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19 results on '"Andrulis, Irene L. [0000-0002-4226-6435]"'

1. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Author

Lisa Devereux, Douglas F. Easton, Simone McInerny, Melissa C. Southey, R. K. Schmutzler, Orland Diez, Muriel A. Adank, Tu Nguyen-Dumont, Alfons Meindl, Alejandro Moles-Fernández, Marjanka K. Schmidt, Rodney J. Scott, Martine Dumont, Paul A. James, Christoph Engel, Fabienne Lesueur, Penny Soucy, Yu Kuan Huang, N Li, Elad Ziv, Elodie Girard, Eric Hahnen, Magnus Zethoven, Jamie Allen, Kylie L. Gorringe, Susan L. Neuhausen, Irene L. Andrulis, Dane Cheasley, Jacques Simard, John L. Hopper, Ian G. Campbell, Niko Thio, Sara Gutiérrez-Enríquez, Institut Català de la Salut, [Li N] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Zethoven M] Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [McInerny S] Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Vic, Australia. [Devereux L] Lifepool, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Huang YK] Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic, Australia. [Thio N] Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia. [Gutiérrez-Enríquez S, Moles-Fernández A] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d’Hebron, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Li, Na [0000-0003-1578-9561], Devereux, Lisa [0000-0003-2435-5888], Huang, Yu-Kuan [0000-0003-2262-7069], Cheasley, Dane [0000-0002-1170-4690], Gutiérrez-Enríquez, Sara [0000-0002-1711-6101], Simard, Jacques [0000-0001-6906-3390], Schmidt, Marjanka K [0000-0002-2228-429X], Andrulis, Irene L [0000-0002-4226-6435], Engel, Christoph [0000-0002-7247-282X], Lesueur, Fabienne [0000-0001-7404-4549], Easton, Douglas F [0000-0003-2444-3247], Scott, Rodney J [0000-0001-7724-3404], Gorringe, Kylie L [0000-0001-5681-2022], James, Paul A [0000-0002-4361-4657], Campbell, Ian G [0000-0002-7773-4155], Apollo - University of Cambridge Repository, Allen, Jamie [0000-0002-8677-2225], Schmidt, Marjanka K. [0000-0002-2228-429X], Andrulis, Irene L. [0000-0002-4226-6435], Easton, Douglas F. [0000-0003-2444-3247], Scott, Rodney J. [0000-0001-7724-3404], Gorringe, Kylie L. [0000-0001-5681-2022], James, Paul A. [0000-0002-4361-4657], and Campbell, Ian G. [0000-0002-7773-4155]

Subjects
0301 basic medicine, Oncology, Mama - Càncer - Prognosi, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, 32 Biomedical and Clinical Sciences, medicine.disease_cause, 631/208/737, Germline, 0302 clinical medicine, Other subheadings::/diagnosis [Other subheadings], Missense mutation, 2.1 Biological and endogenous factors, Pharmacology (medical), 631/208/68, RC254-282, Cancer, 2 Aetiology, Mutation, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], medicine.diagnostic_test, article, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 4203 Health Services and Systems, 3. Good health, 030220 oncology & carcinogenesis, Malalties congènites, Haploinsufficiency, medicine.medical_specialty, DNA repair, Otros calificadores::/diagnóstico [Otros calificadores], 631/67/69, 03 medical and health sciences, Breast cancer, Clinical Research, Internal medicine, Breast Cancer, medicine, Genetics, Radiology, Nuclear Medicine and imaging, Genetic Testing, Genetic testing, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], business.industry, Prevention, Human Genome, 42 Health Sciences, 631/67/1347, medicine.disease, 3211 Oncology and Carcinogenesis, 631/208/199, 030104 developmental biology, business
Abstract

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

Published
2021

2. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Bertrand, Ophélie, Caputo, Sandrine, Dupré, Anaïs, le Mentec, Marine, Belotti, Muriel, Birot, Anne-Marie, Buecher, Bruno, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Houdayer, Claude, Moncoutier, Virginie, de Pauw, Antoine, Saule, Claire, Sinilnikova, Olga, Mazoyer, Sylvie, Damiola, Francesca, Barjhoux, Laure, Verny-Pierre, Carole, Léone, M. lanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Caron, Olivier, Guillaud-Bataille, Marine, Bressac-de-Paillerets, Brigitte, Bignon, Yves- Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Noguchi, Tetsuro, Popovici, Cornel, Sobol, Hagay, Bourdon, Violaine, Remenieras, Audrey, Noguès, Catherine, Coupier, Isabelle, Pujol, Pascal, Dumont, Aurélie, Révillion, Françoise, Adenis, Claude, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Leroux, Dominique, Dreyfus, H. lène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Mari, V. ronique, Vénat-Bouvet, Laurence, Delnatte, Capucine, Bézieau, Stéphane, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Sokolowska, Johanna, Bronner, Myriam, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Ong, Kai-ren, Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brewer, Carole, Davidson, Rosemarie, Izatt, Louise, Brady, Angela, Barwell, Julian, Adlard, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Eeles, Rosalind A., Cook, Jackie, Snape, Katie, Eccles, Diana, Murray, Alex, McCann, Emma, Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Fox, Stephen, Campbell, Ian, Spurdle, Amanda, Webb, Penny, de Fazio, Anna, Tassell, Margaret, Kirk, Judy, Lindeman, Geoff, Price, Melanie, Southey, Melissa, Milne, Roger, Deb, Sid, Bowtell, David, van der Hout, Annemieke H., van den Ouweland, Ans M. W., Mensenkamp, Arjen R., van Deurzen, Carolien H. M., Kets, Carolien M., Seynaeve, Caroline, van Asperen, Christi J., Aalfs, Cora M., Gómez Garcia, Encarna B., van Leeuwen, Flora E., de Bock, G. H., Meijers-Heijboer, Hanne E. J., Obdeijn, Inge M., Gille, J. J. P., Oosterwijk, Jan C., Wijnen, Juul T., van der Kolk, Lizet E., Hooning, Maartje J., Ausems, Margreet G. E. M., Mourits, Marian J. E., Blok, Marinus J., Rookus, Matti A., van der Luijt, Rob B., van Cronenburg, T. C. T. E. F., van der Pol, Carmen C., Russell, Nicola S., Siesling, Sabine, Overbeek, Lucy, Wijnands, R., de Lange, Judith L., Clarke, Christine, Graham, Dinny, Sachchithananthan, Mythily, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, H. kan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, Antoniou, Antonis C., German Cancer Research Center, National Health and Medical Research Council (Australia), United States of Department of Health & Human Services, National Institute for Health Research (Reino Unido), French National Cancer Institute, Ligue Nationale Contre le Cancer (Francia), Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea, Canadian Institutes of Health Research, Cancer Council New South Wales (Australia), KWF Kankerbestrijding, Instituto de Salud Carlos III, Xunta de Galicia (España), Ministerio de Sanidad, Política Social e Igualdad (España), Helmholtz Association, California Breast Cancer Research Program, Federal Ministry of Education & Research (Alemania), Government of Netherlands, Russian Foundation for Basic Research, O’Mara, Tracy A. [0000-0002-5436-3232], Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P. [0000-0003-3724-4757], Barnes, Daniel R. [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Ahearn, Thomas [0000-0003-0771-7752], Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Barrowdale, Daniel [0000-0003-1661-3939], Becher, Heko [0000-0002-8808-6667], Bernstein, Leslie [0000-0002-7692-6518], Bojesen, Stig E. [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Chanock, Stephen J. [0000-0002-2324-3393], Chung, Wendy K. [0000-0003-3438-5685], Claes, Kathleen B. M. [0000-0003-0841-7372], Collée, J. Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Eliassen, A. Heather [0000-0002-3961-6609], Fritschi, Lin [0000-0002-7692-3560], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Gayther, Simon A. [0000-0001-7937-5443], Giles, Graham G. [0000-0003-4946-9099], Greene, Mark H. [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Hart, Steven N. [0000-0001-7714-2734], He, Wei [0000-0003-0161-3274], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J. [0000-0001-8397-4078], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A. [0000-0002-4361-4657], Jensen, Uffe Birk [0000-0002-6205-6355], Jones, Michael E. [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Kurian, Allison W. [0000-0002-6175-9470], Lambrechts, Diether [0000-0002-3429-302X], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John W. M. [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Milne, Roger L. [0000-0001-5764-7268], Nathanson, Katherine L. [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I. [0000-0002-9936-1599], Olson, Janet E. [0000-0003-4944-7789], Ottini, Laura [0000-0001-8030-0449], Parsons, Michael T. [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Pharoah, Paul D. P. [0000-0001-8494-732X], Punie, Kevin [0000-0002-1162-7963], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Sandler, Dale P. [0000-0002-6776-0018], Schmidt, Marjanka K. [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Toland, Amanda E. [0000-0002-0271-1792], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M. [0000-0002-1962-9322], Vega, Ana [0000-0002-7416-5137], Vijai, Joseph [0000-0002-7933-151X], Weitzel, Jeffrey N. [0000-0001-6714-092X], Wolk, Alicja [0000-0001-7387-6845], Yadav, Siddhartha [0000-0003-4630-9903], Yannoukakos, Drakoulis [0000-0001-7509-3510], Ziogas, Argyrios [0000-0003-4529-3727], Zorn, Kristin K. [0000-0003-2143-8979], Park, Sue K. [0000-0001-5002-9707], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Becher, Heiko [0000-0002-8808-6667], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, German Cancer Research Center (DKFZ), National Health and Medical Research Council of Australia, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, National Institute for Health Research (NIHR), Institut National du Cancer (INCA) France, Ligue nationale contre le cancer, Cancer Research UK, European Commision, Canadian Institutes of Health Research (CIHR), Cancer Council New South Wales, Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud, Xunta de Galicia, Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain, Fondo de Investigacion Sanitario, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Netherlands Government, Russian Foundation for Basic Research (RFBR), O'Mara, Tracy A [0000-0002-5436-3232], Tyrer, Jonathan P [0000-0003-3724-4757], Barnes, Daniel R [0000-0002-3781-7570], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Dunning, Alison M [0000-0001-6651-7166], Eliassen, A Heather [0000-0002-3961-6609], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Hart, Steven N [0000-0001-7714-2734], Hulick, Peter J [0000-0001-8397-4078], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kurian, Allison W [0000-0002-6175-9470], Martens, John WM [0000-0002-3428-3366], Milne, Roger L [0000-0001-5764-7268], Nathanson, Katherine L [0000-0002-6740-0901], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Janet E [0000-0003-4944-7789], Parsons, Michael T [0000-0003-3242-8477], Pharoah, Paul DP [0000-0001-8494-732X], Sandler, Dale P [0000-0002-6776-0018], Schmidt, Marjanka K [0000-0002-2228-429X], Toland, Amanda E [0000-0002-0271-1792], Vachon, Celine M [0000-0002-1962-9322], Weitzel, Jeffrey N [0000-0001-6714-092X], Zorn, Kristin K [0000-0003-2143-8979], Park, Sue K [0000-0001-5002-9707], Easton, Douglas F [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Coignard J] Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France. Institut Curie Paris, Paris, France. Mines ParisTech Fontainebleau, Paris, France. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. PSL University Paris, Paris, France. Paris Sud University, Orsay, France. [Lush M, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Beesley J, O'Mara TA] Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Lopez-Fernández A] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, Pathology, and Radiology & Nuclear Medicine

Subjects
0301 basic medicine, Linkage disequilibrium, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], 45/43, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, Breast cancer, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, Genotype, breast neoplasms, Medicine and Health Sciences, 631/208/68, skin and connective tissue diseases, Cancer genetics, adult, alleles, BRCA1 protein, BRCA2 protein, female, genetic predisposition to disease, genome-wide association study, genotype, humans, linkage disequilibrium, middle aged, mutation, quantitative trait loci, risk factors, polymorphism, single nucleotide, HEBON Investigators, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], BRCA1 Protein, Genetic Predisposition to Disease/genetics, article, Single Nucleotide, Middle Aged, BRCA2 Protein/genetics, 3. Good health, Mama - Càncer - Factors de risc, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Genome-Wide Association Study/methods, Medical genetics, Female, Medical Genetics, 692/499, Adult, medicine.medical_specialty, 45/61, Science, 3122 Cancers, Population, Quantitative Trait Loci, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], ABCTB Investigators, 631/67/2324, Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, EMBRACE Collaborators, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Alleles, Medicinsk genetik, BRCA2 Protein, Mutació (Biologia), General Chemistry, 631/67/1347, Genotype frequency, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, BRCA1 Protein/genetics, 3111 Biomedicine, KConFab Investigators, Quantitative Trait Loci/genetics, Genètica, Genome-Wide Association Study
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Published
2021

3. Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Author

Douglas F. Easton, Mads Thomassen, Georgia Chenevix-Trench, Kristiina Aittomäki, Marjanka K. Schmidt, Hebon Investigators, Esther M. John, Irene L. Andrulis, Maartje J. Hooning, Antonis C. Antoniou, Swe-Brca Investigators, Caroline Maria Rossing, Penny Soucy, Jacques Simard, Michael T. Parsons, Julie M. Cunningham, Paul A. James, Joe Dennis, Gabriel Wagner, Melissa C. Southey, Susan M. Domchek, Eric Hahnen, kConFab Investigators, Goska Leslie, Sofia Khan, Katherine L. Nathanson, Rita K. Schmutzler, Anna Jakubowska, Jeffrey N. Weitzel, Taru A. Muranen, Heli Nevanlinna, Barbara Wappenschmidt, Drakoulis Yannoukakos, Judy Garber, Marc Tischkowitz, Conxi Lázaro, Inge Søkilde Pedersen, Carl Blomqvist, Amanda B. Spurdle, Christian F. Singer, Susan L. Slager, Lesley McGuffog, Rainer Fagerholm, Manuel R. Teixeira, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Muranen, Taru A. [0000-0002-5895-1808], Cunningham, Julie M. [0000-0002-8159-3025], Dennis, Joe [0000-0003-4591-1214], Leslie, Goska [0000-0001-5756-6222], Parsons, Michael T. [0000-0003-3242-8477], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Spurdle, Amanda B. [0000-0003-1337-7897], Pedersen, Inge Sokilde [0000-0002-9902-8040], Nathanson, Katherine L. [0000-0002-6740-0901], Lazaro, Conxi [0000-0002-7198-5906], Andrulis, Irene L. [0000-0002-4226-6435], Teixeira, Manuel R. [0000-0002-4896-5982], James, Paul [0000-0002-4361-4657], Weitzel, Jeffrey N. [0000-0001-6714-092X], Jakubowska, Anna [0000-0002-5650-0501], Yannoukakos, Drakoulis [0000-0001-7509-3510], Schmidt, Marjanka K. [0000-0002-2228-429X], Nevanlinna, Heli [0000-0002-0916-2976], Apollo - University of Cambridge Repository, Muranen, Taru A [0000-0002-5895-1808], Cunningham, Julie M [0000-0002-8159-3025], Parsons, Michael T [0000-0003-3242-8477], Easton, Douglas F [0000-0003-2444-3247], Spurdle, Amanda B [0000-0003-1337-7897], Nathanson, Katherine L [0000-0002-6740-0901], Andrulis, Irene L [0000-0002-4226-6435], Teixeira, Manuel R [0000-0002-4896-5982], Weitzel, Jeffrey N [0000-0001-6714-092X], and Schmidt, Marjanka K [0000-0002-2228-429X]

Subjects
0301 basic medicine, Oncology, Etiology, Genome-wide association study, Genome-wide association studies, Germline, 0302 clinical medicine, Breast cancer, PRIMARY THERAPY, Pharmacology (medical), skin and connective tissue diseases, Cancer genetics, RISK, medicine.diagnostic_test, Hazard ratio, article, INTERNATIONAL EXPERT CONSENSUS, Tumor Pathology, OVARIAN, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Etiologia, EXPRESSION, medicine.medical_specialty, GENES, 3122 Cancers, 631/208/205/2138, lcsh:RC254-282, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, 631/67/68, Genetic variation, REVEALS, medicine, Radiology, Nuclear Medicine and imaging, Genetic testing, IDENTIFICATION, business.industry, FALSE DISCOVERY, Cancer, medicine.disease, 030104 developmental biology, CELLS, 692/4028/67/1347, business
Abstract

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Published
2020

4. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author

Escala-Garcia, Maria, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Ashworth, Alan, Auer, Paul L, Auvinen, Päivi, Beckmann, Matthias W, Beesley, Jonathan, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Canzian, Federico, Chang-Claude, Jenny, Chanock, Stephen J, Chin, Suet-Feung, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Dwek, Miriam, Earl, Helena M, Eccles, Diana M, Eliassen, A Heather, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Guo, Qi, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Harrington, Patricia A, Hiller, Louise, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Chiun-Sheng, Huang, Guanmengqian, Hunter, David J, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Kitahara, Cari M, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orr, Nick, Peterlongo, Paolo, Petridis, Christos, Prentice, Ross L, Presneau, Nadege, Punie, Kevin, Ramachandran, Dhanya, Rennert, Gad, Romero, Atocha, Sachchithananthan, Mythily, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schwentner, Lukas, Scott, Christopher, Simard, Jacques, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Terry, Mary Beth, Thorne, Heather, Tollenaar, Rob A E M, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Turnbull, Clare, Vachon, Celine M, van der Kolk, Lizet E, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Ziogas, Argyrios, Pharoah, Paul D P, Hall, Per, Wessels, Lodewyk F A, Chenevix-Trench, Georgia, Bader, Gary D, Dörk, Thilo, Easton, Douglas F, Canisius, Sander, Schmidt, Marjanka K, Gonzalez Neira, Anna, Andrulis, Irene L., Auer, Paul L., Beckmann, Matthias W., Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Brucker, Sara Y., Chanock, Stephen J., Clarke, Christine L., Couch, Fergus J., Cross, Simon S., Daly, Mary B., Dunn, Janet A., Dunning, Alison M., Earl, Helena M., Eccles, Diana M., Eliassen, A. Heather, Evans, D. Gareth, Fasching, Peter A., Gapstur, Susan M., García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Goldgar, David E., Haiman, Christopher A., Harrington, Patricia A., Hooning, Maartje J., Hopper, John L., Hunter, David J., John, Esther M., Kitahara, Cari M., Milne, Roger L., Neuhausen, Susan L., Newman, William G., Olshan, Andrew F., Olson, Janet E., Prentice, Ross L., Sawyer, Elinor J., Schmutzler, Rita K., Southey, Melissa C., Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Tollenaar, Rob A. E. M., Troester, Melissa A., Vachon, Celine M., van der Kolk, Lizet E., Yang, Xiaohong R., Pharoah, Paul D. P., Wessels, Lodewyk F. A., Bader, Gary D., Easton, Douglas F., Schmidt, Marjanka K., HUS Comprehensive Cancer Center, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, National Institute for Health Research (Reino Unido), German Cancer Research Center, United States of Department of Health & Human Services, Cancer Research UK (Reino Unido), European Commission, Canadian Institutes of Health Research, Ministere de l'Economie, Science et Innovation du Quebec (Canadá), Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Deutsche Krebshilfe, Russian Foundation for Basic Research, Swedish Research Council, Breast Cancer Now (Reino Unido), Medical Oncology, Surgery, National Institute for Health Research (NIHR), German Cancer Research Center (DKFZ, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Cancer Research UK, Canadian Institutes of Health Research (CIHR), Ministere de l'Economie, Science et Innovation du Quebec- CANADA, KWF Kankerbestrijding, Asociacion Espanola Contra el Cancer (AECC), Russian Foundation for Basic Research (RFBR), Breast Cancer Now, London, Unión Europea. Comisión Europea, Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Bojesen, Stig E. [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Caldas, Carlos [0000-0003-3547-1489], Canzian, Federico [0000-0002-4261-4583], Chanock, Stephen J. [0000-0002-2324-3393], Chin, Suet-Feung [0000-0001-5697-1082], Dennis, Joe [0000-0003-4591-1214], Devilee, Peter [0000-0002-8023-2009], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A. [0000-0003-4885-8471], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Giles, Graham G. [0000-0003-4946-9099], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Lambrechts, Diether [0000-0002-3429-302X], Milne, Roger L. [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G. [0000-0002-6382-4678], Olson, Janet E. [0000-0003-4944-7789], Orr, Nick [0000-0003-2866-942X], Peterlongo, Paolo [0000-0001-6951-6855], Punie, Kevin [0000-0002-1162-7963], Ramachandran, Dhanya [0000-0001-8139-7799], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Simard, Jacques [0000-0001-6906-3390], Teixeira, Manuel R. [0000-0002-4896-5982], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Winqvist, Robert [0000-0003-0932-9104], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul D. P. [0000-0001-8494-732X], Bader, Gary D. [0000-0003-0185-8861], Dörk, Thilo [0000-0002-9458-0282], Easton, Douglas F. [0000-0003-2444-3247], Canisius, Sander [0000-0003-3888-8829], Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Andrulis, Irene L [0000-0002-4226-6435], Blomqvist, Carl [0000-0003-3041-1938], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Dunning, Alison M [0000-0001-6651-7166], Earl, Helena M [0000-0003-1549-8094], Fasching, Peter A [0000-0003-4885-8471], García-Sáenz, José A [0000-0001-6880-0301], Giles, Graham G [0000-0003-4946-9099], Howell, Anthony [0000-0002-6233-719X], Milne, Roger L [0000-0001-5764-7268], Newman, William G [0000-0002-6382-4678], Olson, Janet E [0000-0003-4944-7789], Olsson, Håkan [0000-0002-8794-9635], Teixeira, Manuel R [0000-0002-4896-5982], Pharoah, Paul D P [0000-0001-8494-732X], Bader, Gary D [0000-0003-0185-8861], Easton, Douglas F [0000-0003-2444-3247], Schmidt, Marjanka K [0000-0002-2228-429X], and Pharoah, Paul DP [0000-0001-8494-732X]

Subjects
0301 basic medicine, PTEN, GTP-Binding Protein alpha Subunits, Gq-G11/genetics, 45/43, Gene regulatory network, General Physics and Astronomy, Estrogen receptor, Genome-wide association study, Apoptosis, Disease, CIRCADIAN CLOCK, VARIANTS, Bioinformatics, Genome-wide association studies, Germline, Metastasis, PATHWAY, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Gene Regulatory Networks, lcsh:Science, Multidisciplinary, TUMOR-GROWTH, Receptors, Estrogen/genetics, Prognosis, GTP-Binding Protein alpha Subunits, 3. Good health, Multidisciplinary Sciences, Receptors, Estrogen, 030220 oncology & carcinogenesis, Medical genetics, Science & Technology - Other Topics, Female, Medical Genetics, Signal Transduction, medicine.medical_specialty, Genotype, Science, 3122 Cancers, 631/208/205/2138, Breast Neoplasms, Biology, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, PROTEIN-COUPLED RECEPTORS, SDG 3 - Good Health and Well-being, Circadian Clocks, medicine, Humans, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Science & Technology, 45, Genetic Variation, Computational Biology, General Chemistry, medicine.disease, GENE, Computational biology and bioinformatics, 030104 developmental biology, Germ Cells, GTP-Binding Protein alpha Subunits/genetics, METASTASIS, GTP-Binding Protein alpha Subunits, Gq-G11, 692/4028/67/1347, lcsh:Q, CELL-GROWTH, 631/114, Genome-Wide Association Study
Abstract

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis., In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Published
2020

5. Two truncating variants in FANCC and breast cancer risk

Author

Dork, T., Peterlongo, P., Mannermaa, A., Bolla, M.K., Wang, Q., Dennis, J., Ahearn, T., Andrulis, I.L., Anton-Culver, H., Arndt, V., Aronson, K.J., Augustinsson, A., Freeman, L.E.B., Beckmann, M.W., Beeghly-Fadiel, A., Behrens, S., Bermisheva, M., Blomqvist, C., Bogdanova, N., Bojesen, S.E., Brauch, H., Brenner, H., Burwinkel, B., Canzian, F., Chan, T.L., Chang-Claude, J., Chanock, S.J., Choi, J.Y., Christiansen, H., Clarke, C.L., Couch, F.J., Czene, K., Daly, M.B., dos-Santos-Silva, I., Dwek, M., Eccles, D.M., Ekici, A.B., Eriksson, M., Evans, D.G., Fasching, P.A., Figueroa, J., Flyger, H., Fritschisl, L., Gabrielson, M., Gago-Dominguez, M., Gao, C., Gapstur, S.M., Garcia-Closas, M., Garcia-Saenz, J.A., Gaudet, M.M., Giles, G.G., Goldberg, M.S., Goldgar, D.E., Guenel, P., Haeberle, L., Haiman, C.A., Hakansson, N., Hall, P., Hamann, U., Hartman, M., Hauke, J., Hein, A., Hillemanns, P., Hogervorst, F.B.L., Hooning, M.J., Hopper, J.L., Howell, T., Huo, D.Z., Ito, H., Iwasaki, M., Jakubowska, A., Janni, W., John, E.M., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Khusnutdinova, E., Kim, S.W., Kitahara, C.M., Koutros, S., Kraft, P., Kristensen, V.N., Kwon, A., Lambrechts, D., Marchand, L. le, Li, J.M., Lindstrom, S., Linet, M., W.Y. lo, Long, J.R., Lophatananon, A., Lubinski, J., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, E., Matsuo, K., Mavroudis, D., Meindl, A., Menon, U., Milne, R.L., Taib, N.A.M., Muir, K., Mulligan, A.M., Neuhausen, S.L., Nevanlinna, H., Neven, P., Newman, W.G., Offit, K., Olopade, O.I., Olshan, A.F., Olson, J.E., Olsson, H., Park, S.K., Park-Simon, T.W., Peto, J., Plaseska-Karanfilska, D., Pohl-Rescigno, E., Presneau, N., Rack, B., Radice, P., Rashid, M.U., Rennert, G., Rennert, H.S., Romero, A., Ruebner, M., Saloustros, E., Schmidt, M.K., Schmutzler, R.K., Schneider, M.O., Schoemaker, M.J., Scott, C., Shen, C.Y., Shu, X.O., Simard, J., Slager, S., Smichkoska, S., Southey, M.C., Spinelli, J.J., Stone, J., Surowy, H., Swerdlow, A.J., Tamimi, R.M., Tapper, W.J., Teo, S.H., Terry, M.B., Toland, A.E., Tollenaar, R.A.E.M., Torres, D., Torres-Mejia, G., Troester, M.A., Truong, T., Tsugane, S., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Veen, E.M. van, Vijai, J., Wendt, C., Wolk, A., Yu, J.C., Zheng, W., Ziogas, A., Ziv, E., Dunning, A.M., Pharoah, P.D.P., Schindler, D., Devilee, P., Easton, D.F., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C.S., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Borresen-Dale, A.L., Alnaes, G.I.G., Sahlberg, K.K., Ottestad, L., Karesen, R., Schlichting, E., Holmen, M.M., Sauer, T., Haakensen, V., Engebraten, O., Naume, B., Fossa, A., Kiserud, C.E., Reinertsen, K.V., Helland, A., Riis, M., Geisler, J., ABCTB Investigators, NBCS Collaborators, Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Dwek, Miriam [0000-0001-7184-2932], Ekici, Arif B [0000-0001-6099-7066], Fasching, Peter A [0000-0003-4885-8471], Figueroa, Jonine [0000-0002-5100-623X], Hein, Alexander [0000-0003-2601-3398], Ito, Hidemi [0000-0002-8023-4581], Matsuo, Keitaro [0000-0003-1761-6314], Menon, Usha [0000-0003-3708-1732], Milne, Roger L [0000-0001-5764-7268], Muir, Kenneth [0000-0001-6429-988X], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G [0000-0002-6382-4678], Peto, Julian [0000-0002-1685-8912], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Schmidt, Marjanka K [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Truong, Thérèse [0000-0002-2943-6786], Tsugane, Shoichiro [0000-0003-4105-2774], Ziogas, Argyrios [0000-0003-4529-3727], Dunning, Alison M [0000-0001-6651-7166], Pharoah, Paul DP [0000-0001-8494-732X], Devilee, Peter [0000-0002-8023-2009], Easton, Douglas F [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Andrulis, Irene L. [0000-0002-4226-6435], Ekici, Arif B. [0000-0001-6099-7066], Fasching, Peter A. [0000-0003-4885-8471], Milne, Roger L. [0000-0001-5764-7268], Newman, William G. [0000-0002-6382-4678], Schmidt, Marjanka K. [0000-0002-2228-429X], Dunning, Alison M. [0000-0001-6651-7166], Pharoah, Paul D. P. [0000-0001-8494-732X], Easton, Douglas F. [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Clinicum, University Management, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Medical Oncology, and Clinical Genetics

Subjects
0301 basic medicine, Oncology, PROTEIN, lcsh:Medicine, 45/47, 0302 clinical medicine, Fanconi anemia, Genotype, lcsh:Science, Sequence Deletion, Multidisciplinary, BRCA1 Protein, Fanconi Anemia Complementation Group C Protein, 1184 Genetics, developmental biology, physiology, BRCA2 Protein, 3. Good health, BIALLELIC MUTATIONS, DNA-REPAIR, Female, 692/499, Medical Genetics, medicine.medical_specialty, PALB2, 3122 Cancers, ABCTB Investigators, Breast Neoplasms, FANCONIS ANEMIA, Article, 692/4028, NBCS Collaborators, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, NONSENSE MUTATION, Genetic Predisposition to Disease, Medicinsk genetik, 45, business.industry, Genetic heterogeneity, lcsh:R, Case-control study, Genetic Variation, Odds ratio, medicine.disease, GENE, Fanconi Anemia, 030104 developmental biology, Risk factors, Case-Control Studies, lcsh:Q, 3111 Biomedicine, business, 030217 neurology & neurosurgery
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

6. Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Author

Figlioli, Gisella, Billaud, Amandine, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Lush, Michael, Kvist, Anders, Adank, Muriel A, Ahearn, Thomas U, Antonenkova, Natalia N, Auvinen, Päivi, Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brüning, Thomas, Camp, Nicola J, Campbell, Archie, Castelao, Jose E, Cessna, Melissa H, Nbcs Collaborators, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Glendon, Gord, Gómez Garcia, Encarna B, González-Neira, Anna, Grassmann, Felix, Guénel, Pascal, Hahnen, Eric, Hamann, Ute, Hillemanns, Peter, Hooning, Maartje J, Hoppe, Reiner, Howell, Anthony, Humphreys, Keith, KConFab Investigators, Jakubowska, Anna, Khusnutdinova, Elza K, Kristensen, Vessela N, Lindblom, Annika, Loizidou, Maria A, Lubiński, Jan, Mannermaa, Arto, Maurer, Tabea, Mavroudis, Dimitrios, Newman, William G, Obi, Nadia, Panayiotidis, Mihalis I, Radice, Paolo, Rashid, Muhammad U, Rhenius, Valerie, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shah, Mitul, Southey, Melissa C, Tomlinson, Ian, Truong, Thérèse, Van Veen, Elke M, Wendt, Camilla, Yang, Xiaohong R, Michailidou, Kyriaki, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Andrulis, Irene L, Evans, D Gareth, Hollestelle, Antoinette, Chang-Claude, Jenny, Milne, Roger L, Peterlongo, Paolo, Figlioli, Gisella [0000-0002-0740-1363], Dennis, Joe [0000-0003-4591-1214], Kvist, Anders [0000-0002-1358-0695], Behrens, Sabine [0000-0002-9714-104X], Bogdanova, Natalia V [0000-0002-9736-4593], Bonanni, Bernardo [0000-0003-3589-2128], Camp, Nicola J [0000-0002-4788-1998], Campbell, Archie [0000-0003-0198-5078], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Eriksson, Mikael [0000-0001-8135-4270], Fasching, Peter A [0000-0003-4885-8471], González-Neira, Anna [0000-0002-5421-2020], Hamann, Ute [0000-0001-6705-7624], Hillemanns, Peter [0000-0001-9829-3531], Humphreys, Keith [0000-0002-7458-8252], Jakubowska, Anna [0000-0002-5650-0501], Loizidou, Maria A [0000-0003-4503-7758], Newman, William G [0000-0002-6382-4678], Obi, Nadia [0000-0002-0903-9142], Panayiotidis, Mihalis I [0000-0002-1450-3552], Radice, Paolo [0000-0001-6298-4111], Rashid, Muhammad U [0000-0002-7684-3122], Saloustros, Emmanouil [0000-0002-0485-0120], Schmidt, Marjanka K [0000-0002-2228-429X], van Veen, Elke M [0000-0001-8618-2332], Michailidou, Kyriaki [0000-0001-7065-1237], Pharoah, Paul DP [0000-0001-8494-732X], Andrulis, Irene L [0000-0002-4226-6435], Evans, D Gareth [0000-0002-8482-5784], Hollestelle, Antoinette [0000-0003-1166-1966], Chang-Claude, Jenny [0000-0001-8919-1971], Peterlongo, Paolo [0000-0001-6951-6855], and Apollo - University of Cambridge Repository

Subjects
breast cancer predisposition, protein truncating variants, FANCM PTVs spectrum, PTVs, breast cancer risk factors
Abstract

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

Published
2023

7. PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants

Author

Easton, Douglas, Antoniou, Antonis, Barnes, Daniel, Bolla, Manjeet, Leslie, Malgorzata, Dennis, Joseph, Wang, Qin, Muranen, Taru A [0000-0002-5895-1808], Khan, Sofia [0000-0003-4185-8882], Dennis, Joe [0000-0003-4591-1214], Keeman, Renske [0000-0002-5452-9933], Leslie, Goska [0000-0001-5756-6222], Parsons, Michael T [0000-0003-3242-8477], Ahearn, Thomas U [0000-0003-0771-7752], Andrulis, Irene L [0000-0002-4226-6435], Behrens, Sabine [0000-0002-9714-104X], Devilee, Peter [0000-0002-8023-2009], Evans, D Gareth [0000-0002-8482-5784], García-Closas, Montserrat [0000-0003-1033-2650], Izatt, Louise [0000-0003-1258-4843], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Lindeman, Geoffrey J [0000-0001-9386-2416], Neuhausen, Susan L [0000-0001-5053-0390], Newman, William G [0000-0002-6382-4678], Peterlongo, Paolo [0000-0001-6951-6855], Saloustros, Emmanouil [0000-0002-0485-0120], Suvanto, Maija [0000-0001-9271-7778], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Nevanlinna, Heli [0000-0002-0916-2976], and Apollo - University of Cambridge Repository

Subjects
HEBON investigators
Abstract

2 We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 3 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators 4 of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). 5 PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier 6 patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished 7 clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by 8 PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but 9 the confidence intervals always included the calibration slope. Altogether, our results encourage the use of 10 the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. 11 For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers 12 (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the 13 prognostic estimates. The breast cancer mortality of BRCA2 carriers was under-estimated at the low end of 14 the PREDICT score distribution, whereas at the high end, the mortality was over-estimated. These data 15 suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when 16 estimating the prognosis of ER-positive breast cancer patients. 17 Keywords: PREDICT, breast cancer, prognosis, BRCA1, BRCA2, validation, survival

Published
2023

8. Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

Author

Lopes Cardozo, Josephine MN, Andrulis, Irene L, Bojesen, Stig E, Dörk, Thilo, Eccles, Diana M, Fasching, Peter A, Hooning, Maartje J, Keeman, Renske, Nevanlinna, Heli, Rutgers, Emiel JT, Easton, Douglas F, Hall, Per, Pharoah, Paul DP, Van 'T Veer, Laura J, Schmidt, Marjanka K, Breast Cancer Association Consortium And MINDACT Collaborators, Lopes Cardozo, Josephine MN [0000-0003-0520-0282], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Dörk, Thilo [0000-0002-9458-0282], Eccles, Diana M [0000-0002-9935-3169], Fasching, Peter A [0000-0003-4885-8471], Hooning, Maartje J [0000-0001-6763-0857], Keeman, Renske [0000-0002-5452-9933], Rutgers, Emiel JT [0000-0002-4244-0106], Easton, Douglas F [0000-0003-2444-3247], Hall, Per [0000-0002-5640-9126], van 't Veer, Laura J [0000-0002-9838-8298], Schmidt, Marjanka K [0000-0002-2228-429X], and Apollo - University of Cambridge Repository

Subjects
Risk Factors, Humans, Female, Breast Neoplasms, Breast, Prognosis, Proportional Hazards Models
Abstract

PURPOSE: A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer. METHODS: Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. RESULTS: The PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. CONCLUSION: An increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

Published
2023

9. 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, NBCS Collaborators, 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, KConFab Investigators, 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 AEM, 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 DP, 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, Peterlongo, Paolo, Figlioli, Gisella [0000-0002-0740-1363], Becher, Heiko [0000-0002-8808-6667], Behrens, Sabine [0000-0002-9714-104X], Blok, Marinus J [0000-0002-7935-5933], Bonanni, Bernardo [0000-0003-3589-2128], Chanock, Stephen J [0000-0002-2324-3393], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Fasching, Peter A [0000-0003-4885-8471], Grassmann, Felix [0000-0003-1390-7528], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Lissowska, Jolanta [0000-0003-2695-5799], Newman, William G [0000-0002-6382-4678], Panayiotidis, Mihalis I [0000-0002-1450-3552], Rashid, Muhammad U [0000-0002-7684-3122], Saloustros, Emmanouil [0000-0002-0485-0120], Yang, Xiaohong R [0000-0003-4451-8664], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Michailidou, Kyriaki [0000-0001-7065-1237], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Andrulis, Irene L [0000-0002-4226-6435], Nevanlinna, Heli [0000-0002-0916-2976], Milne, Roger L [0000-0001-5764-7268], Radice, Paolo [0000-0001-6298-4111], Peterlongo, Paolo [0000-0001-6951-6855], and Apollo - University of Cambridge Repository

Subjects
DNA Helicases, Humans, Female, Breast Neoplasms, Triple Negative Breast Neoplasms, Genetic Predisposition to Disease, KConFab Investigators, NBCS Collaborators
Abstract

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

Published
2022
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10. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Hakkaart, Christopher, Pearson, John F, Marquart, Louise, Dennis, Joe, Wiggins, George AR, Barnes, Daniel R, Robinson, Bridget A, Mace, Peter D, Aittomäki, Kristiina, Andrulis, Irene L, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Belhadj, Sami, Berger, Lieke, Blok, Marinus J, Boonen, Susanne E, Borde, Julika, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, Marie-Agnès, Cook, Jackie, Cosgrove, Casey, Couch, Fergus J, Daly, Mary B, Dandiker, Sita, Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Dhawan, Mallika, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Easton, Douglas F, Ehrencrona, Hans, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Feliubadaló, Lidia, Fostira, Florentia, Friedman, Eitan, Frone, Megan, Frost, Debra, Garber, Judy, Gayther, Simon A, Gehrig, Andrea, Gesta, Paul, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Hahnen, Eric, Hake, Christopher R, Hamann, Ute, Hansen, Thomas VO, Hauke, Jan, Hentschel, Julia, Herold, Natalie, Honisch, Ellen, Hulick, Peter J, Imyanitov, Evgeny N, SWE-BRCA Investigators, KConFab Investigators, HEBON Investigators, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kemp, Zoe, Kirk, Judy, Konstantopoulou, Irene, Koudijs, Marco, Kwong, Ava, Laitman, Yael, Lalloo, Fiona, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Martens, John WM, McGuffog, Lesley, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Montagna, Marco, Moserle, Lidia, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Nambot, Sophie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nguyen-Dumont, Tu, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Osorio, Ana, Ott, Claus-Eric, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peixoto, Ana, Perez-Segura, Pedro, Peterlongo, Paolo, Pocza, Timea, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Rodriguez, Gustavo C, Rønlund, Karina, Rosenberg, Efraim H, Rossing, Maria, Schmutzler, Rita K, Shah, Payal D, Sharif, Saba, Sharma, Priyanka, Side, Lucy E, Simard, Jacques, Singer, Christian F, Snape, Katie, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Trainer, Alison H, Tripathi, Vishakha, Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Walker, Lisa, Weitzel, Jeffrey N, Wevers, Marike R, Chenevix-Trench, Georgia, Spurdle, Amanda B, Antoniou, Antonis C, Walker, Logan C, Pearson, John F [0000-0001-5607-4517], Dennis, Joe [0000-0003-4591-1214], Barnes, Daniel R [0000-0002-3781-7570], Mace, Peter D [0000-0003-2175-9537], Andrulis, Irene L [0000-0002-4226-6435], Azzollini, Jacopo [0000-0002-9364-9778], Blok, Marinus J [0000-0002-7935-5933], Brunet, Joan [0000-0003-1945-3512], Campbell, Ian [0000-0002-7773-4155], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Dandiker, Sita [0000-0003-3837-7690], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Easton, Douglas F [0000-0003-2444-3247], Ehrencrona, Hans [0000-0002-5589-3622], Feliubadaló, Lidia [0000-0002-1736-0112], Gayther, Simon A [0000-0001-7937-5443], Gesta, Paul [0000-0002-4410-8668], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hauke, Jan [0000-0001-8236-4075], Hulick, Peter J [0000-0001-8397-4078], Isaacs, Claudine [0000-0002-9646-1260], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Joseph, Vijai [0000-0002-7933-151X], Karlan, Beth Y [0000-0002-9451-2933], Konstantopoulou, Irene [0000-0002-0470-0309], Lazaro, Conxi [0000-0002-7198-5906], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John WM [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Nambot, Sophie [0000-0002-9630-5049], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Yie, Joanne Ngeow Yuen [0000-0003-1558-3627], Nikitina-Zake, Liene [0000-0003-2491-5187], Olopade, Olufunmilayo I [0000-0002-9936-1599], Osorio, Ana [0000-0001-8124-3984], Ott, Claus-Eric [0000-0003-3627-3791], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peterlongo, Paolo [0000-0001-6951-6855], Radice, Paolo [0000-0001-6298-4111], Rosenberg, Efraim H [0000-0002-3859-6941], Simard, Jacques [0000-0001-6906-3390], Steinemann, Doris [0000-0001-8797-0816], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tripathi, Vishakha [0000-0001-8118-8364], van Rensburg, Elizabeth J [0000-0003-2077-230X], Vega, Ana [0000-0002-7416-5137], Viel, Alessandra [0000-0003-2804-0840], Weitzel, Jeffrey N [0000-0001-6714-092X], Wevers, Marike R [0000-0001-8008-6008], Spurdle, Amanda B [0000-0003-1337-7897], Walker, Logan C [0000-0003-0018-3719], and Apollo - University of Cambridge Repository

Subjects
Heterozygote, DNA Copy Number Variations, 45/43, 45/22, 13/107, 45/23, 13/106, Breast Neoplasms, 13, 14, 13/44, 631/67/68, 38/89, Humans, Genetic Predisposition to Disease, RNA, Messenger, 45/90, 38/109, 64, BRCA2 Protein, 45, BRCA1 Protein, article, 45/77, 692/4028/67, 38/35, 14/63, Female
Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., C12292/A20861 PPRPGM-Nov20\100002

Published
2022
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11. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Qin [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Kristensen, Vessela N [0000-0001-5012-7438], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison M [0000-0001-6651-7166], Pharoah, Paul DP [0000-0001-8494-732X], Easton, Douglas F [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Germ Cells, DNA Copy Number Variations, Genome, Human, Risk Factors, Case-Control Studies, Humans, Breast Neoplasms, Female, Genome-Wide Association Study
Abstract

Funder: CIHR, Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Published
2022
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12. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author

Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez de Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Barnes, Daniel R [0000-0002-3781-7570], Silvestri, Valentina [0000-0003-0712-9379], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Yang, Xin [0000-0003-0037-3790], Adlard, Julian [0000-0002-1693-0435], Agnarsson, Bjarni A [0000-0001-7721-9965], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barkardottir, Rosa B [0000-0003-0629-2772], Barrowdale, Daniel [0000-0003-1661-3939], Benitez, Javier [0000-0002-0923-7202], Boonen, Susanne E [0000-0002-7824-2080], Bozsik, Aniko [0000-0001-5410-9173], Brennan, Paul [0000-0003-1128-6254], Brunet, Joan [0000-0003-1945-3512], Bucalo, Agostino [0000-0003-3475-1067], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian [0000-0002-7773-4155], Cassingham, Hayley [0000-0001-9922-2321], Cini, Giulia [0000-0002-8696-8922], Claes, Kathleen BM [0000-0003-0841-7372], Coppa, Anna [0000-0001-9758-5444], Cortesi, Laura [0000-0001-8950-8561], Darder, Esther [0000-0002-7764-1397], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Del Valle, Jesús [0000-0003-3607-7045], Domchek, Susan M [0000-0002-5914-7272], Donaldson, Alan [0000-0001-9193-4172], Eason, Jacqueline [0000-0002-8711-8671], Engel, Christoph [0000-0002-7247-282X], Fostira, Florentia [0000-0003-2751-2332], Frone, Megan [0000-0001-8273-8866], Glendon, Gord [0000-0001-8630-6673], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hahnen, Eric [0000-0003-2448-7872], Hanson, Helen [0000-0002-3303-8713], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], James, Paul A [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Kroeldrup, Lone [0000-0003-3623-6536], Kruse, Torben A [0000-0002-2460-6483], Lazaro, Conxi [0000-0002-7198-5906], Lesueur, Fabienne [0000-0001-7404-4549], Matrai, Zoltan [0000-0001-8160-7100], Montagna, Marco [0000-0002-4929-2150], Monteiro, Alvaro N [0000-0002-8448-4801], Morrison, Patrick J [0000-0002-2823-1762], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Nguyen-Dumont, Tu [0000-0002-6217-0182], Niederacher, Dieter [0000-0001-6231-9226], Palli, Domenico [0000-0002-5558-2437], Parsons, Michael T [0000-0003-3242-8477], Perez-Segura, Pedro [0000-0001-5049-7199], Peterlongo, Paolo [0000-0001-6951-6855], Pinto, Pedro [0000-0001-6289-5792], Pottinger, Caroline [0000-0003-4233-882X], Radice, Paolo [0000-0001-6298-4111], Robson, Mark [0000-0002-3109-1692], Rump, Andreas [0000-0001-7116-6364], Sharif, Saba [0000-0002-9564-4890], Steele, Linda [0000-0003-3628-2022], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Teixeira, Manuel R [0000-0002-4896-5982], Thull, Darcy L [0000-0001-7999-2804], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], Tripathi, Vishakha [0000-0001-8118-8364], Valentini, Virginia [0000-0003-3393-7185], van Asperen, Christi J [0000-0002-1436-7650], Venturelli, Marta [0000-0003-0658-8004], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Whaite, Anna [0000-0003-4485-0341], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Chenevix-Trench, Georgia [0000-0002-1878-2587], Ottini, Laura [0000-0001-8030-0449], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Published
2022

13. Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry

Author

Dumont, Martine, Weber-Lassalle, Nana, Joly-Beauparlant, Charles, Ernst, Corinna, Droit, Arnaud, Feng, Bing-Jian, Dubois, Stéphane, Collin-Deschesnes, Annie-Claude, Soucy, Penny, Vallée, Maxime, Fournier, Frédéric, Lemaçon, Audrey, Adank, Muriel A, Allen, Jamie, Altmüller, Janine, Arnold, Norbert, Ausems, Margreet GEM, Berutti, Riccardo, Bolla, Manjeet K, Bull, Shelley, Carvalho, Sara, Cornelissen, Sten, Dufault, Michael R, Dunning, Alison M, Engel, Christoph, Gehrig, Andrea, Geurts-Giele, Willemina RR, Gieger, Christian, Green, Jessica, Hackmann, Karl, Helmy, Mohamed, Hentschel, Julia, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Horváth, Judit, Ikram, M Arfan, Kaulfuß, Silke, Keeman, Renske, Kuang, Da, Luccarini, Craig, Maier, Wolfgang, Martens, John WM, Niederacher, Dieter, Nürnberg, Peter, Ott, Claus-Eric, Peters, Annette, Pharoah, Paul DP, Ramirez, Alfredo, Ramser, Juliane, Riedel-Heller, Steffi, Schmidt, Gunnar, Shah, Mitul, Scherer, Martin, Stäbler, Antje, Strom, Tim M, Sutter, Christian, Thiele, Holger, Van Asperen, Christi J, Van Der Kolk, Lizet, Van Der Luijt, Rob B, Volk, Alexander E, Wagner, Michael, Waisfisz, Quinten, Wang, Qin, Wang-Gohrke, Shan, Weber, Bernhard HF, Genome Of The Netherlands Project, Ghs Study Group, Devilee, Peter, Tavtigian, Sean, Bader, Gary D, Meindl, Alfons, Goldgar, David E, Andrulis, Irene L, Schmutzler, Rita K, Easton, Douglas F, Schmidt, Marjanka K, Hahnen, Eric, Simard, Jacques, Dumont, Martine [0000-0002-5488-4839], Ernst, Corinna [0000-0001-7756-8815], Lemaçon, Audrey [0000-0002-1817-7029], Allen, Jamie [0000-0002-8677-2225], Ausems, Margreet GEM [0000-0003-0305-3477], Bull, Shelley [0000-0002-3280-7154], Engel, Christoph [0000-0002-7247-282X], Green, Jessica [0000-0002-7005-2928], Hollestelle, Antoinette [0000-0003-1166-1966], Kaulfuß, Silke [0000-0003-2577-9711], Kuang, Da [0000-0003-3554-0464], Martens, John WM [0000-0002-3428-3366], Nürnberg, Peter [0000-0002-7228-428X], Ott, Claus-Eric [0000-0003-3627-3791], Peters, Annette [0000-0001-6645-0985], Ramirez, Alfredo [0000-0003-4991-763X], Wagner, Michael [0000-0003-2589-6440], Weber, Bernhard HF [0000-0002-8808-7723], Devilee, Peter [0000-0002-8023-2009], Bader, Gary D [0000-0003-0185-8861], Andrulis, Irene L [0000-0002-4226-6435], Schmidt, Marjanka K [0000-0002-2228-429X], Simard, Jacques [0000-0001-6906-3390], Apollo - University of Cambridge Repository, Human genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, and Epidemiology

Subjects
breast cancer, genetic susceptibility, whole-exome sequencing, moderate-penetrance genes, Cancer Research, SDG 3 - Good Health and Well-being, Oncology, Breast Cancer, Genetic Susceptibility, Whole-exome Sequencing, Moderate-penetrance Genes, Article, ddc:610, Technology Platforms, ddc
Abstract

Simple Summary Genetic variants explaining approximately 40% of familial breast cancer risk have been identified, thus leaving a significant fraction of the heritability of this disease still unexplained. The exact nature of this missing fraction is unknown; more extensive sequencing efforts could potentially identify new moderate-penetrance breast cancer risk alleles. The aim of this study was to perform a large-scale whole-exome sequencing study, followed by a targeted validation, in breast cancer patients and healthy women of European descent. We identified 20 novel genes with modest evidence of association (p-value < 0.05) for either overall or subtype-specific breast cancer; however, much larger studies are needed to confirm the exact role of these genes in susceptibility to breast cancer. Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.

Published
2022

14. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Dennis, Joe, Tyrer, Jonathan, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Jean, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Kristensen, Vessela N, Sahlberg, Kristine K, Børresen-Dale, Anne-Lise, Gram, Inger Torhild, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, Alnæs, Grethe I Grenaker, Collée, J Margriet, Lacey, James, Martinez, Elena, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Clarke, Christine, Carpenter, Jane, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Campbell, Ian, De Fazio, Anna, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Milne, Roger, Southey, Melissa, Spurdle, Amanda, Thorne, Heather, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, Soucy, Penny, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wendt, Camilla, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Simard, Jacques, Dunning, Alison, Pharoah, Paul, Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Jean [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Kristensen, Vessela N [0000-0001-5012-7438], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Wilson, Leila [0000-0003-1214-8080], Clinical Genetics, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum

Subjects
endocrine system diseases, 45/43, Medicine (miscellaneous), Genome-wide association studies, Basic medicine, Breast cancer, Other medical sciences, Runx2, Risk Factors, Biology (General), skin and connective tissue diseases, 0303 health sciences, 030305 genetics & heredity, article, 3. Good health, Female, General Agricultural and Biological Sciences, Medical Genetics, Mutations, DNA Copy Number Variations, Locus, QH301-705.5, kConFab/AOCS Investigators, ABCTB Investigators, 631/208/205/2138, Breast Neoplasms, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, NBCS Collaborators, Association, Deletion, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Humans, 030304 developmental biology, Medicinsk genetik, Cancer och onkologi, Genome, Human, Health sciences, 631/67/1347, CTS Consortium, Germ Cells, Genes, Clinical medicine, Cancer and Oncology, Case-Control Studies, 3111 Biomedicine, Structural variation, Brca1, Genome-Wide Association Study
Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value, Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

Published
2021

15. 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, Hillemanns, Peter, Hogervorst, Frans BL, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huebner, Hanna, Hulick, Peter J, Imyanitov, Evgeny N, kConFab Investigators, ABCTB Investigators, Isaacs, Claudine, Izatt, Louise, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Khan, Sofia, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Laenkholm, Anne-Vibeke, Lambrechts, Diether, Larsson, Susanna C, Laurent-Puig, Pierre, Lazaro, Conxi, Lazarova, Emilija, Lejbkowicz, Flavio, Leslie, Goska, Lesueur, Fabienne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing-Yee, Loud, Jennifer T, Lubinski, Jan, Lukomska, Alicja, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matricardi, Laura, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Mingazheva, Elvira, Montagna, Marco, Mulligan, Anna Marie, Mulot, Claire, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Newman, William G, Nielsen, Finn C, Nikitina-Zake, Liene, Nodora, Jesse, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Papi, Laura, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Peissel, Bernard, Peixoto, Ana, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Phillips, Kelly-Anne, Piedmonte, Marion, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Prokofyeva, Darya, Rack, Brigitte, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Risch, Harvey A, Romero, Atocha, Rookus, Matti A, Rübner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Scheuner, Maren T, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Senter, Leigha, Sharma, Priyanka, Sherman, Mark E, Shu, Xiao-Ou, Singer, Christian F, Smichkoska, Snezhana, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Stoppa-Lyonnet, Dominique, EMBRACE Study, GEMO Study Collaborators, Swerdlow, Anthony J, Szabo, Csilla I, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, MaryBeth, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M, van den Ouweland, Ans MW, van der Kolk, Lizet E, van Veen, Elke M, vanRensburg, Elizabeth J, Vega, Ana, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zheng, Wei, Zorn, Kristin K, Milne, Roger L, Kraft, Peter, Simard, Jacques, Pharoah, Paul DP, Michailidou, Kyriaki, Antoniou, Antonis C, Schmidt, Marjanka K, Chenevix-Trench, Georgia, Easton, Douglas F, Chatterjee, Nilanjan, García-Closas, Montserrat, Barnes, Daniel [0000-0002-3781-7570], O'Mara, Tracy A [0000-0002-5436-3232], Dunning, Alison M [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Calvello, Mariarosaria [0000-0003-2113-8503], Chanock, Stephen J [0000-0002-2324-3393], Claes, Kathleen BM [0000-0003-0841-7372], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Ekici, Arif B [0000-0001-6099-7066], Fasching, Peter A [0000-0003-4885-8471], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Harkness, Elaine F [0000-0001-6625-7739], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Huebner, Hanna [0000-0001-6889-1493], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Larsson, Susanna C [0000-0003-0118-0341], Laurent-Puig, Pierre [0000-0001-8475-5459], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Lissowska, Jolanta [0000-0003-2695-5799], Matricardi, Laura [0000-0002-0241-1810], McLean, Catriona [0000-0002-0302-5727], Menon, Usha [0000-0003-3708-1732], Miller, Austin [0000-0001-9739-8462], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G [0000-0002-6382-4678], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Parsons, Michael T [0000-0003-3242-8477], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Stone, Jennifer [0000-0001-5077-0124], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], van Veen, Elke M [0000-0001-8618-2332], vanRensburg, Elizabeth J [0000-0003-2077-230X], Weitzel, Jeffrey N [0000-0001-6714-092X], Winqvist, Robert [0000-0003-0932-9104], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Zheng, Wei [0000-0003-1226-070X], Milne, Roger L [0000-0001-5764-7268], Kraft, Peter [0000-0002-4472-8103], Simard, Jacques [0000-0001-6906-3390], Pharoah, Paul DP [0000-0001-8494-732X], Michailidou, Kyriaki [0000-0001-7065-1237], Schmidt, Marjanka K [0000-0002-2228-429X], Easton, Douglas F [0000-0003-2444-3247], Chatterjee, Nilanjan [0000-0002-9060-008X], García-Closas, Montserrat [0000-0003-1033-2650], and Apollo - University of Cambridge Repository

Subjects
BRCA1 Protein, Case-Control Studies, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Triple Negative Breast Neoplasms, Linkage Disequilibrium, Genome-Wide Association Study
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

16. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).

Published
2020

17. Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I)

Author

Antonis C. Antoniou, Douglas F. Easton, Jean-Yves Masson, Michel Dorval, Samantha Fienberg, Nicole Mittmann, Meghan J. Walker, Jennifer D. Brooks, Michael Wolfson, Irene L. Andrulis, David E. Goldgar, Hermann Nabi, Jean-Sébastien Paquette, Sean V. Tavtigian, Bartha Maria Knoppers, Anna M. Chiarelli, Jacques Simard, Yann Joly, Peter Devilee, Nora Pashayan, Arnaud Droit, Tracy Stockley, Aisha Lofters, Rita K. Schmutzler, Laurence Eloy, Jocelyne Chiquette, Eric Hahnen, Andrea Eisen, Philippe Després, Brooks, Jennifer D [0000-0001-7574-4256], Andrulis, Irene L [0000-0002-4226-6435], Després, Philippe [0000-0002-4163-7353], Devilee, Peter [0000-0002-8023-2009], Dorval, Michel [0000-0002-3207-8211], Droit, Arnaud [0000-0001-7922-790X], Knoppers, Bartha Maria [0000-0001-7004-2722], Paquette, Jean-Sébastien [0000-0002-9524-6761], Pashayan, Nora [0000-0003-0843-2468], Stockley, Tracy [0000-0002-4476-9722], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, Best practice, Population, Medicine (miscellaneous), Context (language use), 03 medical and health sciences, Breast cancer screening, Breast cancer, 0302 clinical medicine, medicine, False positive paradox, Overdiagnosis, education, Risk stratification, 030304 developmental biology, 0303 health sciences, education.field_of_study, medicine.diagnostic_test, business.industry, medicine.disease, 030220 oncology & carcinogenesis, Family medicine, Perspective, Screening, Medicine, Risk Prediction, business, Risk assessment
Abstract

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

Published
2021

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

Author

Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Risk, medicine.medical_specialty, Gene Expression, Genome-wide association study, Breast Neoplasms, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Expression quantitative trait loci, Medical genetics, Female, Gene expression, Breast Cancer Genetics, Genome-Wide Association Study
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 −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Published
2019

19. Shared heritability and functional enrichment across six solid cancers

Author

Graham G. Giles, Diana Eccles, Cezary Cybulski, Catherine M. Tangen, Leon Raskin, Per Hall, Ana Vega, Hedy S. Rennert, Andrew T. Chan, Stephan Lam, Michael Hoffmeister, Angeline S. Andrew, Claudine Isaacs, Matthias W. Beckmann, Vessela N. Kristensen, Julia A. Knight, Mark S. Goldberg, Jonathan Tyrer, Jane C. Figueiredo, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Liene Nikitina-Zake, Goska Leslie, Rosalind A. Eeles, Line Bjørge, Adonina Tardón, Angela Cox, Gregory Idos, Evgeny N. Imyanitov, Manolis Kogevinas, Marc Tischkowitz, Hilary K. Finucane, Hardev Pandha, Rayjean J. Hung, Davor Lessel, Richard S. Houlston, Andrew F. Olshan, André Lopes Carvalho, James D. McKay, Kenneth Offit, Penelope M. Webb, Barry S. Rosenstein, Melinda C. Aldrich, Alice S. Whittemore, Austin Miller, Miguel E. Aguado-Barrera, Amanda E. Toland, Anna Marie Mulligan, Catharine M L West, Susan J. Ramus, Jennifer Stone, David C. Christiani, Clarice R. Weinberg, Olivia Fletcher, Kyriaki Michailidou, Demetrius Albanes, Chu Chen, Jenny L Donovan, Linda E. Kelemen, Carolina Ellberg, Hermann Brenner, Eitan Friedman, Sara Margolin, Jacek Gronwald, Argyrios Ziogas, Elisa V. Bandera, Qin Wang, Christopher I. Amos, Swe-Brca, Douglas F. Easton, Karin Sundfeldt, John L. Hopper, Jong Y. Park, Børge G. Nordestgaard, Johanna Schleutker, Freddie C. Hamdy, Alicja Wolk, Graham Casey, Radka Kaneva, Joe Dennis, Francesmary Modugno, Paolo Radice, Aage Haugen, Ralf Bützow, Barbara Burwinkel, Maria A. Caligo, Paul A. Townsend, Daniel D. Buchanan, Håkan Olsson, Li Li, Elza Khusnutdinova, Karina Dalsgaard Sørensen, Marco Montagna, Patricia A. Ganz, Kirsten B. Moysich, Stephen B. Gruber, Geraldine Cancel-Tassin, Mary Anne Rossing, Mads Thomassen, Manuela Gago-Dominguez, Marjanka K. Schmidt, Jolanta Kupryjanczyk, Melissa C. Southey, Finn Cilius Nielsen, Sara Benlloch, Roger L. Milne, Manuel R. Teixeira, Taymaa May, David V. Conti, Thilo Dörk, Kathleen Claes, Manjeet K. Bolla, Douglas A. Levine, Lorelei A. Mucci, Irene L. Andrulis, Carl Blomqvist, Sara Lindström, Marjorie J. Riggan, Ellen L. Goode, Jenny Lester, Jack A. Taylor, Adam S. Kibel, Jyotsna Batra, Stephen N. Thibodeau, Elinor J. Sawyer, Stefania Boccia, Jacques Simard, Robert J. MacInnis, Fredrik Wiklund, Geoffrey Liu, Robert Winqvist, Robert J. Hamilton, Joan Brunet, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Susan L. Neuhausen, Robert L. Ferris, Georgia Chenevix-Trench, Elizabeth J. van Rensburg, Amanda B. Spurdle, Jeroen R. Huyghe, Stig E. Bojesen, Eric J. Duell, Christopher A. Haiman, Bogdan Pasaniuc, Wilbert H.M. Peters, M. Dawn Teare, Marc T. Goodman, Richa Saxena, Renée T. Fortner, Shanbeh Zienolddiny, Mia M. Gaudet, Stephanie J. Weinstein, Mikael Johansson, Heli Nevanlinna, Nhu D. Le, Rolando Herrero, Peter Kraft, Steven Gallinger, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Gabriella Cadoni, Weiva Sieh, Esther M. John, Rebecca Sutphen, Kari Stefansson, Loic Le Marchand, David J. Hunter, Alkes L. Price, Judy Garber, Mary B. Daly, Flavio Lejbkowicz, Lambertus A. Kiemeney, Martha L. Slattery, Arto Mannermaa, Christian F. Singer, Daniele Campa, Hans Brunnström, Hongbing Shen, Els Van Nieuwenhuysen, V. Wendy Setiawan, Penella J. Woll, Catherine M. Phelan, Christopher I. Li, Robert L. Nussbaum, Niclas Håkansson, Triantafillos Liloglou, Stella Koutros, Kjell Grankvist, James D. Brenton, Annika Lindblom, Gad Rennert, Karoline Kuchenbaecker, Martin Lacko, Gary E. Goodman, Fredrick R. Schumacher, Henrik Grönberg, Diana Torres, J. Margriet Collée, Rosa B. Barkardottir, Amit Joshi, Trinidad Caldés, Mary Beth Terry, Jenny Chang-Claude, Paul Brennan, Simon A. Gayther, Mark H. Greene, Daniel R. Barnes, Janet L. Stanford, Miriam Dwek, Christiane Maier, Susanne K. Kjaer, Florentia Fostira, Miranda Pring, Noralane M. Lindor, Harvey A. Risch, David G. Huntsman, Kim De Ruyck, Judith A. Clements, Pooja Middha, Alison M. Dunning, Nadine Tung, Sebastian Stintzing, Michael O. Woods, Stephen J. Chanock, Andrew K. Godwin, Kenneth Muir, Eloiza H. Tajara, Silvia Franceschi, Xia Jiang, Li Hsu, Emily White, Peter T. Campbell, Paul A. James, Josef Heinz-Lenz, Ali Amin Al Olama, Victoria L. Stevens, Lovise Maehle, Fotios Loupakis, Peter Devilee, Orland Diez, Kristin K. Zorn, Stephanie A. Bien, Maria Teresa Landi, Mark A. Jenkins, Amanda I. Phipps, Alfons Meindl, Frank Claessens, Mark N. Brook, Kathryn L. Penney, Digna R. Velez Edwards, Montserrat Garcia-Closas, Diether Lambrechts, Zsofia Kote-Jarai, Fergus J. Couch, Duncan Thomas, Kathryn L. Terry, Ute Hamann, Heike Bickeböller, Christopher K. Edlund, Ana Osorio, Younghun Han, Jochen Hampe, Tee Kay-Khaw, Corina Lesseur, Peter A. Fasching, Lesley McGuffog, Eunjung Lee, Tabea Kühl, Andy R Ness, Kamila Czene, Angela Risch, Aocs Mod SQuaD, Jeri Kim, Anna H. Wu, Jacqueline M. Lane, Brenda Diergaarde, Ruth C. Travis, Julie M. Cunningham, Philip Lazarus, Shelley S. Tworoger, Natalia Antonenkova, Emmanouil Saloustros, Wei Zheng, Javier Benitez, Dijana Plaseska-Karanfilska, Mark C. Weissler, Marcia Cruz Correa, Hoda Anton-Culver, Neil E. Caporaso, Cornelia M. Ulrich, Stephanie L. Schmit, Antonis C. Antoniou, Victor Moreno, David E. Neal, Tanja Pejovic, Erich H-Wichmann, Pascal Guénel, Mattias Johansson, Florian Heitz, Beth Y. Karlan, Sonja I. Berndt, Anthony J. Swerdlow, Estrid Høgdall, Hiltrud Brauch, Ulrike Peters, D. Gareth Evans, Celine M. Vachon, Edith Olah, Dale P. Sandler, Lisa F. Newcomb, Michael T. Parsons, Lisa A. Cannon-Albright, Peter J. Hulick, José A. García-Sáenz, Sue A. Ingles, Andrew Berchuck, Peter Hillemanns, Matthew B. Schabath, Polly A. Newcomb, Banu Arun, Xifeng Wu, Darya Prokofyeva, Jan Lubinski, Susanne M. Arnold, Natalia Bogdanova, Drakoulis Yannoukakos, Nawaid Usmani, Kristan J. Aronson, Chul Yun-Hong, Monique J. Roobol, Clinical Genetics, Urology, Læknadeild (HÍ), Faculty of Medicine (UI), Lífvísindasetur (HÍ), Biomedical Center (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Finucane, Hilary K [0000-0003-3864-9828], Schumacher, Fredrick R [0000-0002-3073-7463], Schmit, Stephanie L [0000-0001-5931-1194], Michailidou, Kyriaki [0000-0001-7065-1237], Kuchenbaecker, Karoline B [0000-0001-9726-603X], Dennis, Joe [0000-0003-4591-1214], Huyghe, Jeroen R [0000-0001-6027-9806], Andrulis, Irene L [0000-0002-4226-6435], Arnold, Susanne M [0000-0001-6542-9551], Barnes, Daniel R [0000-0002-3781-7570], Batra, Jyotsna [0000-0003-4646-6247], Bojesen, Stig E [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Brenton, James D [0000-0002-5738-6683], Brook, Mark N [0000-0002-8969-2378], Brunet, Joan [0000-0003-1945-3512], Brunnström, Hans [0000-0001-7402-138X], Buchanan, Daniel D [0000-0003-2225-6675], Campbell, Ian [0000-0002-7773-4155], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Chan, Andrew T [0000-0001-7284-6767], Chanock, Stephen J [0000-0002-2324-3393], Claes, Kathleen BM [0000-0003-0841-7372], Cunningham, Julie M [0000-0002-8159-3025], Devilee, Peter [0000-0002-8023-2009], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A [0000-0003-4885-8471], Liloglou, Triantafillos [0000-0003-0460-1404], Fletcher, Olivia [0000-0001-9387-7116], García-Sáenz, José A [0000-0001-6880-0301], Grankvist, Kjell [0000-0003-4289-2097], Greene, Mark H [0000-0003-1852-9239], Gronberg, Henrik [0000-0002-1073-2753], Guénel, Pascal [0000-0002-8359-518X], Hampe, Jochen [0000-0002-2421-6127], Houlston, Richard [0000-0002-5268-0242], Hulick, Peter J [0000-0001-8397-4078], James, Paul [0000-0002-4361-4657], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Lambrechts, Diether [0000-0002-3429-302X], Leslie, Goska [0000-0001-5756-6222], Lessel, Davor [0000-0003-4496-244X], Levine, Douglas A [0000-0003-1038-8232], Miller, Austin [0000-0001-9739-8462], Milne, Roger L [0000-0001-5764-7268], Moreno, Victor [0000-0002-2818-5487], Muir, Kenneth [0000-0001-6429-988X], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Newcomb, Polly A [0000-0001-8786-0043], Nikitina-Zake, Liene [0000-0003-2491-5187], Nordestgaard, Børge G [0000-0002-1954-7220], Olama, Ali Amin Al [0000-0002-7178-3431], Olopade, Olufunmilayo I [0000-0002-9936-1599], Pashayan, Nora [0000-0003-0843-2468], Parsons, Michael T [0000-0003-3242-8477], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Risch, Angela [0000-0002-8026-5505], Roobol, Monique J [0000-0001-6967-1708], Saloustros, Emmanouil [0000-0002-0485-0120], Schabath, Matthew B [0000-0003-3241-3216], Schleutker, Johanna [0000-0002-1863-0305], Schmidt, Marjanka K [0000-0002-2228-429X], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Stintzing, Sebastian [0000-0002-3297-5801], Stone, Jennifer [0000-0001-5077-0124], Tardon, Adonina [0000-0001-5150-1209], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Aguado-Barrera, Miguel Elías [0000-0002-7822-6726], Webb, Penelope M [0000-0003-0733-5930], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Zheng, Wei [0000-0003-1226-070X], Ziogas, Argyrios [0000-0003-4529-3727], Peters, Ulrike [0000-0001-5666-9318], Eeles, Rosalind A [0000-0002-3698-6241], Brennan, Paul J [0000-0002-0518-8714], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Price, Alkes L [0000-0002-2971-7975], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Jiang X] Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. [Finucane HK] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [Schumacher FR] Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Seidman Cancer Center, University Hospitals, Cleveland, OH, USA. [Schmit SL] Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. [Han Y] Department of Biomedical Data Science, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. [Diez O] Grup d'Oncogenètica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain, Hospital Universitari Vall d'Hebron, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Cancer Research UK (Reino Unido), NIHR - Comprehensive Biomedical Research Centre, Guy ’ s & St. Thomas ’ NHS Foundation Trust, NIHR - Oxford Biomedical Research Centre (Reino Unido), German Cancer Research Center, Consejo Nacional de Ciencia y Tecnología (CONACyT), King College London, National Health and Medical Research Council (Australia), Canadian Institutes of Health Research, The BREast Oncology GAlician Network (BREOGAN, Dietmar-Hopp Foundation, Helmholtz Society and the German Cancer Research Center (DKFZ), Asociación Española Contra el Cáncer, Vall d'Hebron Barcelona Hospital Campus, Clinicum, Department of Oncology, University of Helsinki, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center

Subjects
Oncology, Male, Lung Neoplasms, Colorectal cancer, Epidemiology, Inheritance Patterns, Genome-wide association study, 02 engineering and technology, Colorectal Neoplasms/diagnosis, Càncer - Aspectes genètics, 0302 clinical medicine, Neoplasm Proteins/genetics, Brjóstakrabbamein, PARTITIONING HERITABILITY, lcsh:Science, Càncer, Cancer genetics, Cancer, Càncer - Estudi de casos, Ovarian Neoplasms, Prostatic Neoplasms/diagnosis, 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Genomics, Publisher Correction, ddc, 3. Good health, Neoplasm Proteins, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Etiologia, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Neoplasias [ENFERMEDADES], ICEP, Erfðarannsóknir, 0210 nano-technology, Genetic Phenomena::Inheritance Patterns [PHENOMENA AND PROCESSES], medicine.medical_specialty, Biolääketieteet - Biomedicine, Science, Lung Neoplasms/diagnosis, European Continental Ancestry Group, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Syöpätaudit - Cancers, BREAST-CANCER, Humans, Otros calificadores::Otros calificadores::Otros calificadores::/etnología [Otros calificadores], Polymorphism, GENOME-WIDE ASSOCIATION, solid cancers, heritability, enrichment, Settore MED/42 - IGIENE GENERALE E APPLICATA, ResearchInstitutes_Networks_Beacons/mcrc, Fenómenos Genéticos::Patrón de Herencia [FENÓMENOS Y PROCESOS], ANALYSES IDENTIFY, Biology and Life Sciences, fenómenos genéticos::patrones de herencia [FENÓMENOS Y PROCESOS], medicine.disease, Càncer -- Etiologia, 030104 developmental biology, Case-Control Studies, RISK-FACTORS, lcsh:Q, 0301 basic medicine, Etiology, Medizin, General Physics and Astronomy, técnicas de investigación::métodos epidemiológicos::características de los estudios epidemiológicos::estudios epidemiológicos::estudios de casos y controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], head and neck, Prostate cancer, Medicine and Health Sciences, Càncer -- Aspectes genètics, Multidisciplinary, Manchester Cancer Research Centre, Mental Disorders, Codi genètic, Smoking, Single Nucleotide, 021001 nanoscience & nanotechnology, Phenotype, Centre for Surgical Research, Cancer -- Etiology, MENDELIAN RANDOMIZATION, Female, Smoking/ethnology, Colorectal Neoplasms, Mental Disorders/ethnology, Medical Genetics, Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics::Epidemiologic Studies::Case-Control Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Cancer Etiology, Técnicas de Investigación::Métodos Epidemiológicos::Características de Estudios Epidemiológicos::Estudios Epidemiológicos::Estudios de Casos y Controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, All institutes and research themes of the Radboud University Medical Center, Internal medicine, MD Multidisciplinary, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Erfðafræði, Genetic Predisposition to Disease, CELL-TYPES, Lung cancer, Krabbamein, Medicinsk genetik, 030304 developmental biology, Ovarian Neoplasms/diagnosis, Faraldsfræði, Prostatic Neoplasms, Breast Neoplasms/diagnosis, General Chemistry, Heritability, Head and Neck Neoplasms/diagnosis, Neoplasms [DISEASES], Genome-Wide Association Study, 3111 Biomedicine, Ovarian cancer, Other subheadings::Other subheadings::Other subheadings::/ethnology [Other subheadings]
Abstract

Publisher's version (útgefin grein)., Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis., The authors in this manuscript were working on behalf of BCAC, CCFR, CIMBA, CORECT, GECCO, OCAC, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS, TRICL-ILCCO, ABCTB, APCB, BCFR, CONSIT TEAM, EMBRACE, GC-HBOC, GEMO, HEBON, kConFab/AOCS Mod SQuaD, and SWE-BRCA. The breast cancer genome-wide association analyses: BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSR-SIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, and BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). COLBCCC is supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany. D.T. was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C eceives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf-Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and “Practical Research for Innovative Cancer Control (15ck0106177h0001)” from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014, and 17-44-020498. ICICLE was supported by Breast Cancer Now, CRUK, and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (A.L.F.) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (E.V.O.) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.-T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The KOHBRA study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. L.M.B.C. is supported by the ‘Stichting tegen Kanker’. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839, and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286, and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A.-L. Børresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, and U01 CA179715), and the North Carolina University Cancer Research Fund. The NGOBCS was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation, and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956, and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the National Cancer Institute of the National Institutes of Health (R01 CA89085 and P50 CA125183 and the D43 TW009112 grant), Susan G. Komen (SAC110026), the Dr. Ralph and Marian Falk Medical Research Trust, and the Avon Foundation for Women. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. D.G.E. is supported by the all Manchester NIHR Biomedical research center Manchester (IS-BRC-1215-20007). HUNBOCS, Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745, NKFI_OTKA K-112228. C.I. received support from the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI P30-CA-51008) and the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. K.M. is supported by CRUK C18281/A19169. City of Hope Clinical Cancer Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J Weitzel) from the National Cancer Institute and the office of the Directory, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The colorectal cancer genome-wide association analyses: Colorectal Transdisciplinary Study (CORECT): The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the CORECT Consortium. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong. ColoCare: we thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. CCFR: the Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and financial support from the U.S. National Cancer Institute, without which this important registry would not exist. Galeon: GALEON wishes to thank the Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M Redondo, and the staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigación Sanitaria de Santiago (IDIS), Instituto de Investigación Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. MCCS: this study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH: We acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish low-risk colorectal cancer study: we thank Berith Wejderot and the Swedish low-risk colorectal cancer study group. Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO): we thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK: we are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. HPFS, NHS and PHS: we acknowledge Patrice Soule and Hardeep Ranu of the Dana-Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo, and Lixue Zhu who assisted in programming for NHS and HPFS and Haiyan Zhang who assisted in programming for the PHS. We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. PLCO: we thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services Inc., Ms. Barbara O’Brien and staff, Westat Inc. and Drs. Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions for making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI. PMH: we thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short20List.pdf. CORECT: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; and R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 (Gilliland)), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, and U01 CA164930). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S.G.). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai’i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: A.Z., C.O., M.N., N.C., N.H., and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden–Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC: the work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). SEARCH: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: the study was supported by grants from the Swedish research council; K2015-55 × -22674-01-4, K2008-55 × -20157-03-3, K2006-72 × -20157-01-2 and the Stockholm County Council (ALF project). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K.D.), through grant 101HG007491-01 (to C.I.A.). The Norris Cotton Cancer Center - P30CA023108, The Quantitative Biology Research Institute - P20GM103534, and the Coordinating Center for Screen Detected Lesions - U01CA196386 also supported efforts of C.I.A. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (grant number R01 CA060987). DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: National Institutes of Health (grant number R01 CA048998 to M.L.S). HPFS is supported by National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), NHS by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHSII by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and PHS by the National Institutes of Health (grant number R01 CA042182). MEC: National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783); see Colon CFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. and B.W.Z. are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, 23 and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (grant number R01 CA076366). VITAL: National Institutes of Health (grant number K05-CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The head and neck cancer genome-wide association analyses: The study was supported by NIH/NCI: P50 CA097190, and P30 CA047904, Canadian Cancer Society Research Institute (no. 020214) and Cancer Care Ontario Research Chair to R.H. The Princess Margaret Hospital Head and Neck Cancer Translational Research Program is funded by the Wharton family, Joe’s Team, Gordon Tozer, Bruce Galloway and the Elia family. Geoffrey Liu was supported by the Posluns Family Fund and the Lusi Wong Family Fund at the Princess Margaret Foundation, and the Alan B. Brown Chair in Molecular Genomics. This publication presents data from Head and Neck 5000 (H&N5000). H&N5000 was a component of independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) in H&N5000 serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). National Cancer Institute (R01-CA90731); National Institute of Environmental Health Sciences (P30ES10126). The authors thank all the members of the GENCAPO team/The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). CPS-II recruitment and maintenance is supported with intramural research funding from the American Cancer Society. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1 × 01HG007780-0. The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19-CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission’s 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to S.B., and Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). We thank Leticia Fernandez, Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba and Sergio and Rosalina Koifman, for their efforts with the IARC Latin America study São Paulo center. The IARC Central Europe study was supported by European Commission’s INCO-COPERNICUS Program (IC15- CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The lung cancer genome-wide association analyses: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127, CA148127S1, U19CA203654, and Cancer Prevention Research Institute of Texas RR170048). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multi-ethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The Singapore Chinese Health Study (SCHS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568) (to X.W.), Cancer Prevention & Research Institute of Texas (RP130502) (to X.W.), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The deCODE study of smoking and nicotine dependence was funded in part by a grant from NIDA (R01- DA017932). The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Genetic sharing analysis was funded by NIH grant CA194393. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The work to assemble the FTND GWAS meta-analysis was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant number R01 DA035825 (Principal Investigator [PI]: DBH). The study populations included COGEND (dbGaP phs000092.v1.p1 and phs000404.v1.p1), COPDGene (dbGaP phs000179.v3.p2), deCODE Genetics, EAGLE (dbGaP phs000093.vs.p2), and SAGE. dbGaP phs000092.v1.p1). See Hancock et al. Transl Psychiatry 2015 (PMCID: PMC4930126) for the full listing of funding sources and other acknowledgments. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT)study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. The ovarian cancer genome-wide association analysis: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.), and R01-CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP-86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175) and through a grant from the U.S. National Institutes of Health (R01-CA122443 (E.L.G)). Funding for individual studies: AAS: National Institutes of Health (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; and R01-CA080742); DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, and P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey; If Sara Olson and/or Irene Orlow is a co-author, please add NCI CCSG award (P30-CA008748) to the funding sources; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women’s Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50-CA159981, R01-CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01-ES044005 and Z01-ES049033; SMC: The bbSwedish Research Council-SIMPLER infrastructure; the Swedish Cancer Foundation; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and VårKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01-CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academia Reserve. The prostate cancer genome-wide association analyses: we pay tribute to Brian Henderson, who was a driving force behind the OncoArray project, for his vision and leadership, and who sadly passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. The ELLIPSE/PRACTICAL (http//:practical.icr.ac.uk) prostate cancer consortium and his collaborating partners were supported by multiple funding mechanisms enabling this current work. ELLIPSE/PRACTICAL Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA148537 for ELucidating Loci Involved in Prostate Cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392 (F.R.S.). Funding for the iCOGS infrastructure came from the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, C5047/A21332 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010-70 × -20430-04-3, 2014-2269). The Hannover Prostate Cancer Study was supported by the Lower Saxonian Cancer Society. PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. RAPPER was supported by the NIHR Manchester Biomedical Research Center, Cancer Research UK (C147/A25254, C1094/A18504) and the EU’s 7th Framework Programme Grant/Agreement no 60186. Overall: this research has been conducted using the UK Biobank Resource (application number 16549). NHS is supported by UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969, and R01 CA49449. NHSII is supported by UM1 CA176726 (NHSII cohort infrastructure grant), and R01-CA67262. A.L.K. is supported by R01 MH107649. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

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2019

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