Webb, Penelope M, Wentzensen, Nicolas, Werner, Henrica M J, Winham, Stacey J, Wolk, Alicja, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Pharoah, Paul D P, Dunning, Alison M, Kraft, Peter, De Vivo, Immaculata, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, and Thompson, Deborah J
Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
Published: 2018
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19. Genetic overlap between endometriosis and endometrial cancer: Evidence from cross-disease genetic correlation and GWAS meta-analyses

Author: Painter, Jodie N., O'Mara, Tracy A., Cheng, Timothy H.T., Gorman, Maggie, Martin, Lynn, Hodson, Shirley, Martin, Nicholas G., Henders, Anjali K., Attia, John, McEvoy, Mark, Holliday, Elizabeth G., Scott, Rodney J., Webb, Penelope M., Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Hein, Alexander, Rübner, Matthias, Hall, Per, Czene, Kamila, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo, Lambrechts, Diether, Amant, Frederic, Annibali, Daniela, Depreeuw, Jeroen, Vanderstichele, Adriaan, Goode, Ellen L., Cunningham, Julie M., Dowdy, Sean C., Winham, Stacey J., Trovik, Jone, Hoivik, Erling, Werner, Henrica M.J., Krakstad, Camilla, Ashton, Katie, Otton, Geoffrey, Proietto, Tony, Tham, Emma, Mints, Miriam, Ahmed, Shahana, Healey, Catherine S., Shah, Mitul, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe, Bolla, Manjeet K., Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P., Hopper, John L., Peto, Julian, Swerdlow, Anthony J., Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J., Giles, Graham G., Kristensen, Vessela N., Cox, Angela, Zondervan, Krina T., Nyholt, Dale R., MacGregor, Stuart, Montgomery, Grant W., Tomlinson, Ian, Easton, Douglas F., Thompson, Deborah J., Spurdle, Amanda B., Painter, Jodie N., O'Mara, Tracy A., Cheng, Timothy H.T., Gorman, Maggie, Martin, Lynn, Hodson, Shirley, Martin, Nicholas G., Henders, Anjali K., Attia, John, McEvoy, Mark, Holliday, Elizabeth G., Scott, Rodney J., Webb, Penelope M., Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Hein, Alexander, Rübner, Matthias, Hall, Per, Czene, Kamila, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo, Lambrechts, Diether, Amant, Frederic, Annibali, Daniela, Depreeuw, Jeroen, Vanderstichele, Adriaan, Goode, Ellen L., Cunningham, Julie M., Dowdy, Sean C., Winham, Stacey J., Trovik, Jone, Hoivik, Erling, Werner, Henrica M.J., Krakstad, Camilla, Ashton, Katie, Otton, Geoffrey, Proietto, Tony, Tham, Emma, Mints, Miriam, Ahmed, Shahana, Healey, Catherine S., Shah, Mitul, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe, Bolla, Manjeet K., Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P., Hopper, John L., Peto, Julian, Swerdlow, Anthony J., Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J., Giles, Graham G., Kristensen, Vessela N., Cox, Angela, Zondervan, Krina T., Nyholt, Dale R., MacGregor, Stuart, Montgomery, Grant W., Tomlinson, Ian, Easton, Douglas F., Thompson, Deborah J., and Spurdle, Amanda B.
Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 −3 ) and concordance in effect direction (P = 2.0 × 10 −3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Published: 2018

20. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N, O'Mara, Tracy A, Marquart, Louise, Webb, Penelope M, Attia, John, Medland, Sarah E, Cheng, Timothy, Dennis, Joe, Holliday, Elizabeth G, McEvoy, Mark, Scott, Rodney J, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley V, Beckmann, Matthias W, Ekici, Arif B, Fasching, Peter A, Hein, Alexander, Rübner, Matthias, Czene, Kamila, Darabi, Hatef, Hall, Per, Li, Jingmei, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Amant, Frederic, Annibali, Daniela, Depreeuw, Jeroen, Lambrechts, Diether, Neven, Patrick, Cunningham, Julie M, Dowdy, Sean C, Goode, Ellen L, Fridley, Brooke L, Winham, Stacey J, Njølstad, Tormund S, Salvesen, Helga B, Trovik, Jone, Werner, Henrica MJ, Ashton, Katie A, Otton, Geoffrey, Proietto, Anthony, Mints, Miriam, Tham, Emma, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P, Hopper, John L, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Pharoah, Paul DP, Tomlinson, Ian, Dunning, Alison M, Easton, Douglas F, Thompson, Deborah J, Spurdle, Amanda B, AOCS Group, for RENDOCAS, National Study of Endometrial Cancer Genetics Group (NSECG), Australian National Endometrial Cancer Study Group (ANECS), Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], 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: Waist-Hip Ratio, Humans, nutritional and metabolic diseases, Female, Genetic Predisposition to Disease, Obesity, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Body Mass Index, Endometrial Neoplasms
Abstract: BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.
Published: 2016

21. Identification of nine new susceptibility loci for endometrial cancer

Author: O’Mara, Tracy A., primary, Glubb, Dylan M., additional, Amant, Frederic, additional, Annibali, Daniela, additional, Ashton, Katie, additional, Attia, John, additional, Auer, Paul L., additional, Beckmann, Matthias W., additional, Black, Amanda, additional, Bolla, Manjeet K., additional, Brauch, Hiltrud, additional, Brenner, Hermann, additional, Brinton, Louise, additional, Buchanan, Daniel D., additional, Burwinkel, Barbara, additional, Chang-Claude, Jenny, additional, Chanock, Stephen J., additional, Chen, Chu, additional, Chen, Maxine M., additional, Cheng, Timothy H. T., additional, Clarke, Christine L., additional, Clendenning, Mark, additional, Cook, Linda S., additional, Couch, Fergus J., additional, Cox, Angela, additional, Crous-Bous, Marta, additional, Czene, Kamila, additional, Day, Felix, additional, Dennis, Joe, additional, Depreeuw, Jeroen, additional, Doherty, Jennifer Anne, additional, Dörk, Thilo, additional, Dowdy, Sean C., additional, Dürst, Matthias, additional, Ekici, Arif B., additional, Fasching, Peter A., additional, Fridley, Brooke L., additional, Friedenreich, Christine M., additional, Fritschi, Lin, additional, Fung, Jenny, additional, García-Closas, Montserrat, additional, Gaudet, Mia M., additional, Giles, Graham G., additional, Goode, Ellen L., additional, Gorman, Maggie, additional, Haiman, Christopher A., additional, Hall, Per, additional, Hankison, Susan E., additional, Healey, Catherine S., additional, Hein, Alexander, additional, Hillemanns, Peter, additional, Hodgson, Shirley, additional, Hoivik, Erling A., additional, Holliday, Elizabeth G., additional, Hopper, John L., additional, Hunter, David J., additional, Jones, Angela, additional, Krakstad, Camilla, additional, Kristensen, Vessela N., additional, Lambrechts, Diether, additional, Marchand, Loic Le, additional, Liang, Xiaolin, additional, Lindblom, Annika, additional, Lissowska, Jolanta, additional, Long, Jirong, additional, Lu, Lingeng, additional, Magliocco, Anthony M., additional, Martin, Lynn, additional, McEvoy, Mark, additional, Meindl, Alfons, additional, Michailidou, Kyriaki, additional, Milne, Roger L., additional, Mints, Miriam, additional, Montgomery, Grant W., additional, Nassir, Rami, additional, Olsson, Håkan, additional, Orlow, Irene, additional, Otton, Geoffrey, additional, Palles, Claire, additional, Perry, John R. B., additional, Peto, Julian, additional, Pooler, Loreall, additional, Prescott, Jennifer, additional, Proietto, Tony, additional, Rebbeck, Timothy R., additional, Risch, Harvey A., additional, Rogers, Peter A. W., additional, Rübner, Matthias, additional, Runnebaum, Ingo, additional, Sacerdote, Carlotta, additional, Sarto, Gloria E., additional, Schumacher, Fredrick, additional, Scott, Rodney J., additional, Setiawan, V. Wendy, additional, Shah, Mitul, additional, Sheng, Xin, additional, Shu, Xiao-Ou, additional, Southey, Melissa C., additional, Swerdlow, Anthony J., additional, Tham, Emma, additional, Trovik, Jone, additional, Turman, Constance, additional, Tyrer, Jonathan P., additional, Vachon, Celine, additional, VanDen Berg, David, additional, Vanderstichele, Adriaan, additional, Wang, Zhaoming, additional, Webb, Penelope M., additional, Wentzensen, Nicolas, additional, Werner, Henrica M. J., additional, Winham, Stacey J., additional, Wolk, Alicja, additional, Xia, Lucy, additional, Xiang, Yong-Bing, additional, Yang, Hannah P., additional, Yu, Herbert, additional, Zheng, Wei, additional, Pharoah, Paul D. P., additional, Dunning, Alison M., additional, Kraft, Peter, additional, De Vivo, Immaculata, additional, Tomlinson, Ian, additional, Easton, Douglas F., additional, Spurdle, Amanda B., additional, and Thompson, Deborah J., additional
Published: 2018
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22. Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Author: Temko, Daniel, primary, Van Gool, Inge C, additional, Rayner, Emily, additional, Glaire, Mark, additional, Makino, Seiko, additional, Brown, Matthew, additional, Chegwidden, Laura, additional, Palles, Claire, additional, Depreeuw, Jeroen, additional, Beggs, Andrew, additional, Stathopoulou, Chaido, additional, Mason, John, additional, Baker, Ann-Marie, additional, Williams, Marc, additional, Cerundolo, Vincenzo, additional, Rei, Margarida, additional, Taylor, Jenny C, additional, Schuh, Anna, additional, Ahmed, Ahmed, additional, Amant, Frédéric, additional, Lambrechts, Diether, additional, Smit, Vincent THBM, additional, Bosse, Tjalling, additional, Graham, Trevor A, additional, Church, David N, additional, and Tomlinson, Ian, additional
Published: 2018
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23. Ischemia-Induced DNA Hypermethylation during Kidney Transplant Predicts Chronic Allograft Injury

Author: Heylen, Line, primary, Thienpont, Bernard, additional, Naesens, Maarten, additional, Busschaert, Pieter, additional, Depreeuw, Jeroen, additional, Smeets, Dominiek, additional, Jochmans, Ina, additional, Monbaliu, Diethard, additional, Pirenne, Jacques, additional, Lerut, Evelyne, additional, Ghesquiere, Bart, additional, Kuypers, Dirk, additional, Lambrechts, Diether, additional, and Sprangers, Ben, additional
Published: 2018
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24. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Painter, Jodie N., primary, O'Mara, Tracy A., additional, Morris, Andrew P., additional, Cheng, Timothy H. T., additional, Gorman, Maggie, additional, Martin, Lynn, additional, Hodson, Shirley, additional, Jones, Angela, additional, Martin, Nicholas G., additional, Gordon, Scott, additional, Henders, Anjali K., additional, Attia, John, additional, McEvoy, Mark, additional, Holliday, Elizabeth G., additional, Scott, Rodney J., additional, Webb, Penelope M., additional, Fasching, Peter A., additional, Beckmann, Matthias W., additional, Ekici, Arif B., additional, Hein, Alexander, additional, Rübner, Matthias, additional, Hall, Per, additional, Czene, Kamila, additional, Dörk, Thilo, additional, Dürst, Matthias, additional, Hillemanns, Peter, additional, Runnebaum, Ingo, additional, Lambrechts, Diether, additional, Amant, Frederic, additional, Annibali, Daniela, additional, Depreeuw, Jeroen, additional, Vanderstichele, Adriaan, additional, Goode, Ellen L., additional, Cunningham, Julie M., additional, Dowdy, Sean C., additional, Winham, Stacey J., additional, Trovik, Jone, additional, Hoivik, Erling, additional, Werner, Henrica M. J., additional, Krakstad, Camilla, additional, Ashton, Katie, additional, Otton, Geoffrey, additional, Proietto, Tony, additional, Tham, Emma, additional, Mints, Miriam, additional, Ahmed, Shahana, additional, Healey, Catherine S., additional, Shah, Mitul, additional, Pharoah, Paul D. P., additional, Dunning, Alison M., additional, Dennis, Joe, additional, Bolla, Manjeet K., additional, Michailidou, Kyriaki, additional, Wang, Qin, additional, Tyrer, Jonathan P., additional, Hopper, John L., additional, Peto, Julian, additional, Swerdlow, Anthony J., additional, Burwinkel, Barbara, additional, Brenner, Hermann, additional, Meindl, Alfons, additional, Brauch, Hiltrud, additional, Lindblom, Annika, additional, Chang‐Claude, Jenny, additional, Couch, Fergus J., additional, Giles, Graham G., additional, Kristensen, Vessela N., additional, Cox, Angela, additional, Zondervan, Krina T., additional, Nyholt, Dale R., additional, MacGregor, Stuart, additional, Montgomery, Grant W., additional, Tomlinson, Ian, additional, Easton, Douglas F., additional, Thompson, Deborah J., additional, and Spurdle, Amanda B., additional
Published: 2018
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25. Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma

Author: Depreeuw, Jeroen, primary, Stelloo, Ellen, additional, Osse, Elisabeth M., additional, Creutzberg, Carien L., additional, Nout, Remi A., additional, Moisse, Matthieu, additional, Garcia-Dios, Diego A., additional, Dewaele, Michael, additional, Willekens, Karen, additional, Marine, Jean-Christophe, additional, Matias-Guiu, Xavier, additional, Amant, Frédéric, additional, Lambrechts, Diether, additional, and Bosse, Tjalling, additional
Published: 2017
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26. Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Author: Cuppens, Tine, primary, Moisse, Matthieu, additional, Depreeuw, Jeroen, additional, Annibali, Daniela, additional, Colas, Eva, additional, Gil-Moreno, Antonio, additional, Huvila, Jutta, additional, Carpén, Olli, additional, Zikán, Michal, additional, Matias-Guiu, Xavier, additional, Moerman, Philippe, additional, Croce, Sabrina, additional, Lambrechts, Diether, additional, and Amant, Frédéric, additional
Published: 2017
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27. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer

Author: Church, David N., Stelloo, Ellen, Nout, Remi A., Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P. M., Wild, Peter J., Lambrechts, Diether, Jürgenliemk-Schulz, Ina M., Jobsen, Jan J., Smit, Vincent T. H. B. M., Creutzberg, Carien L., Bosse, Tjalling, Church, David N., Stelloo, Ellen, Nout, Remi A., Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P. M., Wild, Peter J., Lambrechts, Diether, Jürgenliemk-Schulz, Ina M., Jobsen, Jan J., Smit, Vincent T. H. B. M., Creutzberg, Carien L., and Bosse, Tjalling
Abstract: Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC
Published: 2017

28. CYP19A1 fine-mapping and Mendelian randomization

Author: Thompson, Deborah J, O'Mara, Tracy A, Glubb, Dylan M, Painter, Jodie N, Cheng, Timothy, Folkerd, Elizabeth J, Doody, Deborah, Dennis, Joe, Webb, Penelope M, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley, Michailidou, Kyriaki, Tyrer, Jonathan P, Maranian, Mel J, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Doerk, Thilo, Hillemanns, Peter, Durst, Matthias, Runnebaum, Ingo, Zhao, Hui, Depreeuw, Jeroen, Schrauwen, Stefanie, Amant, Frederic, Goode, Ellen L, Fridley, Brooke L, Dowdy, Sean C, Winham, Stacey J, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica M J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Carvajal-carmona, Luis, Tham, Emma, Liu, Tao, Mints, Miriam, Scott, Rodney J, McEvoy, Mark G, Attia, John R, Holliday, Elizabeth G, Montgomery, Grant W., Martin, Nicholas G., Nyholt, Dale R, Henders, Anjali K, Hopper, John L, Traficante, Nadia, Ruebner, Matthias, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Lambrechts, Diether, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham, Kristensen, Vessela N, Cox, Angela, Bolla, Manjeet K, Wang, Qin, Bojesen, Stig E, Shah, Mitul, Luben, Robert, Khaw, Kay-Tee, Pharoah, Paul P D, Dunning, Alison M, Tomlinson, Ian, Dowsett, Mitch, Easton, Douglas F, and Spurdle, Amanda B
Abstract: Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Published: 2016

29. SO009ISCHEMIA IN KIDNEY TRANSPLANTATION CAUSES DNA HYPERMETHYLATION AND PREDICTS GRAFT FIBROSIS: AN EPIGENOME-WIDE ASSOCIATION STUDY

Author: Heylen, Line, primary, Thienpont, Bernard, additional, Naesens, Maarten, additional, Busschaert, Pieter, additional, Depreeuw, Jeroen, additional, Jochmans, Ina, additional, Monbaliu, Diethard, additional, Pirenne, Jacques, additional, Kuypers, Dirk, additional, Lerut, Evelyne, additional, Lambrechts, Diether, additional, and Sprangers, Ben, additional
Published: 2017
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30. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Author: O'Mara, Tracy A, Glubb, Dylan M, Painter, Jodie N, Cheng, Timothy, Dennis, Joe, Australian National Endometrial Cancer Study Group (ANECS), Attia, John, Holliday, Elizabeth G, McEvoy, Mark, Scott, Rodney J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Shah, Mitul, Ahmed, Shahana, Healey, Catherine S, Gorman, Maggie, Martin, Lynn, National Study of Endometrial Cancer Genetics Group (NSECG), Hodgson, Shirley, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Dürst, Matthias, Runnebaum, Ingo, Hillemanns, Peter, Dörk, Thilo, Lambrechts, Diether, Depreeuw, Jeroen, Annibali, Daniela, Amant, Frederic, Zhao, Hui, Goode, Ellen L, Dowdy, Sean C, Fridley, Brooke L, Winham, Stacey J, Salvesen, Helga B, Njølstad, Tormund S, Trovik, Jone, Werner, Henrica MJ, Tham, Emma, Liu, Tao, Mints, Miriam, RENDOCAS, Bolla, Manjeet K, Michailidou, Kyriaki, Tyrer, Jonathan P, Wang, Qin, Hopper, John L, AOCS Group, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Easton, Douglas F, Thompson, Deborah J, Spurdle, Amanda B, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], 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, ESR1, fine-mapping analysis, Estrogen Receptor alpha, Computational Biology, Nuclear Proteins, Breast Neoplasms, Nerve Tissue Proteins, Prognosis, Polymorphism, Single Nucleotide, Endometrial Neoplasms, Cytoskeletal Proteins, Meta-Analysis as Topic, Genetic Loci, Risk Factors, Case-Control Studies, endometrial cancer, single-nucleotide polymorphisms, Databases, Genetic, Humans, Female, Genetic Predisposition to Disease, Promoter Regions, Genetic
Abstract: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
Published: 2015

31. 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, Luis G., O’Mara, Tracy A., Painter, Jodie N., Lose, Felicity A., Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P., Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S., Pooley, Karen, Beesley, Jonathan, Cheng, Timothy, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, Wentzensen, Nicholas, Fasching, Peter A., Hein, Alexander, Beckmann, Matthias W., Renner, Stefan P., Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C., Goode, Ellen L., Teoman, Attila, Salvesen, Helga B., Trovik, Jone, Njolstad, Tormund S., Werner, Henrica M. J., Scott, Rodney J., Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Wersäll, Ofra, Mints, Miriam, Tham, Emma, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L., Southey, Melissa C., Ekici, Arif B., Ruebner, Matthias, Johnson, Nichola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K., Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J., Olson, Janet E., Giles, Graham G., Bruinsma, Fiona, Cunningham, Julie M., Fridley, Brooke L., Børresen-Dale, Anne-Lise, Kristensen, Vessela N., Cox, Angela, Swerdlow, Anthony J., Orr, Nicholas, Bolla, Manjeet K., Wang, Qin, Weber, Rachel Palmieri, Chen, Zhihua, Shah, Mitul, Pharoah, Paul D. P., Dunning, Alison M., Tomlinson, Ian, Easton, Douglas F., Spurdle, Amanda B., Thompson, Deborah J., and Other departments
Subjects: Models, Genetic, chromosome 5p15, Membrane Proteins, macromolecular substances, Polymorphism, Single Nucleotide, single-nucleotide polymorphisms (SNPs), Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Haplotypes, Genetic Loci, Risk Factors, Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Medisinske Fag: 700 [VDP], Genetics, Chromosomes, Human, Pair 5, Humans, Genetics(clinical), Female, Databases, Nucleic Acid, Promoter Regions, Genetic, multiple cancer types, Telomerase, Original Investigation
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 (TERTP = 1.5 × 10−18, CLPTM1LP = 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. Electronic supplementary material The online version of this article (doi:10.1007/s00439-014-1515-4) contains supplementary material, which is available to authorized users.
Published: 2014

32. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N., primary, O'Mara, Tracy A., additional, Marquart, Louise, additional, Webb, Penelope M., additional, Attia, John, additional, Medland, Sarah E., additional, Cheng, Timothy, additional, Dennis, Joe, additional, Holliday, Elizabeth G., additional, McEvoy, Mark, additional, Scott, Rodney J., additional, Ahmed, Shahana, additional, Healey, Catherine S., additional, Shah, Mitul, additional, Gorman, Maggie, additional, Martin, Lynn, additional, Hodgson, Shirley V., additional, Beckmann, Matthias W., additional, Ekici, Arif B., additional, Fasching, Peter A., additional, Hein, Alexander, additional, Rübner, Matthias, additional, Czene, Kamila, additional, Darabi, Hatef, additional, Hall, Per, additional, Li, Jingmei, additional, Dörk, Thilo, additional, Dürst, Matthias, additional, Hillemanns, Peter, additional, Runnebaum, Ingo B., additional, Amant, Frederic, additional, Annibali, Daniela, additional, Depreeuw, Jeroen, additional, Lambrechts, Diether, additional, Neven, Patrick, additional, Cunningham, Julie M., additional, Dowdy, Sean C., additional, Goode, Ellen L., additional, Fridley, Brooke L., additional, Winham, Stacey J., additional, Njølstad, Tormund S., additional, Salvesen, Helga B., additional, Trovik, Jone, additional, Werner, Henrica M.J., additional, Ashton, Katie A., additional, Otton, Geoffrey, additional, Proietto, Anthony, additional, Mints, Miriam, additional, Tham, Emma, additional, Bolla, Manjeet K., additional, Michailidou, Kyriaki, additional, Wang, Qin, additional, Tyrer, Jonathan P., additional, Hopper, John L., additional, Peto, Julian, additional, Swerdlow, Anthony J., additional, Burwinkel, Barbara, additional, Brenner, Hermann, additional, Meindl, Alfons, additional, Brauch, Hiltrud, additional, Lindblom, Annika, additional, Chang-Claude, Jenny, additional, Couch, Fergus J., additional, Giles, Graham G., additional, Kristensen, Vessela N., additional, Cox, Angela, additional, Pharoah, Paul D.P., additional, Tomlinson, Ian, additional, Dunning, Alison M., additional, Easton, Douglas F., additional, Thompson, Deborah J., additional, and Spurdle, Amanda B., additional
Published: 2016
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33. Genomic Characterisation and Response to Trastuzumab and Paclitaxel in Advanced or Recurrent HER2-positive Endometrial Carcinoma

Author: KOSKAS, MARTIN, primary, DEPREEUW, JEROEN, additional, MOENS, STIJN, additional, ANNIBALI, DANIELA, additional, CUPPENS, TINE, additional, MOERMAN, PHILIPPE, additional, LAMBRECHTS, DIETHER, additional, and AMANT, FREDERIC, additional
Published: 2016
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34. Successful application of endoscopic ultrasound-guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study

Author: Hermans, Els, additional, Van der Merwe, Schalk, additional, Depreeuw, Jeroen, additional, Dekervel, Jeroen, additional, Radaelli, Enrico, additional, Roskams, Tania, additional, van Pelt Jos, Jos, additional, Topal, Baki, additional, Verslype, Chris, additional, Prenen, Hans, additional, Van Steenbergen, Werner, additional, Nevens, Frederik, additional, Lambrechts, Diether, additional, and Amant, Frédéric, additional
Published: 2016
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35. Abstract A26: The successful application of endoscopic ultrasound guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts

Author: Hermans, Els, primary, Merwe, Schalk Van der, additional, Depreeuw, Jeroen, additional, Dekervel, Jeroen, additional, Radaelli, Enrico, additional, Topal, Baki, additional, Lambrechts, Diether, additional, and Amant, Frédéric, additional
Published: 2016
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36. Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies

Author: UCL - (SLuc) Service de gynécologie et d'andrologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Depreeuw, Jeroen, Hermans, Els, Schrauwen, Stefanie, Annibali, Daniela, Coenegrachts, Lieve, Thomas, Debby, Luyckx, Mathieu, Gutierrez-Roelens, Ilse, Debruyne, David, Konings, Katrien, Moerman, Philippe, Vergote, Ignace, Lambrechts, Diether, Amant, Frédéric, UCL - (SLuc) Service de gynécologie et d'andrologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Depreeuw, Jeroen, Hermans, Els, Schrauwen, Stefanie, Annibali, Daniela, Coenegrachts, Lieve, Thomas, Debby, Luyckx, Mathieu, Gutierrez-Roelens, Ilse, Debruyne, David, Konings, Katrien, Moerman, Philippe, Vergote, Ignace, Lambrechts, Diether, and Amant, Frédéric
Abstract: Objective Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients. Methods Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations. Results We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy. Conclusion The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups
Published: 2015

37. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author: Cheng, Timothy H. T., Thompson, Deborah, Painter, Jodie, O’Mara, Tracy, Gorman, Maggie, Martin, Lynn, Palles, Claire, Jones, Angela, Buchanan, Daniel D., Win, Aung Ko, Hopper, John, Jenkins, Mark, Lindor, Noralane M., Newcomb, Polly A., Gallinger, Steve, Conti, David, Schumacher, Fred, Casey, Graham, Giles, Graham G., Pharoah, Paul, Peto, Julian, Cox, Angela, Swerdlow, Anthony, Couch, Fergus, Cunningham, Julie M., Goode, Ellen L., Winham, Stacey J., Lambrechts, Diether, Fasching, Peter, Burwinkel, Barbara, Brenner, Hermann, Brauch, Hiltrud, Chang Claude, Jenny, Salvesen, Helga B., Kristensen, Vessela, Darabi, Hatef, Li, Jingmei, Liu, Tao, Lindblom, Annika, Hall, Per, Echeverry de Polanco, Magdalena, Sans, Monica, Carracedo, Angel, Castellvi Bel, Sergi, Rojas Martínez, Augusto, Aguiar Jnr, Samuel, Teixeira, Manuel R., Dunning, Alison M, Dennis, Joe, Otton, Geoffrey, Proietto, Tony, Holliday, Elizabeth, Attia, John, Ashton, Katie, Scott, Rodney J, McEvoy, Mark, Dowdy, Sean C, Fridley, Brooke L, Werner, Henrica MJ, Trovik, Jone, Njolstad, Tormund S, Tham, Emma, Mints, Miriam, Runnebaum, Ingo, Hillemanns, Peter, Dörk, Thilo, Amant, Frederic, Schrauwen, Stefanie, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif, Czene, Kamila, Meindl, Alfons, Bolla, Manjeet K, Michailidou, Kyriaki, Tyrer, Jonathan P., Wang, Qin, Ahmed, Shahana, Healey, Catherine S., Shah, Mitul, Annibali, Daniela, Depreeuw, Jeroen, Al-Tassan, Nada A., Harris, Rebecca, Meyer, Brian F., Whiffin, Nicola, Hosking, Fay J, Kinnersley, Ben, Farrington, Susan M., Timofeeva, Maria, Tenesa, Albert, Campbell, Harry, Haile, Robert W., Hodgson, Shirley, Carvajal Carmona, Luis, Cheadle, Jeremy P., Easton, Douglas, Dunlop, Malcolm, Houlston, Richard, Spurdle, Amanda, Tomlinson, Ian, Cheng, Timothy H. T., Thompson, Deborah, Painter, Jodie, O’Mara, Tracy, Gorman, Maggie, Martin, Lynn, Palles, Claire, Jones, Angela, Buchanan, Daniel D., Win, Aung Ko, Hopper, John, Jenkins, Mark, Lindor, Noralane M., Newcomb, Polly A., Gallinger, Steve, Conti, David, Schumacher, Fred, Casey, Graham, Giles, Graham G., Pharoah, Paul, Peto, Julian, Cox, Angela, Swerdlow, Anthony, Couch, Fergus, Cunningham, Julie M., Goode, Ellen L., Winham, Stacey J., Lambrechts, Diether, Fasching, Peter, Burwinkel, Barbara, Brenner, Hermann, Brauch, Hiltrud, Chang Claude, Jenny, Salvesen, Helga B., Kristensen, Vessela, Darabi, Hatef, Li, Jingmei, Liu, Tao, Lindblom, Annika, Hall, Per, Echeverry de Polanco, Magdalena, Sans, Monica, Carracedo, Angel, Castellvi Bel, Sergi, Rojas Martínez, Augusto, Aguiar Jnr, Samuel, Teixeira, Manuel R., Dunning, Alison M, Dennis, Joe, Otton, Geoffrey, Proietto, Tony, Holliday, Elizabeth, Attia, John, Ashton, Katie, Scott, Rodney J, McEvoy, Mark, Dowdy, Sean C, Fridley, Brooke L, Werner, Henrica MJ, Trovik, Jone, Njolstad, Tormund S, Tham, Emma, Mints, Miriam, Runnebaum, Ingo, Hillemanns, Peter, Dörk, Thilo, Amant, Frederic, Schrauwen, Stefanie, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif, Czene, Kamila, Meindl, Alfons, Bolla, Manjeet K, Michailidou, Kyriaki, Tyrer, Jonathan P., Wang, Qin, Ahmed, Shahana, Healey, Catherine S., Shah, Mitul, Annibali, Daniela, Depreeuw, Jeroen, Al-Tassan, Nada A., Harris, Rebecca, Meyer, Brian F., Whiffin, Nicola, Hosking, Fay J, Kinnersley, Ben, Farrington, Susan M., Timofeeva, Maria, Tenesa, Albert, Campbell, Harry, Haile, Robert W., Hodgson, Shirley, Carvajal Carmona, Luis, Cheadle, Jeremy P., Easton, Douglas, Dunlop, Malcolm, Houlston, Richard, Spurdle, Amanda, and Tomlinson, Ian
Published: 2015

38. Prognostic significance of POLE proofreading mutations in endometrial cancer

Author: Church, David N, Stelloo, Ellen, Nout, Remi A, Valtcheva, Nadejda, Depreeuw, Jeroen, Ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P M, Wild, Peter J, Lambrechts, Diether, Jürgenliemk-Schulz, Ina M, Jobsen, Jan J, Smit, Vincent T H B M, Creutzberg, Carien L, Bosse, Tjalling, Church, David N, Stelloo, Ellen, Nout, Remi A, Valtcheva, Nadejda, Depreeuw, Jeroen, Ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P M, Wild, Peter J, Lambrechts, Diether, Jürgenliemk-Schulz, Ina M, Jobsen, Jan J, Smit, Vincent T H B M, Creutzberg, Carien L, and Bosse, Tjalling
Abstract: BACKGROUND: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. METHODS: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. RESULTS: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). CONCLUSION: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.
Published: 2015

39. CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Author: Thompson, Deborah J, primary, O'Mara, Tracy A, additional, Glubb, Dylan M, additional, Painter, Jodie N, additional, Cheng, Timothy, additional, Folkerd, Elizabeth, additional, Doody, Deborah, additional, Dennis, Joe, additional, Webb, Penelope M, additional, _, _, additional, Gorman, Maggie, additional, Martin, Lynn, additional, Hodgson, Shirley, additional, Michailidou, Kyriaki, additional, Tyrer, Jonathan P, additional, Maranian, Mel J, additional, Hall, Per, additional, Czene, Kamila, additional, Darabi, Hatef, additional, Li, Jingmei, additional, Fasching, Peter A, additional, Hein, Alexander, additional, Beckmann, Matthias W, additional, Ekici, Arif B, additional, Dörk, Thilo, additional, Hillemanns, Peter, additional, Dürst, Matthias, additional, Runnebaum, Ingo, additional, Zhao, Hui, additional, Depreeuw, Jeroen, additional, Schrauwen, Stefanie, additional, Amant, Frederic, additional, Goode, Ellen L, additional, Fridley, Brooke L, additional, Dowdy, Sean C, additional, Winham, Stacey J, additional, Salvesen, Helga B, additional, Trovik, Jone, additional, Njolstad, Tormund S, additional, Werner, Henrica M J, additional, Ashton, Katie, additional, Proietto, Tony, additional, Otton, Geoffrey, additional, Carvajal-Carmona, Luis, additional, Tham, Emma, additional, Liu, Tao, additional, Mints, Miriam, additional, Scott, Rodney J, additional, McEvoy, Mark, additional, Attia, John, additional, Holliday, Elizabeth G, additional, Montgomery, Grant W, additional, Martin, Nicholas G, additional, Nyholt, Dale R, additional, Henders, Anjali K, additional, Hopper, John L, additional, Traficante, Nadia, additional, Ruebner, Matthias, additional, Swerdlow, Anthony J, additional, Burwinkel, Barbara, additional, Brenner, Hermann, additional, Meindl, Alfons, additional, Brauch, Hiltrud, additional, Lindblom, Annika, additional, Lambrechts, Diether, additional, Chang-Claude, Jenny, additional, Couch, Fergus J, additional, Giles, Graham G, additional, Kristensen, Vessela N, additional, Cox, Angela, additional, Bolla, Manjeet K, additional, Wang, Qin, additional, Bojesen, Stig E, additional, Shah, Mitul, additional, Luben, Robert, additional, Khaw, Kay-Tee, additional, Pharoah, Paul D P, additional, Dunning, Alison M, additional, Tomlinson, Ian, additional, Dowsett, Mitch, additional, Easton, Douglas F, additional, and Spurdle, Amanda B, additional
Published: 2015
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40. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Author: O'Mara, Tracy A, primary, Glubb, Dylan M, additional, Painter, Jodie N, additional, Cheng, Timothy, additional, Dennis, Joe, additional, _, _, additional, Attia, John, additional, Holliday, Elizabeth G, additional, McEvoy, Mark, additional, Scott, Rodney J, additional, Ashton, Katie, additional, Proietto, Tony, additional, Otton, Geoffrey, additional, Shah, Mitul, additional, Ahmed, Shahana, additional, Healey, Catherine S, additional, Gorman, Maggie, additional, Martin, Lynn, additional, Hodgson, Shirley, additional, Fasching, Peter A, additional, Hein, Alexander, additional, Beckmann, Matthias W, additional, Ekici, Arif B, additional, Hall, Per, additional, Czene, Kamila, additional, Darabi, Hatef, additional, Li, Jingmei, additional, Dürst, Matthias, additional, Runnebaum, Ingo, additional, Hillemanns, Peter, additional, Dörk, Thilo, additional, Lambrechts, Diether, additional, Depreeuw, Jeroen, additional, Annibali, Daniela, additional, Amant, Frederic, additional, Zhao, Hui, additional, Goode, Ellen L, additional, Dowdy, Sean C, additional, Fridley, Brooke L, additional, Winham, Stacey J, additional, Salvesen, Helga B, additional, Njølstad, Tormund S, additional, Trovik, Jone, additional, Werner, Henrica M J, additional, Tham, Emma, additional, Liu, Tao, additional, Mints, Miriam, additional, Bolla, Manjeet K, additional, Michailidou, Kyriaki, additional, Tyrer, Jonathan P, additional, Wang, Qin, additional, Hopper, John L, additional, Peto, Julian, additional, Swerdlow, Anthony J, additional, Burwinkel, Barbara, additional, Brenner, Hermann, additional, Meindl, Alfons, additional, Brauch, Hiltrud, additional, Lindblom, Annika, additional, Chang-Claude, Jenny, additional, Couch, Fergus J, additional, Giles, Graham G, additional, Kristensen, Vessela N, additional, Cox, Angela, additional, Pharoah, Paul D P, additional, Dunning, Alison M, additional, Tomlinson, Ian, additional, Easton, Douglas F, additional, Thompson, Deborah J, additional, and Spurdle, Amanda B, additional
Published: 2015
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41. Microsatellite Instable and Microsatellite Stable Primary Endometrial Carcinoma Cells and Their Subcutaneous and Orthotopic Xenografts Recapitulate the Characteristics of the Corresponding Primary Tumor

Author: MSc, Stefanie Schrauwen, primary, Coenegrachts, Lieve, additional, Depreeuw, Jeroen, additional, Luyten, Catherina, additional, Verbist, Godelieve, additional, Debruyne, David, additional, Vergote, Ignace, additional, Lambrechts, Diether, additional, and Amant, Frédéric, additional
Published: 2015
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42. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer

Author: Church, David N., primary, Stelloo, Ellen, additional, Nout, Remi A., additional, Valtcheva, Nadejda, additional, Depreeuw, Jeroen, additional, ter Haar, Natalja, additional, Noske, Aurelia, additional, Amant, Frederic, additional, Tomlinson, Ian P. M., additional, Wild, Peter J., additional, Lambrechts, Diether, additional, Jürgenliemk-Schulz, Ina M., additional, Jobsen, Jan J., additional, Smit, Vincent T. H. B. M., additional, Creutzberg, Carien L., additional, and Bosse, Tjalling, additional
Published: 2014
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43. Successful application of endoscopic ultrasoundguided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study.

Author: Hermans, Els, Van der Merwe, Schalk W., Depreeuw, Jeroen, Dekervel, Jeroen, Radaelli, Enrico, Roskams, Tania, van Pelt Jos, Jos, Topal, Baki, Verslype, Chris, Prenen, Hans, Van Steenbergen, Werner, Nevens, Frederik, Lambrechts, Diether, and Amant, Frédéric
Subjects: ENDOSCOPIC surgery, NEEDLE biopsy, PANCREATIC tumors, XENOGRAFTS, ULTRASONIC imaging, PILOT projects, TUMOR treatment
Abstract: Background and study aim: Typically, pancreatic patient-derived tumor xenografts (PDXs) are established by transplanting large tumor biopsies obtained through invasive surgery approaches into immunocompromised mice.We aimed to develop pancreatic PDXs by transplanting tumor tissue acquired by endoscopic ultrasound (EUS)- guided fine needle biopsies (FNB), assess take rates compared to surgery-derived PDXs, and demonstrate the histological and genetic resemblance to the original tumor. Patients and methods: Biopsies of untreated pancreatic carcinoma were collected at surgery and during EUS and processed to generate PDXs. Results: By centrifugation of FNB-derived tissue prior to engraftment, we achieved an engraftment rate of 60% (6/10). Despite a decrease in stromal tissue, the general morphology of FNBderived PDXs was conserved as assessed by histopathology. At the genetic level, somatic mutation and copy number profiles were largely similar to the primary tumor. Conclusion:We show that it is technically feasible to establish pancreatic PDXs using aminimally invasive sampling technique, such as EUS-FNB. Although only a limited amount of tumor tissue was acquired, we obtained results similar to those from surgery-derived PDXs. [ABSTRACT FROM AUTHOR]
Published: 2016
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44. Microsatellite Instable and Microsatellite Stable Primary Endometrial Carcinoma Cells and Their Subcutaneous and Orthotopic Xenografts Recapitulate the Characteristics of the Corresponding Primary Tumor.

Author: Schrauwen, Stefanie, Coenegrachts, Lieve, Depreeuw, Jeroen, Luyten, Catherina, Verbist, Godelieve, Debruyne, David, Vergote, Ignace, Lambrechts, Diether, and Amant, Frédéric
Published: 2015
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45. Candidate locus analysis of the TERT- CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Author: Fasching, Peter, Lambrechts, Diether, Amant, Frederic, Salvesen, Helga, Trovik, Jone, Njolstad, Tormund, Werner, Henrica, Scott, Rodney, Ashton, Katie, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida, Depreeuw, Jeroen, Moisse, Matthieu, Couch, Fergus, Giles, Graham, Cunningham, Julie, Børresen-Dale, Anne-Lise, and Kristensen, Vessela
Subjects: ENDOMETRIAL cancer risk factors, SINGLE nucleotide polymorphisms, HUMAN chromosomes, DNA repair, DNA replication
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 to P = 7.7 × 10). 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, CLPTM1L P = 1.5 × 10). 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. [ABSTRACT FROM AUTHOR]
Published: 2015
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46. Five endometrial cancer risk loci identified through genome-wide association analysis

Author: Cheng, Timothy H T, Thompson, Deborah J, O'Mara, Tracy A, Painter, Jodie N, Glubb, Dylan M, Flach, Susanne, Lewis, Annabelle, French, Juliet D, Freeman-Mills, Luke, Church, David, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley, Webb, Penelope M, Attia, John, Holliday, Elizabeth G, McEvoy, Mark, Scott, Rodney J, Henders, Anjali K, Martin, Nicholas G, Montgomery, Grant W, Nyholt, Dale R, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Dennis, Joe, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Hall, Per, Czene, Kamila, Darabi, Hatef, Li, Jingmei, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo, Amant, Frederic, Schrauwen, Stefanie, Zhao, Hui, Lambrechts, Diether, Depreeuw, Jeroen, Dowdy, Sean C, Goode, Ellen L, Fridley, Brooke L, Winham, Stacey J, Njølstad, Tormund S, Salvesen, Helga B, Trovik, Jone, Werner, Henrica M J, Ashton, Katie, Otton, Geoffrey, Proietto, Tony, Liu, Tao, Mints, Miriam, Tham, Emma, Li, Mulin Jun, Yip, Shun H, Wang, Junwen, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P, Dunlop, Malcolm, Houlston, Richard, Palles, Claire, Hopper, John L, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Cunningham, Julie M, Pharoah, Paul D P, Dunning, Alison M, Edwards, Stacey L, Easton, Douglas F, Tomlinson, Ian, and Spurdle, Amanda B
Abstract: We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2= 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
Published: 2016
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47. ISCHAEMIA-INDUCED DNA HYPERMETHYLATION PREDICTS CHRONIC ALLOGRAFT INJURY IN KIDNEY TRANSPLANTATION: AN EPIGENOME-WIDE ASSOCIATION STUDY ACROSS MULTIPLE COHORTS

Author: Heylen, Line, Thienpont, Bernard, Naesens, Maarten, Busschaert, Pieter, Depreeuw, Jeroen, Jochmans, Ina, Monbaliu, Diethard, Jacques PIRENNE, Lerut, Evelyne, Ghesquiere, Bart, Kuypers, Dirk, Lambrechts, Diether, and Sprangers, Ben

48. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Painter, Jodie N, O'Mara, Tracy A, Marquart, Louise, Webb, Penelope M, Attia, John, Medland, Sarah E, Cheng, Timothy, Dennis, Joe, Holliday, Elizabeth G, McEvoy, Mark, Scott, Rodney J, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Gorman, Maggie, Martin, Lynn, Hodgson, Shirley V, Beckmann, Matthias W, Ekici, Arif B, Fasching, Peter A, Hein, Alexander, Rübner, Matthias, Czene, Kamila, Darabi, Hatef, Hall, Per, Li, Jingmei, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Amant, Frederic, Annibali, Daniela, Depreeuw, Jeroen, Lambrechts, Diether, Neven, Patrick, Cunningham, Julie M, Dowdy, Sean C, Goode, Ellen L, Fridley, Brooke L, Winham, Stacey J, Njølstad, Tormund S, Salvesen, Helga B, Trovik, Jone, Werner, Henrica MJ, Ashton, Katie A, Otton, Geoffrey, Proietto, Anthony, Mints, Miriam, Tham, Emma, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P, Hopper, John L, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Pharoah, Paul DP, Tomlinson, Ian, Dunning, Alison M, Easton, Douglas F, Thompson, Deborah J, Spurdle, Amanda B, AOCS Group, For RENDOCAS, National Study Of Endometrial Cancer Genetics Group (NSECG), and Australian National Endometrial Cancer Study Group (ANECS)
Subjects: 2. Zero hunger, Waist-Hip Ratio, nutritional and metabolic diseases, Humans, Female, Genetic Predisposition to Disease, Obesity, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, 3. Good health, Body Mass Index, Endometrial Neoplasms
Abstract: BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.

49. Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses

Author: Painter, Jodie N, O'Mara, Tracy A, Morris, Andrew P, Cheng, Timothy HT, Gorman, Maggie, Martin, Lynn, Hodson, Shirley, Jones, Angela, Martin, Nicholas G, Gordon, Scott, Henders, Anjali K, Attia, John, McEvoy, Mark, Holliday, Elizabeth G, Scott, Rodney J, Webb, Penelope M, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Rübner, Matthias, Hall, Per, Czene, Kamila, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo, Lambrechts, Diether, Amant, Frederic, Annibali, Daniela, Depreeuw, Jeroen, Vanderstichele, Adriaan, Goode, Ellen L, Cunningham, Julie M, Dowdy, Sean C, Winham, Stacey J, Trovik, Jone, Hoivik, Erling, Werner, Henrica MJ, Krakstad, Camilla, Ashton, Katie, Otton, Geoffrey, Proietto, Tony, Tham, Emma, Mints, Miriam, Ahmed, Shahana, Healey, Catherine S, Shah, Mitul, Pharoah, Paul DP, Dunning, Alison M, Dennis, Joe, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Tyrer, Jonathan P, Hopper, John L, Peto, Julian, Swerdlow, Anthony J, Burwinkel, Barbara, Brenner, Hermann, Meindl, Alfons, Brauch, Hiltrud, Lindblom, Annika, Chang-Claude, Jenny, Couch, Fergus J, Giles, Graham G, Kristensen, Vessela N, Cox, Angela, Zondervan, Krina T, Nyholt, Dale R, MacGregor, Stuart, Montgomery, Grant W, Tomlinson, Ian, Easton, Douglas F, Thompson, Deborah J, and Spurdle, Amanda B
Subjects: endometriosis, STAT3 Transcription Factor, genome-wide association study, Australia, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Cross-disease analysis, genetic correlation, Polymorphism, Single Nucleotide, 3. Good health, Endometrial Neoplasms, Endometrium, endometrial cancer, Humans, Female, Genetic Predisposition to Disease
Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

50. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer

Author: Church, David N., Stelloo, Ellen, Nout, Remi A., Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P. M., Wild, Peter J., Lambrechts, Diether, Jürgenliemk-Schulz, Ina M., Jobsen, Jan J., Smit, Vincent T. H. B. M., Creutzberg, Carien L., Bosse, Tjalling, Church, David N., Stelloo, Ellen, Nout, Remi A., Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P. M., Wild, Peter J., Lambrechts, Diether, Jürgenliemk-Schulz, Ina M., Jobsen, Jan J., Smit, Vincent T. H. B. M., Creutzberg, Carien L., and Bosse, Tjalling
Abstract: Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC

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