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2. Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease

Author

Ramachandran, Dhanya, Tyrer, Jonathan P, Kommoss, Stefan, DeFazio, Anna, Riggan, Marjorie J, Webb, Penelope M, Fasching, Peter A, Lambrechts, Diether, García, María J, Rodríguez-Antona, Cristina, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Karlan, Beth Y, Lester, Jenny, Kjaer, Susanne K, Jensen, Allan, Høgdall, Estrid, Goode, Ellen L, Cliby, William A, Kumar, Amanika, Wang, Chen, Cunningham, Julie M, Winham, Stacey J, Monteiro, Alvaro N, Schildkraut, Joellen M, Cramer, Daniel W, Terry, Kathryn L, Titus, Linda, Bjorge, Line, Thomsen, Liv Cecilie Vestrheim, Pejovic, Tanja, Høgdall, Claus K, McNeish, Iain A, May, Taymaa, Huntsman, David G, Pfisterer, Jacobus, Canzler, Ulrich, Park-Simon, Tjoung-Won, Schröder, Willibald, Belau, Antje, Hanker, Lars, Harter, Philipp, Sehouli, Jalid, Kimmig, Rainer, de Gregorio, Nikolaus, Schmalfeldt, Barbara, Baumann, Klaus, Hilpert, Felix, Burges, Alexander, Winterhoff, Boris, Schürmann, Peter, Speith, Lisa-Marie, Hillemanns, Peter, Berchuck, Andrew, Johnatty, Sharon E, Ramus, Susan J, Chenevix-Trench, Georgia, Pharoah, Paul DP, Dörk, Thilo, and Heitz, Florian

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Prevention, Human Genome, Clinical Research, Ovarian Cancer, Women's Health, Orphan Drug, Rare Diseases, 2.1 Biological and endogenous factors, AOCS Group, OPAL Study Group, Medical biotechnology
Abstract

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Published
2024

4. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author

Levi, Hagai, Carmi, Shai, Rosset, Saharon, Yerushalmi, Rinat, Zick, Aviad, Yablonski-Peretz, Tamar, Consortium, The BCAC, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura Beane, Beckmann, Matthias, Behrens, Sabine, Bermisheva, Marina, Bodelon, Clara, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Byers, Helen, Camp, Nicola, Castelao, Jose, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chung, Wendy, Clarke, Christine, Collaborators, NBCS, Collee, Margriet J, Colonna, Sarah, Consortium, CTS, Couch, Fergus, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary, Devilee, Peter, Dork, Thilo, Dossus, Laure, Eccles, Diana M, Eliassen, A Heather, Eriksson, Mikael, Evans, Gareth, Fasching, Peter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Garcia-Saenz, Jose Angel, Genkinger, Jeanine, Giles, Graham G, Goldberg, Mark, Guénel, Pascal, Hall, Per, Hamann, Ute, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John, Investigators, ABCTB, Jakovchevska, Simona, Jakubowska, Anna, Jernström, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Vijai, Joseph, Kaaks, Rudolf, Khusnutdinova, Elza, Kitahara, Cari, Koutros, Stella, Kristensen, Vessela, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Loibl, Sibylle, Lori, Adriana, Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Mavroudis, Dimitrios, Menon, Usha, Mulligan, AnnaMarie, Murphy, Rachel, Nevelsteen, Ines, Newman, William G, and Obi, Nadia

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Prevention, Cancer, Humans, Female, Breast Neoplasms, Genome-Wide Association Study, Jews, Israel, Genetic Predisposition to Disease, Risk Factors, Multifactorial Inheritance, Transcription Factors, Genomics, Polymorphism, Genetic, BCAC Consortium, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Polymorphism, Genetic, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Published
2023

6. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author

Dixon-Suen, Suzanne C, Lewis, Sarah J, Martin, Richard M, English, Dallas R, Boyle, Terry, Giles, Graham G, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Investigators, ABCTB, Ahearn, Thomas U, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brüning, Thomas, Buys, Saundra S, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Cessna, Melissa H, Chang-Claude, Jenny, Chanock, Stephen J, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Goldberg, Mark S, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Häberle, Lothar, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hart, Steven N, Harvie, Michelle, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J, Hoppe, Reiner, Hopper, John, Howell, Anthony, Hunter, David J, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Loibl, Sibylle, Lubiński, Jan, Mannermaa, Arto, and Manoochehri, Mehdi

Subjects
Aging, Genetics, Breast Cancer, Clinical Research, Cancer, Prevention, Female, Humans, Breast Neoplasms, Exercise, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Sedentary Behavior, Breast Cancer Association Consortium, Breast, Physical activity, Sedentary Behaviour, Engineering, Medical and Health Sciences, Education, Sport Sciences
Abstract

ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Published
2022

7. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial

Author

Mackensen, Andreas, Haanen, John B.A.G., Koenecke, Christian, Alsdorf, Winfried, Wagner-Drouet, Eva, Borchmann, Peter, Heudobler, Daniel, Ferstl, Barbara, Klobuch, Sebastian, Bokemeyer, Carsten, Desuki, Alexander, Lüke, Florian, Kutsch, Nadine, Müller, Fabian, Smit, Eveline, Hillemanns, Peter, Karagiannis, Panagiotis, Wiegert, Erol, He, Ying, Ho, Thang, Kang-Fortner, Qing, Schlitter, Anna Melissa, Schulz-Eying, Catrine, Finlayson, Andrew, Flemmig, Carina, Kühlcke, Klaus, Preußner, Liane, Rengstl, Benjamin, Türeci, Özlem, and Şahin, Uğur

Published
2023
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13. Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7

Author

Heublein, Sabine, Pfisterer, Jacobus, du Bois, Andreas, Anglesio, Michael, Aminossadati, Behnaz, Bhatti, Irfan, Sehouli, Jalid, Wimberger, Pauline, Schochter, Fabienne, Hilpert, Felix, Hillemanns, Peter, Kalder, Matthias, Schroeder, Willibald, Mahner, Sven, Burges, Alexander, Canzler, Ulrich, Gropp-Meier, Martina, Jackisch, Christian, Harter, Philipp, Kommoss, Stefan, and Marmé, Frederik

Published
2024
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14. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author

Figlioli, Gisella, Billaud, Amandine, Ahearn, Thomas U., Antonenkova, Natalia N., Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blok, Marinus J., Bogdanova, Natalia V., Bonanni, Bernardo, Burwinkel, Barbara, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Cessna, Melissa H., Chanock, Stephen J., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine D., Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harrington, Patricia A., He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, Jager, Agnes, Jakubowska, Anna, Khusnutdinova, Elza K., Ko, Yon-Dschun, Kristensen, Vessela N., Lindblom, Annika, Lissowska, Jolanta, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Newman, William G., Obi, Nadia, Panayiotidis, Mihalis I., Rashid, Muhammad U., Rhenius, Valerie, Rookus, Matti A., Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sironen, Reijo, Southey, Melissa C., Suvanto, Maija, Tollenaar, Rob A. E. M., Tomlinson, Ian, Truong, Thérèse, van der Kolk, Lizet E., van Veen, Elke M., Wappenschmidt, Barbara, Yang, Xiaohong R., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Lush, Michael, Michailidou, Kyriaki, Pharoah, Paul D. P., Wang, Qin, Adank, Muriel A., Schmidt, Marjanka K., Andrulis, Irene L., Chang-Claude, Jenny, Nevanlinna, Heli, Chenevix-Trench, Georgia, Evans, D. Gareth, Milne, Roger L., Radice, Paolo, and Peterlongo, Paolo

Published
2023
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15. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Author

Kar, Siddhartha P, Considine, Daniel PC, Tyrer, Jonathan P, Plummer, Jasmine T, Chen, Stephanie, Dezem, Felipe S, Barbeira, Alvaro N, Rajagopal, Padma S, Rosenow, Will T, Moreno, Fernando, Bodelon, Clara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, deFazio, Anna, Dörk, Thilo, Ekici, Arif B, Ewing, Ailith, Fountzilas, George, Goode, Ellen L, Hartman, Mikael, Heitz, Florian, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Huzarski, Tomasz, Jensen, Allan, Karlan, Beth Y, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Li, Jingmei, Liebrich, Clemens, May, Taymaa, Olsson, Håkan, Permuth, Jennifer B, Peterlongo, Paolo, Radice, Paolo, Ramus, Susan J, Riggan, Marjorie J, Risch, Harvey A, Saloustros, Emmanouil, Simard, Jacques, Szafron, Lukasz M, Titus, Linda, Thompson, Cheryl L, Vierkant, Robert A, Winham, Stacey J, Zheng, Wei, Doherty, Jennifer A, Berchuck, Andrew, Lawrenson, Kate, Im, Hae Kyung, Manichaikul, Ani W, Pharoah, Paul DP, Gayther, Simon A, and Schildkraut, Joellen M

Subjects
Biotechnology, Genetics, Prevention, Cancer, Breast Cancer, Human Genome, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Published
2021

16. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Author

Dorling, Leila, Carvalho, Sara, Allen, Jamie, González-Neira, Anna, Luccarini, Craig, Wahlström, Cecilia, Pooley, Karen A, Parsons, Michael T, Fortuno, Cristina, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Keeman, Renske, Alonso, M Rosario, Álvarez, Nuria, Herraez, Belen, Fernandez, Victoria, Núñez-Torres, Rocio, Osorio, Ana, Valcich, Jeanette, Li, Minerva, Törngren, Therese, Harrington, Patricia A, Baynes, Caroline, Conroy, Don M, Decker, Brennan, Fachal, Laura, Mavaddat, Nasim, Ahearn, Thomas, Aittomäki, Kristiina, Antonenkova, Natalia N, Arnold, Norbert, Arveux, Patrick, Ausems, Margreet GEM, Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Briceno, Ignacio, Brüning, Thomas, Burwinkel, Barbara, Cameron, David A, Camp, Nicola J, Campbell, Archie, Carracedo, Angel, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, Christiansen, Hans, Collée, J Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Czene, Kamila, Dörk, Thilo, Ekici, Arif B, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Försti, Asta, Gabrielson, Marike, Gago-Dominguez, Manuela, Georgoulias, Vassilios, Gil, Fabian, Giles, Graham G, Glendon, Gord, Garcia, Encarna B Gómez, Alnæs, Grethe I Grenaker, Guénel, Pascal, Hadjisavvas, Andreas, Haeberle, Lothar, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Ho, Weang Kee, Hooning, Maartje J, Howell, Anthony, Humphreys, Keith, Idris, Faiza, Jakubowska, Anna, and Jung, Audrey

Subjects
Breast Cancer, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Logistic Models, Middle Aged, Mutation, Missense, Odds Ratio, Risk, Sequence Analysis, DNA, Young Adult, Breast Cancer Association Consortium, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.MethodsWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.ResultsProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.ConclusionsThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

Published
2021

17. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Author

Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise A, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, McAlpine, Jessica N, and McGuire, Valerie

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Human Genome, Uterine Cancer, Genetics, Biotechnology, Ovarian Cancer, Prevention, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Endometrial Neoplasms, Female, Genome-Wide Association Study, Humans, Ovarian Neoplasms, Quantitative Trait Loci, Risk Factors, OPAL Study Group, AOCS Group, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundAccumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.MethodsUsing LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.ResultsGenetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.ConclusionsUsing cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.ImpactOur research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Published
2021

19. Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Author

Liu, Jingjing, Prager-van der Smissen, Wendy JC, Collée, J Margriet, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Ahearn, Thomas U, Aittomäki, Kristiina, Ambrosone, Christine B, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Augustinsson, Annelie, Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bernstein, Leslie, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Cai, Hui, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Christiaens, Melissa, Clarke, Christine L, NBCS Collaborators, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harrington, Patricia A, Hart, Steven N, Hartman, Mikael, Hillemanns, Peter, Hopper, John L, Hou, Ming-Feng, Hunter, David J, Huo, Dezheng, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, and Mariapun, Shivaani

Subjects
NBCS Collaborators, ABCTB Investigators
Abstract

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

Published
2020

20. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author

Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, and Hillemanns, Peter

Subjects
kConFab Investigators, ABCTB Investigators, EMBRACE Study, GEMO Study Collaborators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Case-Control Studies, Linkage Disequilibrium, Mutation, Female, Genome-Wide Association Study, Triple Negative Breast Neoplasms, Human Genome, Cancer, Prevention, Genetics, Breast Cancer, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P

Published
2020

21. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Author

Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Group, OPAL Study, Group, AOCS, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant B, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, and May, Taymaa

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Statistics, Mathematical Sciences, Oncology and Carcinogenesis, Aging, Rare Diseases, Human Genome, Cancer, Uterine Cancer, Ovarian Cancer, Prevention, Biotechnology, Aetiology, 2.1 Biological and endogenous factors
Abstract

Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Published
2020

22. Two truncating variants in FANCC and breast cancer risk.

Author

Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans BL, Hooning, Maartje J, Hopper, John L, Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindström, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, and Meindl, Alfons

Subjects
ABCTB Investigators, NBCS Collaborators, Humans, Breast Neoplasms, Fanconi Anemia, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Case-Control Studies, Sequence Deletion, Female, Fanconi Anemia Complementation Group C Protein, Genetic Variation, Clinical Research, Breast Cancer, Genetics, Cancer, 2.1 Biological and endogenous factors, Biochemistry and Cell Biology, Other Physical Sciences
Abstract

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Published
2019

23. Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

Author

Shu, Xiang, Wu, Lang, Khankari, Nikhil K, Shu, Xiao-Ou, Wang, Thomas J, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Pharoah, Paul DP, Andrulis, Irene L, Hunter, David J, Simard, Jacques, Easton, Douglas F, Zheng, Wei, Alicia, Beeghly-Fadiel J, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beane Freeman, Laura E, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, David Cheng, Ting-Yuan, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Dwek, Miriam, Earp, H Shelton, Eccles, Diana M, Heather Eliassen, A, Engel, Christoph, Eriksson, Mikael, Gareth Evans, D, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, He, Wei, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hogervorst, Frans B, Hollestelle, Antoinette, and Hoover, Robert N

Subjects
Clinical Research, Diabetes, Prevention, Nutrition, Obesity, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Blood Glucose, Body Mass Index, Breast Neoplasms, Diabetes Mellitus, Type 2, Female, Humans, Insulin, Mendelian Randomization Analysis, Middle Aged, Obesity, Abdominal, Waist-Hip Ratio, Breast cancer, insulin, glucose, obesity, genetics, Mendelian randomization analysis, Breast Cancer Association Consortium, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Published
2019

24. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author

Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, and Holleczek, Bernd

Subjects
NBCS Collaborators, Chromosomes, Human, Pair 7, Humans, Breast Neoplasms, Receptors, Estrogen, Prognosis, Proportional Hazards Models, Bayes Theorem, Female, Genetic Variation, Genome-Wide Association Study, White People, Genetics, Breast Cancer, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P

Published
2019

26. Criteria for second generation comparator tests in validation of novel HPV DNA tests for use in cervical cancer screening.

Author

Arbyn, Marc, Cuschieri, Kate, Bonde, Jesper, Schuurman, Rob, Cocuzza, Clementina, Broeck, Davy Vanden, Zhao, Fang‐Hui, Rezhake, Remila, Gultekin, Murat, de Sanjosé, Silvia, Canfell, Karen, Hawkes, David, Saville, Marion, Hillemanns, Peter, Dillner, Joakim, Berkhof, Johannes, Prétet, Jean‐Luc, Gheit, Tarik, Clifford, Gary, and Basu, Partha

Subjects
EARLY detection of cancer, HUMAN papillomavirus, SAMPLING (Process), CERVICAL cancer, COMPARATOR circuits
Abstract

While HC2 and GP5+/6+ PCR‐EIA were pivotal in test validation of new HPV assays, they represent the first generation of comparator tests based upon technologies that are not in widespread use anymore. In the current guideline, criteria for second‐generation comparator tests are presented that include more detailed resolution of HPV genotypes. Second‐generation comparator tests should preferentially target only the 12 genotypes classified as carcinogenic (IARC‐group I), and show consistent non‐inferior sensitivity for CIN2+ and CIN3+ and specificity for ≤CIN1 compared to one of the first‐generations comparators, in at least three validation studies using benchmarks of 0.95 for relative sensitivity and 0.98 for relative specificity. Validation should take into account used storage media and other sample handling procedures. Meta‐analyses were conducted to identify the assays that fulfill these stringent criteria. Four tests fulfilled the new criteria: (1) RealTime High‐Risk HPV Test (Abbott), (2) Cobas‐4800 HPV test (Roche Molecular System), (3) Onclarity HPV Assay (BD Diagnostics), and (4) Anyplex II HPV HR Detection (Seegene), each evaluated in three to six studies. Whereas the four assays target 14 carcinogenic genotypes, the first two identify separately HPV16 and 18, the third assay identifies five types separately and the fourth identifies all the types separately. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Accuracy of GynTect ® Methylation Markers to Detect Recurrent Disease in Patients Treated for CIN3: A Proof-of-Concept Case-Control Study.

Author

Hoyer, Heike, Scheungraber, Cornelia, Mehlhorn, Grit, Hagemann, Ingke, Scherbring, Sarah, Wölber, Linn, Petzold, Annett, Wunsch, Kristina, Schmitz, Martina, Hampl, Monika, Böhmer, Gerd, Hillemanns, Peter, Runnebaum, Ingo B., and Dürst, Matthias

Subjects
CERVICAL intraepithelial neoplasia, CYTOLOGY, RESEARCH funding, PILOT projects, PAPILLOMAVIRUSES, DNA methylation, CASE-control method, DISEASE relapse, COLLECTION & preservation of biological specimens, CONFIDENCE intervals, SENSITIVITY & specificity (Statistics), MOLECULAR diagnosis, PATIENT aftercare, EVALUATION
Abstract

Simple Summary: Women treated for cervical precancers (CIN2/3) have an increased risk for recurrent lesions and therefore require post-treatment monitoring. Standard follow-up care based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. Host cell methylation correlates highly with CIN2/3 and may thus be a more suitable marker than hrHPV, particularly since HPV infection is not confined to women with the disease. Here, we show that in combination with cytology, the methylation markers comprising GynTect® are as sensitive as hrHPV for the detection of recurrent CIN2/3 lesions but are more specific. A reduction in the rate of false positive results would not only be more cost-effective but may also reduce the number of women requiring re-treatment. These findings must be verified in a sufficiently large validation study. Post-treatment follow-up in women with CIN3 is mandatory due to relapse in up to 15% of patients within 2 years. Standard follow-up care based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our proof-of-concept case-control study was to evaluate the performance of the methylation test GynTect® for the detection of recurrent CIN2/3 during follow-up. Residual clinical material from a recent, prospective, multicenter, observational study was available for further analysis. We studied a sample of 17 cases with recurrent CIN2/3 diagnosed within 24 months of follow-up and 31 controls without recurrence. DNA from cervical scrapes at baseline (immediately before CIN3 surgery) and up to three follow-up visits were analyzed for hrHPV and GynTect® methylation status. Cytology data were available from the previous study. Overall, 12 cases and 21 controls were GynTect-positive at baseline. In these subgroups, single test sensitivity at first follow-up was 67% (95% CI 39–87%) for GynTect® compared to 83% (95% CI 55–96%) for hrHPV (p = 0.50). Single test specificity was significantly higher for GynTect® (90%, 95% CI 71–98% vs. 62%, 95% CI 40–80%) (p = 0.03). In a co-testing setting, both hrHPV/cytology and GynTect®/cytology detected all recurrences. Specificity for GynTect®/cytology was higher than for hrHPV/cytology, but this difference was not statistically significant. In conclusion, for initially GynTect-positive patients, both hrHPV and GynTect® tests detected recurrent disease with similar sensitivity, but the GynTect® assay has a higher specificity. Incident hrHPV infection and/or persisting multifocal hrHPV infections without clinical disease are most likely responsible for the poorer specificity of the hrHPV test. A future prospective validation study will have to show whether GynTect®/cytology co-testing can outperform hrHPV/cytology co-testing in post-treatment surveillance. [ABSTRACT FROM AUTHOR]

Published
2024
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29. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Author

Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Vestrheim Thomsen, Liv Cecilie, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen

Subjects
Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
Abstract

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Published
2018

30. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, and Huang, Guanmengqian

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Prevention, Breast Cancer, Women's Health, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, Generic health relevance, Breast Neoplasms, Case-Control Studies, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk, Transcriptome, NBCS Collaborators, kConFab/AOCS Investigators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P

Published
2018

31. Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study

Author

Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta

Subjects
Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Nutrition, Rare Diseases, Prevention, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Coffee, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

Published
2018

32. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author

Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Women's Health, Cancer, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Body Height, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Geography, Humans, Mendelian Randomization Analysis, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Published
2018

33. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author

Earp, Madalene, Tyrer, Jonathan P, Winham, Stacey J, Lin, Hui-Yi, Chornokur, Ganna, Dennis, Joe, Aben, Katja KH, Anton‐Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Høgdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Jung, Audrey Y, Karlan, Beth Y, Kellar, Melissa, Kiemeney, Lambertus A, Lim, Boon Kiong, Kjaer, Susanne K, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Lester, Jenny, Levine, Douglas A, Li, Zheng, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jenny B, Pike, Malcolm C, Poole, Elizabeth M, Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H, and Runnebaum, Ingo B

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Oncology and Carcinogenesis, Biotechnology, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, A Kinase Anchor Proteins, Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Monomeric GTP-Binding Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rho Guanine Nucleotide Exchange Factors, Risk Factors, General Science & Technology
Abstract

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Published
2018

35. Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer: A Subset Analysis of the AGO-CaRE-1 Study

Author

Woelber, Linn, Bommert, Mareike, Harter, Philipp, Prieske, Katharina, zu Eulenburg, Christine, Jueckstock, Julia, Hilpert, Felix, de Gregorio, Nikolaus, Iborra, Severine, Sehouli, Jalid, Ignatov, Atanas, Hillemanns, Peter, Fuerst, Sophie, Strauss, Hans-Georg, Baumann, Klaus, Beckmann, Matthias, Mustea, Alexander, Meier, Werner, Mahner, Sven, and Jaeger, Anna

Published
2021
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37. Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study

Author

Prieske, Katharina, Woelber, Linn, Muallem, Mustafa Zelal, Eulenburg, Christine, Jueckstock, Julia Kathrin, Hilpert, Felix, de Gregorio, Nikolaus, Iborra, Severine, Ignatov, Atanas, Hillemanns, Peter, Fuerst, Sophie, Strauss, Hans-Georg, Baumann, Klaus, Beckmann, Matthias, Mustea, Alexander, Meier, Werner, Harter, Philipp, Wimberger, Pauline, Sehouli, Jalid, and Mahner, Sven

Published
2021
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38. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author

Glubb, Dylan M, Johnatty, Sharon E, Quinn, Michael CJ, O’Mara, Tracy A, Tyrer, Jonathan P, Gao, Bo, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Thompson, Pamela J, Dörk, Thilo, Dürst, Matthias, Modungo, Francesmary, Moysich, Kirsten, Heitz, Florian, du Bois, Andreas, Pfisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y, Lester, Jenny, Goode, Ellen L, Cunningham, Julie M, Winham, Stacey J, Larson, Melissa C, McCauley, Bryan M, Kjær, Susanne Krüger, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Salvesen, Helga B, Bjorge, Line, Webb, Penny M, Grant, Peter, Pejovic, Tanja, Moffitt, Melissa, Hogdall, Claus K, Hogdall, Estrid, Paul, James, Glasspool, Rosalind, Bernardini, Marcus, Tone, Alicia, Huntsman, David, Woo, Michelle, Group, AOCS, deFazio, Anna, Kennedy, Catherine J, Pharoah, Paul DP, MacGregor, Stuart, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Cancer, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, ovarian cancer outcome, genetic association, gene regulation, meta-analysis, Oncology and carcinogenesis
Abstract

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

Published
2017

39. Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Author

Dicks, Ed, Song, Honglin, Ramus, Susan J, Van Oudenhove, Elke, Tyrer, Jonathan P, Intermaggio, Maria P, Kar, Siddhartha, Harrington, Patricia, Bowtell, David D, Group, AOCS Study, Cicek, Mine S, Cunningham, Julie M, Fridley, Brooke L, Alsop, Jennifer, Jimenez-Linan, Mercedes, Piskorz, Anna, Goranova, Teodora, Kent, Emma, Siddiqui, Nadeem, Paul, James, Crawford, Robin, Poblete, Samantha, Lele, Shashi, Sucheston-Campbell, Lara, Moysich, Kirsten B, Sieh, Weiva, McGuire, Valerie, Lester, Jenny, Odunsi, Kunle, Whittemore, Alice S, Bogdanova, Natalia, Dürst, Matthias, Hillemanns, Peter, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Tischkowitz, Marc, Levine, Douglas, Brenton, James D, Dörk, Thilo, Goode, Ellen L, Gayther, Simon A, and Pharoah, Paul DP

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Genetic Testing, Rare Diseases, Ovarian Cancer, Clinical Research, Cancer, Prevention, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, ovarian cancer, susceptibility genes, DNA repair, next generation sequencing, Next generation sequencing, Susceptibility Genes, Oncology and carcinogenesis
Abstract

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8x10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Published
2017

40. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author

Minlikeeva, Albina N, Freudenheim, Jo L, Cannioto, Rikki A, Szender, J Brian, Eng, Kevin H, Modugno, Francesmary, Ness, Roberta B, LaMonte, Michael J, Friel, Grace, Segal, Brahm H, Odunsi, Kunle, Mayor, Paul, Zsiros, Emese, Schmalfeldt, Barbara, Klapdor, Rüdiger, Dӧrk, Thilo, Hillemanns, Peter, Kelemen, Linda E, Kӧbel, Martin, Steed, Helen, de Fazio, Anna, on behalf of the Australian Ovarian Cancer Study Group, Jordan, Susan J, Nagle, Christina M, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Edwards, Robert, Matsuo, Keitaro, Mizuno, Mika, Karlan, Beth Y, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Schildkraut, Joellen M, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Paddock, Lisa E, Kiemeney, Lambertus A, Massuger, Leon F, Kupryjanczyk, Jolanta, Berchuck, Andrew, Chang-Claude, Jenny, Diergaarde, Brenda, Webb, Penelope M, Moysich, Kirsten B, and on behalf of the Ovarian Cancer Association Consortium

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Diabetes, Ovarian Cancer, Rare Diseases, Genetics, Cardiovascular, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Adrenergic beta-Antagonists, Adult, Aged, Diabetes Mellitus, Disease-Free Survival, Female, Heart Diseases, Humans, Hypertension, Hypoglycemic Agents, Insulin, Middle Aged, Ovarian Neoplasms, Risk, Survival Rate, Ovarian cancer prognosis, Medications, Mortality, Beta blockers, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology and carcinogenesis
Abstract

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Published
2017

42. Criteria for second generation comparator tests in validation of novel HPV DNA tests for use in cervical cancer screening

Author

MMB, MMB Medische Staf, Infection & Immunity, Arbyn, Marc, Cuschieri, Kate, Bonde, Jesper, Schuurman, Rob, Cocuzza, Clementina, Broeck, Davy Vanden, Zhao, Fang Hui, Rezhake, Remila, Gultekin, Murat, de Sanjosé, Silvia, Canfell, Karen, Hawkes, David, Saville, Marion, Hillemanns, Peter, Dillner, Joakim, Berkhof, Johannes, Prétet, Jean Luc, Gheit, Tarik, Clifford, Gary, Basu, Partha, Almonte, Maribel, Wentzensen, Nicolas, Poljak, Mario, MMB, MMB Medische Staf, Infection & Immunity, Arbyn, Marc, Cuschieri, Kate, Bonde, Jesper, Schuurman, Rob, Cocuzza, Clementina, Broeck, Davy Vanden, Zhao, Fang Hui, Rezhake, Remila, Gultekin, Murat, de Sanjosé, Silvia, Canfell, Karen, Hawkes, David, Saville, Marion, Hillemanns, Peter, Dillner, Joakim, Berkhof, Johannes, Prétet, Jean Luc, Gheit, Tarik, Clifford, Gary, Basu, Partha, Almonte, Maribel, Wentzensen, Nicolas, and Poljak, Mario

Published
2024

43. Criteria for second generation comparator tests in validation of novel HPV DNA tests for use in cervical cancer screening

Author

Arbyn, M, Cuschieri, K, Bonde, J, Schuurman, R, Cocuzza, C, Broeck, D, Zhao, F, Rezhake, R, Gultekin, M, de Sanjosé, S, Canfell, K, Hawkes, D, Saville, M, Hillemanns, P, Dillner, J, Berkhof, J, Prétet, J, Gheit, T, Clifford, G, Basu, P, Almonte, M, Wentzensen, N, Poljak, M, Arbyn, Marc, Cuschieri, Kate, Bonde, Jesper, Schuurman, Rob, Cocuzza, Clementina, Broeck, Davy Vanden, Zhao, Fang‐Hui, Rezhake, Remila, Gultekin, Murat, de Sanjosé, Silvia, Canfell, Karen, Hawkes, David, Saville, Marion, Hillemanns, Peter, Dillner, Joakim, Berkhof, Johannes, Prétet, Jean‐Luc, Gheit, Tarik, Clifford, Gary, Basu, Partha, Almonte, Maribel, Wentzensen, Nicolas, Poljak, Mario, Arbyn, M, Cuschieri, K, Bonde, J, Schuurman, R, Cocuzza, C, Broeck, D, Zhao, F, Rezhake, R, Gultekin, M, de Sanjosé, S, Canfell, K, Hawkes, D, Saville, M, Hillemanns, P, Dillner, J, Berkhof, J, Prétet, J, Gheit, T, Clifford, G, Basu, P, Almonte, M, Wentzensen, N, Poljak, M, Arbyn, Marc, Cuschieri, Kate, Bonde, Jesper, Schuurman, Rob, Cocuzza, Clementina, Broeck, Davy Vanden, Zhao, Fang‐Hui, Rezhake, Remila, Gultekin, Murat, de Sanjosé, Silvia, Canfell, Karen, Hawkes, David, Saville, Marion, Hillemanns, Peter, Dillner, Joakim, Berkhof, Johannes, Prétet, Jean‐Luc, Gheit, Tarik, Clifford, Gary, Basu, Partha, Almonte, Maribel, Wentzensen, Nicolas, and Poljak, Mario

Abstract

While HC2 and GP5+/6+ PCR-EIA were pivotal in test validation of new HPV assays, they represent the first generation of comparator tests based upon technologies that are not in widespread use anymore. In the current guideline, criteria for second-generation comparator tests are presented that include more detailed resolution of HPV genotypes. Second-generation comparator tests should preferentially target only the 12 genotypes classified as carcinogenic (IARC-group I), and show consistent non-inferior sensitivity for CIN2+ and CIN3+ and specificity for ≤CIN1 compared to one of the first-generations comparators, in at least three validation studies using benchmarks of 0.95 for relative sensitivity and 0.98 for relative specificity. Validation should take into account used storage media and other sample handling procedures. Meta-analyses were conducted to identify the assays that fulfill these stringent criteria. Four tests fulfilled the new criteria: (1) RealTime High-Risk HPV Test (Abbott), (2) Cobas-4800 HPV test (Roche Molecular System), (3) Onclarity HPV Assay (BD Diagnostics), and (4) Anyplex II HPV HR Detection (Seegene), each evaluated in three to six studies. Whereas the four assays target 14 carcinogenic genotypes, the first two identify separately HPV16 and 18, the third assay identifies five types separately and the fourth identifies all the types separately.

Published
2024

44. Validation and functional follow‐up of cervical cancer risk variants at the HLA locus.

Author

Eisenblätter, Rieke, Seifert, Finja, Schürmann, Peter, Beckhaus, Theresa, Hanel, Patricia, Jentschke, Matthias, Böhmer, Gerd, Strauß, Hans‐Georg, Hirchenhain, Christine, Schmidmayr, Monika, Müller, Florian, Hein, Alexander, Stuebs, Frederik, Koch, Martin, Ruebner, Matthias, Beckmann, Matthias W., Fasching, Peter A., Luyten, Alexander, Häfner, Norman, and Hillemanns, Peter

Subjects
CERVICAL cancer, EPITHELIUM, CANCER susceptibility, DISEASE risk factors, CANCER invasiveness, DYSPLASIA
Abstract

Cervical cancer is the fourth most common cancer in females. Genome‐wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital‐based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55–0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17–2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest eQTL pairs were rs9272117 and HLA‐DRB6 (p = 1.9x10E‐5), rs1056429 and HLA‐DRB5 (p = 2.5x10E‐4), and rs535777 and HLA‐DRB1 (p = 2.7x10E‐4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA‐B, LTB, NFKBIL1) or downregulated (HLA‐C, HLA‐DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ‐IFN led to a dose‐dependent induction of HCP5, HLA‐B, HLA‐C, HLA‐DQB1, HLA‐DRB1, HLA‐DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation‐responsive in cervical epithelium and associate with HPV (HCP5, HLA‐B, HLA‐C) and/or with genomic cervical cancer risk variants (HLA‐DRB1, HLA‐DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV‐infection. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Quality of ChatGPT-Generated Therapy Recommendations for Breast Cancer Treatment in Gynecology.

Author

Stalp, Jan Lennart, Denecke, Agnieszka, Jentschke, Matthias, Hillemanns, Peter, and Klapdor, Rüdiger

Subjects
CHATGPT, BREAST cancer, CANCER treatment, ARTIFICIAL intelligence, GYNECOLOGY
Abstract

Introduction: Artificial intelligence (AI) is revolutionizing medical workflows, with self-learning systems like ChatGPT showing promise in therapy recommendations. Our study evaluated ChatGPT's performance in suggesting treatments for 30 breast cancer cases. AI's role in healthcare is expanding, particularly with tools like ChatGPT becoming accessible. However, understanding its limitations is vital for safe implementation. Material and Methods: We used 30 breast cancer cases from our medical board, assessing ChatGPT's suggestions. The input was standardized, incorporating relevant patient details and treatment options. ChatGPT's output was evaluated by oncologists based on a given questionnaire. Results: Treatment recommendations by ChatGPT were overall rated sufficient with minor limitations by the oncologists. The HER2 treatment category was the best-rated therapy option, with the most accurate recommendations. Primary cases received more accurate recommendations, especially regarding chemotherapy. Conclusions: While ChatGPT demonstrated potential, difficulties were shown in intricate cases and postoperative scenarios. Challenges arose in offering chronological treatment sequences and partially lacked precision. Refining inputs, addressing ethical intricacies, and ensuring chronological treatment suggestions are essential. Ongoing research is vital to improving AI's accuracy, balancing AI-driven suggestions with expert insights and ensuring safe and reliable AI integration into patient care. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author

Hampras, Shalaka S, Sucheston-Campbell, Lara E, Cannioto, Rikki, Chang-Claude, Jenny, Modugno, Francesmary, Dörk, Thilo, Hillemanns, Peter, Preus, Leah, Knutson, Keith L, Wallace, Paul K, Hong, Chi-Chen, Friel, Grace, Davis, Warren, Nesline, Mary, Pearce, Celeste L, Kelemen, Linda E, Goodman, Marc T, Bandera, Elisa V, Terry, Kathryn L, Schoof, Nils, Eng, Kevin H, Clay, Alyssa, Singh, Prashant K, Joseph, Janine M, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Cook, Linda S, Cramer, Daniel W, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A, du Bois, Andreas, Dürst, Matthias, Easton, Doug, Eccles, Diana, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hogdall, Claus, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Klapdor, Rüdiger, Kolomeyevskaya, Nonna, Krakstad, Camilla, Kjaer, Susanne K, Kruszka, Bridget, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashikant, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Liu, Song, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, and McGuire, Valeria

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Ovarian Cancer, Rare Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Clear Cell, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Risk Factors, T-Lymphocytes, Regulatory, ovarian cancer, immunosuppression, biomarkers, genetic variation, TGFBR2, TGFBR2, Oncology and carcinogenesis
Abstract

BackgroundRegulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.MethodsIn a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.ResultsThe most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).ConclusionsCommon inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

50. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Author

Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, and Poole, Elizabeth M

Subjects
Australian Ovarian Cancer Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Vitamin D, Odds Ratio, Risk Factors, Polymorphism, Single Nucleotide, Female, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Prevention, Rare Diseases, Nutrition, Clinical Research, Cancer, Ovarian Cancer, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.MethodsWe employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).ResultsThe odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).ConclusionsGenetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

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