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1. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Author

Sevelda, Paul, Haslbauer, Ferdinand, Penzinger, Monika, Öhler, Leopold, Tinchon, Christoph, Greil, Richard, Heibl, Sonja, Bartsch, Rupert, Wette, Viktor, Singer, Christian F., Pasterk, Claudia, Helfgott, Ruth, Pristauz-Telsnigg, Gunda, Stöger, Herbert, Weltermann, Angsar, Egle, Daniel, Thiel, Irene, Fuchs, David, Rumpold, Holger, Strasser-Weippl, Kathrin, Rautenberg, Beate, Müller, Volkmar, Schmidt, Marcus, Paepke, Stefan, Aydogdu, Mustafa, Thomssen, Christoph, Rom, Joachim, Mau, Christine, Fasching, Peter, Göhring, Uwe-Jochen, Kühn, Thorsten, Noeding, Stefanie, Kümmel, Sherko, Hackmann, John, Stickeler, Elmar, Joshi, Abhishek, Dewar, Joanna, Friedlander, Michael, Phillips, Kelly-Anne, Antill, Yoland, Woodward, Natasha, Abdi, Ehtesham, Tiley, Susan, George, Mathew, Boadle, David, Goodwin, Annabel, van der Westhuizen, Andre, Kannourakis, George, Murray, Nicholas, McCarthy, Nicole, Kroep, Judith, de Boer, Maaike, Heijns, Joan, Jager, Agnes, Erdkamp, Franciscus, Bakker, Sandra, Sonke, Gabe S., Sami, Amer, Mackey, John, Prady, Catherine, Eisen, Andrea, Desbiens, Christine, Patocskai, Erica, Ferrario, Cristiano, Gelmon, Karen, Bordeleau, Louise, Chalchal, Haji, Niraula, Saroj, ido wolf, Senkus, Elżbieta, Duhoux, François, Randal d’Hondt, Luce, Sylvie, Roodenbeke, Daphné t’Kint de, Papadimitriou, Konstantinos, Borms, Marleen, Quaghebeur, Claire, Jacot, William, Brain, Etienne, Venat-Bouvet, Laurence, Lortholary, Alain, Nowecki, Zbigniew, Cardoso, Fátima, Hayward, Richard, Bella, Santiago, Lazzaro, Mauricio Fernández, Pilnik, Norma, Fein, Luis E., Blajman, Cesar, Lerzo, Guillermo, Varela, Mirta, Zarba, Juan Jose, Kaen, Diego, Constanzo, Maria Victoria, Tio, Joke, Siggelkow, Wulf, Jackisch, Christian, Grischke, Eva Maria, Zahm, Dirk, Tato-Varela, Sara, Schmatloch, Sabine, Klare, Peter, Stefek, Andrea, Rhiem, Kerstin, Hoffmann, Oliver, Deryal, Mustafa, Gröll, Isolde, Ledwon, Peter, Uleer, Christoph, Krabisch, Petra, Potenberg, Jochem, Darsow, Maren, Park-Simon, Tjoung-Won, Höffkes, Heinz-Gert, Emde, Till-Oliver, Graffunder, Gerd, Tomé, Oliver, Forstmeyer, Dirk, Terhaag, Jürgen, Salat, Christoph, Kast, Karin, Weniger, Steffi, Schreiber, Carsten, Heinrich, Bernhard, Dieterich, Max, Wüllner, Michaela Penelope, Conejero, Raquel Andrés, García Sáenz, José Ángel, Martinez, Lourdes Calvo, Lanza, Angels Arcusa, Murillo, Serafín Morales, Carrasco, Fernando Henao, Tormo, Salvador Blanch, López, Isabel Álvarez, Delgado Mingorance, Juan Ignacio, Gomez, Elena Álvarez, Santisteban, Marta, Jurado, Josefina Cruz, Quiroga, Vanesa, Borrego, Manuel Ruiz, Martínez de Dueñas, Eduardo, Alés Martínez, Jose Enrique, De la Haba, Juan, Jañez, Noelia Martínez, Lescure, Álvaro Rodríguez, Torres, Antonio Antón, Crusades, Gema Llort, González-Santiago, Santiago, Aragones, Antonia Marquez, Ortega, Ana Laura, Molins, Agusti Barnadas, Chacón López-Muñiz, José Ignacio, Jiménez, Miguel Martín, Bertrán, Ana Santaballa, Rodríguez, César, Cortijo, Lucía González, Cretella, Elisabetta, Cortesi, Laura, Ruggeri, Enzo Maria, Verusio, Claudio, Gori, Stefania, Bonetti, Andrea, Mosconi, Anna Maria, Johannsson, Oskar, Jerusalem, Guy, Neven, Patrick, Nagy, Tünde, Pinotti, Graziella, Colleoni, Marco A., Bernardo, Antonio, Gianni, Lorenzo, Bucci, Eraldo, Biganzoli, Laura, Dedes, Konstantin, Novak, Urban, Zaman, Khalil, Braybrooke, Jeremy, Winter, Matthew, Rea, Daniel, Kelleher, Muireann, Barrett, Sophie, Chan, Stephen, Hickish, Tamas, Hurwitz, Jane, Conibear, John, Jegannathen, Apurna, Parton, Marina, Tutt, Andrew, Allerton, Rozenn, Borley, Annabel, Armstrong, Anne, Copson, Ellen, Levitt, Nicola, Abraham, Jean, Perren, Timothy, Roylance, Rebecca, Ishida, Kazushige, Toyama, Tatsuya, Masuda, Norikazu, Watanabe, Junichiro, Tokunaga, Eriko, Kinoshita, Takayuki, Rai, Yoshiaki, Takada, Masahiro, Yanagita, Yasuhiro, Nakamura, Rikiya, Nakayama, Takahiro, Naoi, Yasuto, Iwata, Hiroji, Nakamura, Seigo, Takahashi, Masato, Aogi, Kenjiro, Tsugawa, Koichiro, Mukai, Hirofumi, Takano, Toshimi, Osaki, Akihiko, Sato, Nobuaki, Yamauchi, Hideko, Tokuda, Yutaka, Ito, Mitsuya, Sugimoto, Takeki, Bahadur, Shakeela W., Ganz, Patricia A., Lu, Min J., Mita, Monica M., Waisman, James, Polikoff, Jonathan A., Telli, Melinda L., Seaward, Samantha A., Suga, J. Marie, Durna, Lara N., Carney, Jennifer Fu, Menter, Alex, Puthillath, Ajithkumar, Rohatgi, Nitin, Feusner, James H., Bobolis, Kristie A., Eisenberg, Peter D., Wong, Derrick, Borges, Virginia F., Urquhart, Alexander T., Hofstatter, Erin W., McCarron, Edward C., Isaacs, Claudine, Herbolsheimer, Pia, Varadarajan, Ramya, Raben, Adam, Deveras, Ruby Anne E., Valdes-Albini, Frances, Mahtani, Reshma L., Meisel, Jane L., Sumrall, Bradley T., Jones, Cheryl F., Ofori, Samuel N., Sumida, Kenneth N.M., Karwal, Mark, Wilbur, Deborah W., Singh, (Joe), Spector, David M., Schallenkamp, John, Merkel, Douglas E., Lo, Shelly S., Khosla, Pam G., Cristofanilli, Massimo, Flaum, Lisa, Hoskins, Kent F., Cobleigh, Melody A., Lambiase, Elyse A., Hahn, Olwen M., Oliff, Ira A., Faller, Bryan A., Wade, James L., Burhani, Nafisa D., Gil, Amaryllis, Einhorn, Harvey E., Storniolo, Anna M.V., Chang, Brian K., Kalra, Maitri, Robin, Erwin L., Ansari, Bilal, Sharma, Priyanka, Dakhil, Shaker R., Deming, Richard L., Cole, John T., Hanson, David S., Ochoa, Augusto C., Garber, Judy E., Zimbler, Harvey, Armstrong, Deborah K., Tkaczuk, Katherine H.R., Riseberg, David A., O'Connor, Brian M., Openshaw, Thomas H., Zakalik, Dana, Vakhariya, Cynthia M., Schott, Anne F., Simon, Michael S., Doyle, Thomas J., Al Baghdadi, Tareq, VanderWoude, Amy, Flynn, Patrick J., Zera, Richard T., Friday, Bret E.B., Ruddy, Kathryn J., Smith, Ron, Ademuyiwa, Olabisi, Foluso, Ellis, Robert, Carlson, Jay W., Marchello, T, Benjamin, Levine, Edward A., Marcom, Paul K., Harkness, Cameron B., Tan, Antoinette R., Charles, William J., Kuzma, Charles S., Asaad, Shonda, Radford, James E., Steen, Preston D., Unnikrishnan, Madhu, Seeger, Grant R., Leu, Kirsten M.H., Copur, Mehmet S., Hauke, Ralph J., Soori, Gamini S., Arrick, Bradley A., Reeder, Jennifer G., Toppmeyer, Deborah L., Dayao, Zoneddy R., Adams, Sylvia, Andreopoulou, Eleni, Allison, Magnuson, Anampa Mesias, Jesus D., Sharma, Ruby, Ramaswamy, Bhuvaneswari, Gerds, Aaron T., Shenk, Robert R., Gross, Howard M., Trehan, Shruti, Razaq, Wajeeha, Mansoor, Abdul H., Hilton, Christie J., Brufsky, Adam M., Huynh, Chanh, Chowdhury, Nabila, Domchek, Susan M., Sigurdson, Elin R., Cescon, Terrence P., Rovito, Marc A., DeNittis, Albert S., Vogel, Victor G., Julian, Thomas B., Boyle, L.E., Baez-Diaz, Luis, Brescia, Frank J., Doster, John E., Siegel, Robert D., Wong, Lucas, Patel, Tejal, Nangia, Julie R., Jones, Catherine A., Cannon, George M., Bear, Harry D., Vachhani, Hetal, Wilkinson, Mary, Wood, Marie E., Yan, Fengting, Sui, Xingwei, van Haelst, Carol M., Specht, Jennifer M., Zhuo, Ying, Qamar, Rubina, Ryan, Matthew L., Stockham, Abigail, Virani, Shamsuddin, Gayle, Arlene A., Jubelirer, Steven J., Kurian, Sobha, Salkeni, Mohamad A., Loman, Niklas, Linderholm, Barbro, Silander, Gustav, Hallbeck, Anna-Lotta, von Wachenfeldt Väppling, Anna, Curtit, Elsa, Cardoso, Catarina, Braga, Sofia, Abreu, Miguel, Casa-Nova, Mafalda, Nave, Mónica, Ciruelos Gil, Eva María, Gelpi, Judith Balmaña, Ortega, Adela Fernández, Padró, Josep Gumà, Bermejo de las Heras, Begoña, Cao, María González, Bañuelos, Juan Cueva, Company, Jesús Alarcon, Villaró, Gemma Viñas, Estevez, Laura García, Huober, Jens, Busch, Steffi, Fehm, Tanja, Hahn, Antje, Grafe, Andrea, Noesselt, Thomas, Dewitz, Thomas, Wagner, Harald, Bechtner, Christina, Weigel, Michael, Kolberg, Hans-Christian, Decker, Thomas, Thomalla, Jörg, Hesse, Tobias, Harbeck, Nadia, Jens-Uwe Blohmer, Jan Schröder, Wolf Sütterlin, Marc, Altena, Renske, Chiu, Chang-Fang, Chen, Shin-Cheh, Hou, Ming-Feng, Chang, Yuan-Ching, Chen, Shang-Hung, Chen, Shou-Tung, Huang, Chiun-Sheng, Yeh, Dah-Cherng, Yu, Jyh-Cherng, Tseng, Ling-Ming, Chung, Wei-Pang, Mailliez, Audrey, Petit, Thierry, Delaloge, Suzette, Lévy, Christelle, Dalivoust, Philippe, Extra, Jean-Marc, Mouret-Reynier, Marie-Ange, Hardy-Bessard, Anne-Claire, Simon, Hélène, L'Haridon, Tiffenn, Mege, Alice, Giacchetti, Sylvie, Chakiba-Brugere, Camille, Gratet, Alain, Pottier, Virginie, Ferrero, Jean-Marc, Tennevet, Isabelle, Perrin, Christophe, Canon, Jean-Luc, Joris, Sofie, Shao, Zhimin, Xu, Binghe, Jiang, ZeFei, Sun, Qiang, Shen, Kunwei, Pang, Da, Zhang, Jin, Wang, Shui, Yang, Hongjian, Liao, Ning, Zheng, Hong, Fu, Peifen, Song, Chuangui, Wang, Yongsheng, Fan, Zhimin, Geng, Cuizhi, Tredan, Olivier, Landherr, László, Kaufman, Bella, Yerushalmi, Rinat, Uziely, Beatrice, Conte, Pierfranco, Zamagni, Claudio, Bianchini, Giampaolo, De Laurentiis, Michelino, Tondini, Carlo, Gebbia, Vittorio, Ciccarese, Mariangela, Sarosiek, Tomasz, Mackiewicz, Jacek, Słowińska, Anna, Kalinka, Ewa, Huzarski, Tomasz, Im, Seock-Ah, Jung, Kyung Hae, Sohn, Joo Hyuk, Kim, Jee Hyun, Lee, Keun Seok, Park, Yeon Hee, Lee, Kyoung Eun, Chae, Yee Soo, Cho, Eun Kyung, Geyer, C.E., Jr., Garber, J.E., Gelber, R.D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A.C., Arnedos, M., Balmaña, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S.M., Eisen, A., Elsafy, F., Fein, L.E., Fielding, A., Ford, J.M., Friedman, S., Gelmon, K.A., Gianni, L., Gnant, M., Hollingsworth, S.J., Im, S.-A., Jager, A., Jóhannsson, Ó. Þ, Lakhani, S.R., Janni, W., Linderholm, B., Liu, T.-W., Loman, N., Korde, L., Loibl, S., Lucas, P.C., Marmé, F., Martinez de Dueñas, E., McConnell, R., Phillips, K.-A., Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C.F., Španić, T., Stickeler, E., Toi, M., Traina, T.A., Viale, G., Zoppoli, G., Park, Y.H., Yerushalmi, R., Yang, H., Pang, D., Jung, K.H., Mailliez, A., Fan, Z., Tennevet, I., Zhang, J., Nagy, T., Sonke, G.S., Sun, Q., Parton, M., Colleoni, M.A., Schmidt, M., Brufsky, A.M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., and Tutt, A.N.J.

Published
2022
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3. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Author

Antoniou, AC, Cunningham, AP, Peto, J, Evans, DG, Lalloo, F, Narod, SA, Risch, HA, Eyfjord, JE, Hopper, JL, Southey, MC, Olsson, H, Johannsson, O, Borg, A, Passini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tryggvadottir, L, Syrjakoski, K, Kallioniemi, O-P, Eerola, H, Nevanlinna, H, Pharoah, PDP, and Easton, DF

Subjects
Breast Cancer, Ovarian Cancer, Cancer, Genetics, Genetic Testing, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 2.6 Resources and infrastructure (aetiology), Adult, Age Factors, Aged, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening, Genetic Predisposition to Disease, Humans, Middle Aged, Models, Genetic, Mutation, Neoplasms, Second Primary, Ovarian Neoplasms, BRCA1, BRCA2, cancer risk model, genetic testing, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

Published
2008

4. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Author

Antoniou, AC, Pharoah, PDP, Narod, S, Risch, HA, Eyfjord, JE, Hopper, JL, Olsson, H, Johannsson, O, Borg, A, Pasini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tulinius, H, Thorlacius, S, Eerola, H, Nevanlinna, H, Syrjäkoski, K, Kallioniemi, O-P, Thompson, D, Evans, C, Peto, J, Lalloo, F, Evans, DG, and Easton, DF

Subjects
Breast Cancer, Ovarian Cancer, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Breast Neoplasms, Female, Founder Effect, Genes, BRCA1, Genes, BRCA2, Heterozygote, Humans, Incidence, Jews, Meta-Analysis as Topic, Middle Aged, Mutation, Ovarian Neoplasms, Penetrance, Prevalence, Risk Assessment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Published
2005

6. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author

Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., and Eeles R.A.

Abstract

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHOD(S): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This

Published
2022

7. Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Author

Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., Johannsson, O. Th, Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., and Johannsson, O. Th

Abstract

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistical

Published
2022

9. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study

Author

Bancroft, EK, Page, EC, Brook, MN, Thomas, S, Taylor, N, Pope, J, McHugh, J, Jones, A-B, Karlsson, Q, Merson, S, Ong, KR, Hoffman, J, Huber, C, Maehle, L, Grindedal, EM, Stormorken, A, Evans, DG, Rothwell, J, Lalloo, F, Brady, AF, Bartlett, M, Snape, K, Hanson, H, James, P, McKinley, J, Mascarenhas, L, Syngal, S, Ukaegbu, C, Side, L, Thomas, T, Barwell, J, Teixeira, MR, Izatt, L, Suri, M, Macrae, FA, Poplawski, N, Chen-Shtoyerman, R, Ahmed, M, Musgrave, H, Nicolai, N, Greenhalgh, L, Brewer, C, Pachter, N, Spigelman, AD, Azzabi, A, Helfand, BT, Halliday, D, Buys, S, Cajal, TRY, Donaldson, A, Cooney, KA, Harris, M, McGrath, J, Davidson, R, Taylor, A, Cooke, P, Myhill, K, Hogben, M, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Dias, A, Dudderidge, T, Eccles, DM, Green, K, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lilja, H, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Raghallaigh, HN, Rennert, G, Collier, R, Offman, J, Kote-Jarai, Z, Eeles, RA, Bancroft, EK, Page, EC, Brook, MN, Thomas, S, Taylor, N, Pope, J, McHugh, J, Jones, A-B, Karlsson, Q, Merson, S, Ong, KR, Hoffman, J, Huber, C, Maehle, L, Grindedal, EM, Stormorken, A, Evans, DG, Rothwell, J, Lalloo, F, Brady, AF, Bartlett, M, Snape, K, Hanson, H, James, P, McKinley, J, Mascarenhas, L, Syngal, S, Ukaegbu, C, Side, L, Thomas, T, Barwell, J, Teixeira, MR, Izatt, L, Suri, M, Macrae, FA, Poplawski, N, Chen-Shtoyerman, R, Ahmed, M, Musgrave, H, Nicolai, N, Greenhalgh, L, Brewer, C, Pachter, N, Spigelman, AD, Azzabi, A, Helfand, BT, Halliday, D, Buys, S, Cajal, TRY, Donaldson, A, Cooney, KA, Harris, M, McGrath, J, Davidson, R, Taylor, A, Cooke, P, Myhill, K, Hogben, M, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Dias, A, Dudderidge, T, Eccles, DM, Green, K, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lilja, H, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Raghallaigh, HN, Rennert, G, Collier, R, Offman, J, Kote-Jarai, Z, and Eeles, RA

Abstract

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This s

Published
2021

10. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies

Author

Antoniou, A., Pharoah, P.D.P., Narod, S., Risch, H.A., Eyfjord, J.E., Hopper, J.L., Loman, N., Olsson, H., Johannsson, O., Borg, A., Pasini, B., Radice, P., Manoukian, S., Eccles, D.M., Tang, N., Olah, E., Anton-Culver, H., Warner, E., Lubinski, J., Gronwald, J., Gorski, B., Tulinius, H., Thorlacius, S., Eerola, H., Nevanlinna, H., Syrjakoski, K., Kallioniemi, O.-P., Thompson, D., Evans, C., Peto, J., Lalloo, F., Evans, D.G., and Easton, D.F.

Subjects
Breast cancer -- Genetic aspects, Breast cancer -- Risk factors, Oncogenes -- Research, Ovarian cancer -- Genetic aspects, Ovarian cancer -- Risk factors, Gene mutations -- Research, Biological sciences
Published
2003

11. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, Anita V., Bancroft, Elizabeth K., Barbachano, Yolanda, Page, Elizabeth C., Foster, C. S., Jameson, C., Mitchell, G., Lindeman, G. J., Stapleton, A., Suthers, G., Evans, D. G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P. J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W. S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Ramon y Cajal, T., Spigelman, A., Teo, S. H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Grönberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schröder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y. J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., van Asperen, C., Kiemeney, L., Easton, D. F., and Eeles, Rosalind A.

Published
2011
Full Text
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16. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition (vol 118, pg 266, 2018)

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Published
2018

20. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Author

Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., Schmutzler R.K., Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., and Schmutzler R.K.

Abstract

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective(s): To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at

Published
2019

21. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

Author

Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, Okoth, L, Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, and Okoth, L

Abstract

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support t

Published
2019

22. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers

Author

Page, EC, Bancroft, EK, Brook, MN, Assel, M, Al Battat, MH, Thomas, S, Taylor, N, Chamberlain, A, Pope, J, Ni Raghallaigh, H, Evans, DG, Rothwell, J, Maehle, L, Grindedal, EM, James, P, Mascarenhas, L, McKinley, J, Side, L, Thomas, T, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Jensen, TD, Osther, PJS, Helfand, BT, Genova, E, Oldenburg, RA, Cybulski, C, Wokolorczyk, D, Ong, K-R, Huber, C, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oosterwijk, JC, van Zelst-Stams, W, Cook, J, Rosario, DJ, Domchek, S, Powers, J, Buys, S, O'Toole, K, Ausems, MGEM, Schmutzler, RK, Rhiem, K, Izatt, L, Tripathi, V, Teixeira, MR, Cardoso, M, Foulkes, WD, Aprikian, A, van Randeraad, H, Davidson, R, Longmuir, M, Ruijs, MWG, Helderman van den Enden, ATJM, Adank, M, Williams, R, Andrews, L, Murphy, DG, Halliday, D, Walker, L, Liljegren, A, Carlsson, S, Azzabi, A, Jobson, I, Morton, C, Shackleton, K, Snape, K, Hanson, H, Harris, M, Tischkowitz, M, Taylor, A, Kirk, J, Susman, R, Chen-Shtoyerman, R, Spigelman, A, Pachter, N, Ahmed, M, Ramon y Cajal, T, Zgajnar, J, Brewer, C, Gadea, N, Brady, AF, van Os, T, Gallagher, D, Johannsson, O, Donaldson, A, Barwell, J, Nicolai, N, Friedman, E, Obeid, E, Greenhalgh, L, Murthy, V, Copakova, L, Saya, S, McGrath, J, Cooke, P, Ronlund, K, Richardson, K, Henderson, A, Teo, SH, Arun, B, Kast, K, Dias, A, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Eccles, DM, Tricker, K, Eyfjord, J, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Stefansdottir, V, Khoo, V, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Dudderidge, T, Offman, J, Kote-Jarai, Z, Vickers, A, Lilja, H, Eeles, RA, Page, EC, Bancroft, EK, Brook, MN, Assel, M, Al Battat, MH, Thomas, S, Taylor, N, Chamberlain, A, Pope, J, Ni Raghallaigh, H, Evans, DG, Rothwell, J, Maehle, L, Grindedal, EM, James, P, Mascarenhas, L, McKinley, J, Side, L, Thomas, T, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Jensen, TD, Osther, PJS, Helfand, BT, Genova, E, Oldenburg, RA, Cybulski, C, Wokolorczyk, D, Ong, K-R, Huber, C, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oosterwijk, JC, van Zelst-Stams, W, Cook, J, Rosario, DJ, Domchek, S, Powers, J, Buys, S, O'Toole, K, Ausems, MGEM, Schmutzler, RK, Rhiem, K, Izatt, L, Tripathi, V, Teixeira, MR, Cardoso, M, Foulkes, WD, Aprikian, A, van Randeraad, H, Davidson, R, Longmuir, M, Ruijs, MWG, Helderman van den Enden, ATJM, Adank, M, Williams, R, Andrews, L, Murphy, DG, Halliday, D, Walker, L, Liljegren, A, Carlsson, S, Azzabi, A, Jobson, I, Morton, C, Shackleton, K, Snape, K, Hanson, H, Harris, M, Tischkowitz, M, Taylor, A, Kirk, J, Susman, R, Chen-Shtoyerman, R, Spigelman, A, Pachter, N, Ahmed, M, Ramon y Cajal, T, Zgajnar, J, Brewer, C, Gadea, N, Brady, AF, van Os, T, Gallagher, D, Johannsson, O, Donaldson, A, Barwell, J, Nicolai, N, Friedman, E, Obeid, E, Greenhalgh, L, Murthy, V, Copakova, L, Saya, S, McGrath, J, Cooke, P, Ronlund, K, Richardson, K, Henderson, A, Teo, SH, Arun, B, Kast, K, Dias, A, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Eccles, DM, Tricker, K, Eyfjord, J, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Stefansdottir, V, Khoo, V, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Dudderidge, T, Offman, J, Kote-Jarai, Z, Vickers, A, Lilja, H, and Eeles, RA

Abstract

BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at

Published
2019

23. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Subjects
predictive model, prostate cancer, BRCA1, urologic and male genital diseases, genetic predisposition, BRCA2, PSA velocity
Abstract

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Results: 1634 participants had >= 3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml(-1), PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P = 0.031) and BRCA2 status and PSAV (P = 0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

24. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author

Lecarpentier, J., Kuchenbaecker, K. B., Barrowdale, D., Dennis, J., Mcguffog, L., Leslie, G., Lee, A., Al Olama, A. A., Tyrer, J. P., Frost, D., Ellis, S., Easton, D. F., Antoniou, A. C., Tischkowitz, M., Evans, D. G., Henderson, A., Brewer, C., Eccles, D., Cook, J., Ong, K. -R., Walker, L., Side, L. E., Hodgson, S., Izatt, L., Eeles, R., Orr, N., Porteous, M. E., Davidson, R., Adlard, J., Silvestri, V., Rizzolo, P., Navazio, A. S., Valentini, V., Zelli, V., Ottini, L., Toss, A., Medici, V., Cortesi, L., Zanna, I., Palli, D., Radice, P., Manoukian, S., Peissel, B., Azzollini, J., Peterlongo, P., Viel, A., Cini, G., Damante, G., Tommasi, S., Alducci, E., Tognazzo, S., Montagna, M., Caligo, M. A., Soucy, P., Simard, J., Mulligan, A. M., Andrulis, I. L., Glendon, G., Southey, M., Campbell, I., James, P., Mitchell, G., Spurdle, A. B., Holland, H., Chenevix-Trench, G., John, E. M., Steele, L., Ding, Y. C., Neuhausen, S. L., Weitzel, J. N., Conner, T. A., Buys, S. S., Goldgar, D. E., Godwin, A. K., Sharma, P., Rebbeck, T. R., Vijai, J., Robson, M., Lincoln, A., Musinsky, J., Gaddam, P., Offit, K., Loud, J. T., Greene, M. H., Toland, A. E., Senter, L., Huo, D., Nielsen, S. M., Olopade, O. I., Nathanson, K. L., Domchek, S. M., Lorenchick, C., Jankowitz, R. C., Couch, F. J., Janavicius, R., Hansen, T. V. O., Bojesen, A., Nielsen, H. R., Skytte, A. -B., Sunde, L., Jensen, U. B., Pedersen, I. S., Krogh, L., Kruse, T. A., Thomassen, M., Osorio, A., De La Hoya, M., Garcia-Barberan, V., Caldes, T., Segura, P. P., Balmana, J., Gutierrez-Enriquez, S., Diez, O., Teule, A., Del Valle, J., Feliubadalo, L., Pujana, M. A., Lazaro, C., Izquierdo, A., Darder, E., Brunet, J., Fostira, F., Hamann, U., Sutter, C., Meindl, A., Ditsch, N., Gehrig, A., Dworniczak, B., Engel, C., Wand, D., Niederacher, D., Steinemann, D., Hahnen, E., Hauke, J., Rhiem, K., Wappenschmidt, B., Schmutzler, R. K., Kast, K., Arnold, N., Wang-Gohrke, S., Lasset, C., Damiola, F., Barjhoux, L., Mazoyer, S., Stoppa-Lyonnet, D., Belotti, M., Van Heetvelde, M., Poppe, B., De Leeneer, K., Claes, K. B. M., Kiiski, J. I., Khan, S., Nevanlinna, H., Aittomaki, K., Vvan Asperen, C. J., Vaszko, T., Kasler, M., Olah, E., Arason, A., Agnarsson, B. A., Johannsson, O. Th., Barkardottir, R. B., Teixeira, M. R., Pinto, P., Lee, J. W., Lee, M. H., Lee, J., Kim, S. -W., Kang, E., Park, S. K., Kim, Z., Tan, Y. Y., Berger, A., Singer, C. F., Yoon, S. -Y., Teo, S. -H., Von Wachenfeldt, A., Italian Association for Cancer Research, Ministère de Économie, Innovation et Exportation (Canadá), Canadian Institutes of Health Research, United States of Department of Health & Human Services, Cancer Research UK (Reino Unido), National Cancer Center. National R&D Program for Cancer Control (República de Corea), German Cancer Aid, Fondation ARC pour la recherche sur le cancer, Lietuvos Mokslo Taryba (Lituania), Asociación Española Contra el Cáncer, Fundación Mutua Madrileña, University of Kansas. Cancer Center (Estados Unidos), Ministerio de Economía y Competitividad (España), Finlands Akademi (Finlandia), Instituto de Salud Carlos III, Dutch Research Council (Holanda), Pink Ribbons Project, Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Transcan grant, Government of Catalonia (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministry of Health and Welfare (Corea del Sur), Ministry of Science, Technology and Innovation (Malasia), Victorian Cancer Agency, and Ministry of Higher Education (Malasia)

Subjects
Adult, Male, Cancer Research, Heterozygote, Multifactorial Inheritance, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Male, Age Factors, Aged, Aged, 80 and over, Case-Control Studies, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Humans, Middle Aged, Prostatic Neoplasms, Mutation, Oncology, 80 and over, Polymorphism, skin and connective tissue diseases, Single Nucleotide, BRCA1, BRCA2, Genes
Abstract

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management. We thank Sue Healey for her contribution to CIMBA, in particular, for taking on the task of mutation classification with Olga Sinilnikova. BCFR Australia: We acknowledge Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR Ontario: We thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section): We acknowledge Vilius Rudaitis and Laimonas Griˇskeviˇcius. CBCS (Copenhagen Breast Cancer Study, Rigshospitalet): We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants. CNIO (Spanish National Cancer Centre): We thank Alicia Barroso, Rosario Alonso, and Guillermo Pita for their assistance. COH-CCGCRN (City of Hope Clinical Cancer Genomics Community Research Network): Patients were recruited for study from the City of Hope Clinical Cancer Genomics Community Research Network. CONSIT TEAM:We acknowledge Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy; Brunella Pilato of the Istituto Nazionale Tumori “Giovanni Paolo II”, Bari, Italy; and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FCCC (Fox Chase Cancer Center):We thank Jo EllenWeaver and Betsy Bove, MD, for their technical support. GEMO (GeneticModifiers of cancer risk in BRCA1/2 mutation carriers):We pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet, initiated and coordinated GEMO until she died on June 30, 2014, and we thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unit´e Mixte de G´en´etique Constitutionnelle des Cancers Fr´equents, Hospices Civils de Lyon–Centre L´eon B´erard, Equipe G´en´etique du cancer du sein, Centre de Rechercheen Canc´erologie de Lyon: Olga Sinilnikova (deceased), Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, M´elanie L´eone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de G´en´etique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agn`es Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot; Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud- Bataille; Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer; Centre L´eon B´erard, Lyon: Christine Lasset, Val´erie Bonadona, Sandrine Handallou; Centre François Baclesse, Caen: Agn`es Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera; Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger; CHUArnaud-de-Villeneuve,Montpellier: Isabelle Coupier, Pascal Pujol; Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Jo¨elle Fournier, Françoise R´evillion, Philippe Vennin (deceased), Claude Adenis; Centre Paul Strauss, Strasbourg: Dani`ele Muller, Jean-Pierre Fricker; Institut Bergoni´e, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy; Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel; CHU Grenoble: Dominique Leroux, H´el`ene Dreyfus, Christine Rebischung, Magalie Peysselon; CHU Dijon: Fanny Coron, Laurence Faivre; CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz; HˆotelDieu Centre Hospitalier, Chamb´ery: Sandra Fert Ferrer; Centre Antoine Lacassagne, Nice: Marc Fr´enay; CHU Limoges: Laurence V´enat-Bouvet; CHU Nantes: Capucine Delnatte; CHU Bretonneau, Tours: Isabelle Mortemousque; Groupe Hospitalier Piti´e-Salp´etri`ere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, MathildeWarcoin; CHU Vandoeuvre-les- Nancy: Johanna Sokolowska, Myriam Bronner; CHU Besançon: Marie-Agn`es Collonge-Rame, Alexandre Damette; Creighton University, Omaha, NE: Henry T. Lynch, Carrie L. Snyder. G-FAST (Ghent University Hospital): B.P. is a senior clinical investigator of FWO. We acknowledge the technical support of Ilse Coeneen Brecht Crombez. HCSC (Hospital Clinico San Carlos): We acknowledge Alicia Tosar and Paula Diaque for their technical assistance. HEBCS (Helsinki Breast Cancer Study):We thank Taru A. Muranen, Carl Blomqvist, MD, Kirsimari Aaltonen, MD, Irja Erkkil¨a, RN, and Virpi Palola, RN, for their help with the HEBCS data and samples. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON consists of the following collaborating centers: Coordinating center: Netherlands Cancer Institute, Amsterdam: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center: J.M. Coll´ee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University NijmegenMedical Center: C.M. Kets, A.R.Mensenkamp; UniversityMedical Center Utrecht: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center: C.M. Aalfs, T.A.M. van Os; Vrije Universiteit Medical Center: J.J.P. Gille, Q.Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht: E.B. G´omez-Garcia, M.J. Blok; University Medical Center Groningen: J.C. Oosterwijk, A.H. van der Hout, M.J.Mourits, G.H. de Bock; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J. Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HUNBOCS (Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary):We thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. HVH (University Hospital Vall d’Hebron): We thank the Cellex Foundation for providing research facilities and equipment. ICO (Institut Catal`a d’Oncologia): We thank the ICO Hereditary Cancer Program team led by Gabriel Capella, MD. INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility):We thank Martine Dumont, MD, Martine Tranchant and St´ephane Dubois for QC, sample management and skillful assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS and Oncoarray (BCAC and CIMBA). IPOBCS (Portuguese Oncology Institute-Porto jco.org © 2017 by American Society of Clinical Oncology Polygenic Risk Scores in Male BRCA1 and BRCA2 Mutation Carriers Downloaded from ascopubs.org by CNIO-FUND on September 27, 2019 from 193.147.150.201 Copyright © 2019 American Society of Clinical Oncology. All rights reserved. Breast Cancer Study): We thank Catarina Santos, MD, for her skillful contribution to the study. kConFab (Kathleen Cuningham Consortium for Research into Familial Breast Cancer): We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab.Memorial Sloan Kettering Cancer Center:We acknowledge Lauren Jacobs, MD. OCGN (Ontario Cancer Genetics Network): We thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSUCCG (The Ohio State University Comprehensive Cancer Center): Kevin Sweet, Caroline Craven, Julia Cooper, Leigha Senter, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records, and database management. SEABASS (South East Asian Breast Cancer Association Study): We thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively. SWE-BRCA (Swedish Breast Cancer Study): Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: A° ke Borg, H°akan Olsson, Helena Jernstr¨om, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna O¨ fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna vonWachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume°a University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstr¨om Pigg, Richard Rosenquist; from Link¨oping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. University of Chicago: O.I.O. is an ACS Clinical Research Professor. We thank Cecilia Zvocec, Qun Niu, physicians, genetic counsellors, research nurses, and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. VFCTG (Victorian Familial Cancer Trials Group):We acknowledge Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group.We thank Sarah Sawyer and Rebecca Driessen for assembling these data and Ella Thompson for performing all DNA amplification. © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Sí

Published
2017

27. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Author

Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., Boshari T., Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., and Boshari T.

Abstract

Background:Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Method(s):PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Result(s):1634 participants had 3/43 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml -l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusion(s):PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

28. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition (vol 118, pg 266, 2018)

Author

Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, MGEM, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van den Enden, ATJM, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA, Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, S-H, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, Eeles, RA, Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, MGEM, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van den Enden, ATJM, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA, Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, S-H, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, and Eeles, RA

Abstract

This corrects the article DOI: 10.1038/bjc.2017.429.

Published
2018

29. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J (Jan), Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, Rogier, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, M, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van d Enden, A, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA (Muriel), Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, Van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, SH, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C.H., Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS (Christopher), Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, Eeles, RA, Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J (Jan), Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, Rogier, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, M, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van d Enden, A, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA (Muriel), Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, Van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, SH, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C.H., Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS (Christopher), Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, and Eeles, RA

Published
2018

31. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

Author

Bancroft, EK, Page, EC, Castro, E, Lilja, H, Vickers, A, Sjoberg, D, Assel, M, Foster, CS, Mitchell, G, Drew, K, Maehle, L, Axcrona, K, Evans, DG, Bulman, B, Eccles, D, McBride, D, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Selkirk, C, Hulick, PJ, Bojesen, A, Skytte, AB, Lam, J, Taylor, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Blanco, I, Salinas, M, Cook, J, Rosario, DJ, Buys, S, Conner, T, Ausems, MG, Ong, KR, Hoffman, J, Domchek, S, Powers, J, Teixeira, MR, Maia, S, Foulkes, WD, Taherian, N, Ruijs, M, Helderman-van den Enden, AT, Izatt, L, Davidson, R, Adank, MA, Walker, L, Schmutzler, R, Tucker, K, Kirk, J, Hodgson, S, Harris, M, Douglas, F, Lindeman, GJ, Zgajnar, J, Tischkowitz, M, Clowes, VE, Susman, R, Cajal, TRY, Patcher, N, Gadea, N, Spigelman, A, van Os, T, Liljegren, A, Side, L, Brewer, C, Brady, AF, Donaldson, A, Stefansdottir, V, Friedman, E, Chen-Shtoyerman, R, Amor, DJ, Copakova, L, Barwell, J, Giri, VN, Murthy, V, Nicolai, N, Teo, SH, Greenhalgh, L, Strom, S, Henderson, A, McGrath, J, Gallagher, D, Aaronson, N, Ardern-Jones, A, Bangma, C, Dearnaley, D, Costello, P, Eyfjord, J, Rothwell, J, Falconer, A, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Kote-Jarai, Z, Lubinski, J, Axcrona, U, Melia, J, McKinley, J, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Killick, E, Moss, S, Eeles, RA, Taylor, N, Pope, J, Saya, S, Martin, S, Keating, D, Petelin, L, Murphy, M, Doherty, R, Pratt, S, Murphy, D, Cleeve, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Bowman, M, Patel, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Shackleton, K, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Gleeson, M, Scott, R, Burke, J, Patterson, B, Bacic, S, Swindle, P, Aprikian, A, Bojeson, A, Cruger, D, Osther, P, Gerdes, AM, Rhiem, K, Luedtke-Heckenkamp, K, Ochsendorf, N, Fiddike, K, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Bambury, R, Farrell, M, Gallagher, F, Ben-Yehoshua, SJ, Nissani, R, Appelman, Z, Moriel, E, Radice, P, Valdagni, R, Magnani, T, Meng, TH, Yoon, SY, Thong, MK, Kiemeney, B, Van der Luijt, RB, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Joao, PS, Nogueira, P, Krajc, M, Vrecar, A, Capella, G, Fisas, D, Balmana, J, Morote, J, Hjalm-Eriksson, M, Ekdahl, KJ, Carlsson, S, Hanson, H, Shanley, S, Goh, C, Wiggins, J, Kohut, K, Van As, N, Thompson, A, Ogden, C, Borley, N, Woodhouse, C, Kumar, P, Mercer, C, Paterson, J, Taylor, A, Newcombe, B, Halliday, D, Stayner, B, Fleming-Brown, D, Brice, G, Homfray, T, Hammond, C, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Jobson, I, Paez, E, Tomkins, S, Pichert, G, Jacobs, C, Langman, C, Weston, M, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Male, A, Simon, K, Rees, K, Compton, C, Tidey, L, Nevitt, L, Ingram, S, Catto, J, Howson, J, Chapman, C, Cole, T, Heaton, T, Burgess, L, Longmuir, M, Watt, C, Duncan, A, Kockelbergh, R, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Roberts, G, Woodward, A, Sutton, V, Cornford, P, Treherne, K, Griffiths, J, Cogley, L, Rubinstein, W, Brendler, C, Helfand, B, McGuire, M, Kaul, K, Shevrin, D, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Goldgar, D, Venne, V, Stephenson, R, Dechet, C, Arun, B, Davis, JW, Yamamura, Y, and Gross, L

Subjects
Prostate cancer, BRCA1, BRCA2, Prostate-specific antigen, Targeted screening
Abstract

Background: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective: To report the first year's screening results for all men at enrolment in the study. Design, setting and participants: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA > 3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA > 3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate-or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate-or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. Patient summary: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment. (C) 2014 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Published
2014

32. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author

Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Scott, R.J., McGuffog, L., Healy, S., Sinilnikova, O.M., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Paligo, M., Aretini, P., Kantala, J., Aroer, B., Wachenfeldt, A. von, Liljegren, A., Loman, N., Herbst, K., Kristoffersson, U., Rosenquist, R., Karlsson, P., Stenmark-Askmalm, M., Melin, B., Nathanson, K.L., Domchek, S.M., Byrski, T., Huzarski, T., Gronwald, J., Menkiszak, J., Cybulski, C., Serrano, P., Osorio, A., Cajal, T.R., Tsitlaidou, M., Benitez, J., Gilbert, M., Rookus, M., Aalfs, C.M., Kluijt, I., Boessenkool-Pape, J.L., Meijers-Heijboer, H.E.J., Oosterwijk, J.C., Asperen, C.J. van, Blok, M.J., Nelen, M.R., Ouweland, A.M.W. van den, Seynaeve, C., Luijt, R.B. van der, Devilee, P., Easton, D.F., Peock, S., Frost, D., Platte, R., Ellis, S.D., Fineberg, E., Evans, D.G., Lalloo, F., Eeles, R., Jacobs, C., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Godwin, A., Bove, B., Stoppa-Lyonnet, D., Caux-Moncoutier, V., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Boutry-Kryza, N., Pujol, P., Coupier, I., Peyrat, J.P., Vennin, P., Muller, D., Fricker, J.P., Venat-Bouvet, L., Johannsson, O., Isaacs, C., Schmutzler, R., Wappenschmidt, B., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Preisler-Adams, S., Simard, J., Soucy, P., Durocher, F., Chenevix-Trench, G., Beesley, J., Chen, X., Rebbeck, T., Couch, F., Wang, X., Lindor, N., Fredericksen, Z., Pankratz, V.S., Peterlongo, P., Bonanni, B., Fortuzzi, S., Peissel, B., Szabo, C., Mai, P.L., Loud, J.T., Lubinski, J., OCGN, SWE BRCA, HEBON, EMBRACE, GEMO Study Collaborators, KConFab, CIMBA, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Medical Oncology, IHS, Human genetics, and CCA - Oncogenesis

Subjects
Oncology, Cancer Research, endocrine system diseases, BRCA1/2 mutation carriers, METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR, Genes, BRCA2, Genes, BRCA1, DCN PAC - Perception action and control, SUSCEPTIBILITY, medicine.disease_cause, Bioinformatics, T+polymorphism%22">PHB 1630 C>T polymorphism, 0302 clinical medicine, PROHIBITIN 3'-UNTRANSLATED REGION, Genotype, Prohibitin, skin and connective tissue diseases, breast/ovarian cancer risk, Ovarian Neoplasms, 0303 health sciences, FOLATE STATUS, CARCINOGENESIS, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Female, +T+polymorphism%22">PHB 1630 C > T polymorphism, CHROMOSOME-17, Risk, EXPRESSION, medicine.medical_specialty, Heterozygote, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, +T+polymorphism%22">MTHFR 677 C > T polymorphism, Biology, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Internal medicine, Prohibitins, medicine, Humans, Genetic Predisposition to Disease, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, Polymorphism, Genetic, Hereditary cancer and cancer-related syndromes [ONCOL 1], Biology and Life Sciences, Genetics and Genomics, medicine.disease, GENE, Minor allele frequency, Repressor Proteins, COMMON MUTATION, T+polymorphism%22">MTHFR 677 C>T polymorphism, Methylenetetrahydrofolate reductase, Mutation, biology.protein, RNA, Carcinogenesis, Ovarian cancer
Abstract

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK

Published
2012
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33. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

Author

Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A.-M., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Stenmark Askmalm, M., Barbany Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. M. W., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. J. J. P., Peock, S., Frost, D., Evans, D. G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M.-A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M. B., Singer, C. F., Dressler, A.-C., Tea, M.-K., Hansen, T. V. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., Dumont, M., Greene, M., Glendon, G., Selander, T., Weerasooriya, N., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark-Askmalm, M., Liedgren, S., Loman, N., Olsson, H., Kristoffersson, U., Soller, M., Jernstrom, H., Harbst, K., Henriksson, K., Lindblom, A., Arver, B., von Wachenfeldt, A., Liljegren, A., Barbany-Bustinza, G., Rantala, J., Melin, B., Gronberg, H., Stattin, E.-L., Emanuelsson, M., Ehrencrona, H., Torres, D., Rashid, M. U., Seidel-Renkert, A., Hogervorst, F. B. L., Verhoef, S., Verheus, M., van't Veer, L. J., van Leeuwen, F. E., Collee, M., Jager, A., Hooning, M. J., Tilanus-Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., van der Luijt, R. B., van Os, T. A., Gille, J. J. P., Waisfisz, Q., Meijers-Heijboer, H. E. J., Gomez-Garcia, E. B., van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., van der Hout, A. H., Mourits, M. J., Vasen, H. F., Cook, M., Platte, R., Miedzybrodzka, Z., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Ong, K.-r., Hoffman, J., Donaldson, A., James, M., Downing, S., Taylor, A., Murray, A., Rogers, M. T., McCann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Davidson, R., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Lalloo, F., Taylor, J., Side, L., Male, A., Berlin, C., Collier, R., Douglas, F., Claber, O., Jobson, I., Walker, L., McLeod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern-Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Cook, J., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Eccles, D., Lucassen, A., Crawford, G., McBride, D., Smalley, S., Sinilnikova, O., Leone, M., Buecher, B., Houdayer, C., Belotti, M., Tirapo, C., de Pauw, A., Bressac-de-Paillerets, B., Remenieras, A., Byrde, V., Lenoir, G., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Bourdon, V., Noguchi, T., Coulet, F., Colas, C., Soubrier, F., Coupier, I., Pujol, P., Peyrat, J.-P., Fournier, J., Revillion, F., Vennin, P., Adenis, C., Rouleau, E., Lidereau, R., Demange, L., Nogues, C., Muller, D., Fricker, J.-P., Longy, M., Sevenet, N., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Leroux, D., Dreyfus, H., Rebischung, C., Coron, F., Faivre, L., Prieur, F., Lebrun, M., Ferrer, S. F., Frenay, M., Venat-Bouvet, L., Mortemousque, I., Lynch, H. T., Snyder, C. L., Ejlertsen, B., Andersen, M. K., Kjaergaard, S., Senter, L., Sweet, K., O'Connor, M., Craven, C., Pharoah, P., Ramus, S., Pye, C., Harrington, P., Wozniak, E., Varon-Mateeva, R., Kast, K., Preisler-Adams, S., Deissler, H., Schonbuchner, I., Heinritz, W., Schafer, D., Aittomaki, K., Blomqvist, C., Heikkinen, T., Erkkila, R. N. I., Thorne, H., Niedermayr, E., de la Hoya, M., Perez-Segura, P., Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Department of Pediatrics, CHU Sainte Justine [Montréal], Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Queensland Institute of Medical Research, University of Delaware [Newark], Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Clinical Genetics, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Department of Oncology, Sahlgrenska University Hospital [Gothenburg], Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Addenbrookes Hospital, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, génétique, Institut Curie [Paris], Service de Génétique Oncologique, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Consultation d'Oncogénétique, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre René Gauducheau, CRLCC René Gauducheau, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Internal Medicine, Huntsman Cancer Institute, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Faculty of Medicine, University of Iceland [Reykjavik], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Lombardi Comprehensive Cancer Center, Georgetown University, Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Heidelberg University Hospital [Heidelberg], Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Universität Regensburg (UR), Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 6, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Research Centre, CHU Ste Justine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Human Genetics, Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Tel Aviv University (TAU), University of Pennsylvania-University of Pennsylvania, Universiteit Leiden-Universiteit Leiden, Nottingham University Hospitals NHS Trust (NUH), Roswell Park Cancer Institute [Buffalo] (RPCI), Georgetown University [Washington] (GU), Universität Leipzig, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Génétique moléculaire, signalisation et cancer ( GMSC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Cambridge [UK] ( CAM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), Sahlgrenska University Hospital, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Deutsches Krebsforschungszentrum ( DKFZ ), INSTITUT CURIE, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre François Baclesse, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Mount Sinai Hospital ( MSH ), Medical University of Vienna-Department of OB/GYN, Medical University of Vienna, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximilians-Universität München, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Hannover Medical School [Hannover] ( MHH ), University Regensburg, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Human genetics, and CCA - Oncogenesis

Subjects
endocrine system diseases, Electrophoretic Mobility Shift Assay, MESH : Breast Neoplasms, medicine.disease_cause, Linkage Disequilibrium, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Genes, Reporter, Risk Factors, MESH: Risk Factors, Genotype, MESH : Female, Luciferases, skin and connective tissue diseases, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, Genetics, 0303 health sciences, MESH : Linkage Disequilibrium, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Genes, Reporter, MESH : Risk Factors, 3. Good health, MESH: Linkage Disequilibrium, 030220 oncology & carcinogenesis, MESH : Electrophoretic Mobility Shift Assay, Female, Breast disease, MESH : Mutation, MESH : Heterozygote, Heterozygote, MESH: Mutation, Single-nucleotide polymorphism, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, medicine, Humans, MESH : BRCA1 Protein, MESH : HeLa Cells, Genetic Predisposition to Disease, ddc:610, Allele, Molecular Biology, MESH : Haplotypes, Alleles, Genetic Association Studies, 030304 developmental biology, MESH: BRCA1 Protein, MESH : Luciferases, MESH: Humans, Hereditary cancer and cancer-related syndromes [ONCOL 1], MESH: Alleles, Haplotype, MESH : Humans, MESH: Genes, Reporter, Cancer, MESH : Genetic Association Studies, MESH: Haplotypes, medicine.disease, Haplotypes, Mutation, MESH: Electrophoretic Mobility Shift Assay, MESH: HeLa Cells, Cancer research, MESH : Genetic Predisposition to Disease, MESH: Luciferases, Carcinogenesis, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms, HeLa Cells
Abstract

Item does not contain fulltext Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Published
2011
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34. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, A.V., Bancroft, E.K., Barbachano, Y., Page, E.C., Foster, C.S., Jameson, C., Mitchell, G., Lindeman, G.J., Stapleton, A., Suthers, G., Evans, D.G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P.J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W.S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Cajal, T.R.Y., Spigelman, A., Teo, S.H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Gronberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schroder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y.J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., Asperen, C. van, Kiemeney, L., Easton, D.F., Eeles, R.A., and IMPACT Study Collaborators

Subjects
prostate cancer BRCA1 BRCA2 PSA genetic predisposition high-risk families jewish men antigen carriers erspc population history trial ng/ml 1st, skin and connective tissue diseases
Abstract

What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Published
2011

35. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Author

Osorio, A, Milne, R L, Pita, G, Peterlongo, P, Heikkinen, T, Simard, J, Chenevix-Trench, G, Spurdle, A B, Beesley, J, Chen, X, Healey, S, Group, KConFab, Neuhausen, S L, Ding, Y C, Couch, F J, Wang, X, Lindor, N, Manoukian, S, Barile, M, Viel, A, Tizzoni, L, Szabo, C I, Foretova, L, Zikan, M, Claes, K, Greene, M H, Mai, P, Rennert, G, Lejbkowicz, F, Barnett-Griness, O, Andrulis, I L, Ozcelik, H, Weerasooriya, N, Group, OCGN, Gerdes, A-M, Thomassen, M, Cruger, D G, Caligo, M A, Friedman, E, Kaufman, B, Laitman, Y, Cohen, S., Kontorovich, T, Gershoni-Baruch, R, Dagan, E, Jernström, H, Askmalm, M S, Arver, B, Malmer, B, Group, SWE-BRCA, Domchek, S M, Nathanson, K L, Brunet, J, Ramón Y Cajal, T, Yannoukakos, D, Hamann, U, Group, HEBON, Hogervorst, F B L, Verhoef, S, García, Eb Gómez, Wijnen, J T, van den Ouweland, A, Group, EMBRACE, Easton, D F, Peock, S, Cook, M, Oliver, C T, Frost, D, Luccarini, C, Evans, D G, Lalloo, F, Eeles, R, Pichert, G, Cook, J, Hodgson, S, Morrison, P J, Douglas, F, Godwin, A K, Group, GEMO, Sinilnikova, O M, Barjhoux, L, Moncoutier, V, Giraud, S, Cassini, C, Olivier-Faivre, L, Révillion, F, Peyrat, J-P, Muller, D, Fricker, J-P, Lynch, H T, John, E M, Buys, S, Daly, M, Hopper, J L, Terry, M B, Miron, A, Yassin, Y, Goldgar, D, Family Registry, Breast Cancer, Singer, C F, Gschwantler-Kaulich, D, Pfeiler, G, Spiess, A-C, Hansen, Thomas V O, Johannsson, O T, Kirchhoff, T, Offit, K, Kosarin, K, Piedmonte, M, Rodriguez, G C, Wakeley, K, Boggess, J F, Basil, J, Blank, S V, Toland, A E, Montagna, M, Casella, C, Imyanitov, E N, Allavena, A, Schmutzler, R K, Versmold, B, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Niederacher, D, Deißler, H, Fiebig, B, Varon-Mateeva, R, Schaefer, D, Froster, U G, Caldes, T, de la Hoya, M, McGuffog, L, Antoniou, A C, Nevanlinna, H, Radice, P, Benítez, J, and Human Genetics

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Heterozygote, Medicin och hälsovetenskap, endocrine system diseases, Population, Genes, BRCA2, Genes, BRCA1, Single-nucleotide polymorphism, Biology, BRCA1, BRCA2, ERCC4, breast cancer, Polymorphism, Single Nucleotide, Medical and Health Sciences, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, SNP, Humans, education, skin and connective tissue diseases, 030304 developmental biology, Retrospective Studies, 0303 health sciences, education.field_of_study, Cancer, Retrospective cohort study, Genetics and Genomics, medicine.disease, 3. Good health, DNA-Binding Proteins, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Breast disease
Abstract

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. British Journal of Cancer (2009) 101, 2048-2054. doi: 10.1038/sj.bjc.6605416 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK

Published
2009
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36. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.

Author

Domchek S., Blanco I., Salinas M., Cook J., Rosario D.J., Buys S., Conner T., Ausems M.G., Ong K.-R., Hoffman J., Powers J., Teixeira M.R., Maia S., Foulkes W.D., Taherian N., Ruijs M., Den Enden A.T.H.-V., Izatt L., Davidson R., Adank M.A., Walker L., Schmutzler R., Tucker K., Kirk J., Hodgson S., Harris M., Douglas F., Lindeman G.J., Zgajnar J., Tischkowitz M., Clowes V.E., Susman R., Ramon Y Cajal T., Patcher N., Gadea N., Spigelman A., Van Os T., Liljegren A., Side L., Brewer C., Brady A.F., Donaldson A., Stefansdottir V., Friedman E., Chen-Shtoyerman R., Amor D.J., Copakova L., Barwell J., Giri V.N., Murthy V., Nicolai N., Teo S.-H., Greenhalgh L., Strom S., Henderson A., McGrath J., Gallagher D., Aaronson N., Ardern-Jones A., Bangma C., Dearnaley D., Costello P., Eyfjord J., Rothwell J., Falconer A., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Kote-Jarai Z., Lubinski J., Axcrona U., Melia J., McKinley J., Mitra A.V., Moynihan C., Rennert G., Suri M., Wilson P., Killick E., Moss S., Eeles R.A., Bancroft E.K., Page E.C., Castro E., Lilja H., Vickers A., Sjoberg D., Assel M., Foster C.S., Mitchell G., Drew K., Maehle L., Axcrona K., Evans D.G., Bulman B., Eccles D., McBride D., Van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Selkirk C., Hulick P.J., Bojesen A., Skytte A.-B., Lam J., Taylor L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Domchek S., Blanco I., Salinas M., Cook J., Rosario D.J., Buys S., Conner T., Ausems M.G., Ong K.-R., Hoffman J., Powers J., Teixeira M.R., Maia S., Foulkes W.D., Taherian N., Ruijs M., Den Enden A.T.H.-V., Izatt L., Davidson R., Adank M.A., Walker L., Schmutzler R., Tucker K., Kirk J., Hodgson S., Harris M., Douglas F., Lindeman G.J., Zgajnar J., Tischkowitz M., Clowes V.E., Susman R., Ramon Y Cajal T., Patcher N., Gadea N., Spigelman A., Van Os T., Liljegren A., Side L., Brewer C., Brady A.F., Donaldson A., Stefansdottir V., Friedman E., Chen-Shtoyerman R., Amor D.J., Copakova L., Barwell J., Giri V.N., Murthy V., Nicolai N., Teo S.-H., Greenhalgh L., Strom S., Henderson A., McGrath J., Gallagher D., Aaronson N., Ardern-Jones A., Bangma C., Dearnaley D., Costello P., Eyfjord J., Rothwell J., Falconer A., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Kote-Jarai Z., Lubinski J., Axcrona U., Melia J., McKinley J., Mitra A.V., Moynihan C., Rennert G., Suri M., Wilson P., Killick E., Moss S., Eeles R.A., Bancroft E.K., Page E.C., Castro E., Lilja H., Vickers A., Sjoberg D., Assel M., Foster C.S., Mitchell G., Drew K., Maehle L., Axcrona K., Evans D.G., Bulman B., Eccles D., McBride D., Van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Selkirk C., Hulick P.J., Bojesen A., Skytte A.-B., Lam J., Taylor L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., and Oosterwijk J.C.

Abstract

Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48% - double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful for

Published
2014

37. Air breathing in Magadi tilapiaAlcolapia grahami, under normoxic and hyperoxic conditions, and the association with sunlight and reactive oxygen species

Author

Johannsson, O. E., primary, Bergman, H. L., additional, Wood, C. M., additional, Laurent, P., additional, Kavembe, D. G., additional, Bianchini, A., additional, Maina, J. N., additional, Chevalier, C., additional, Bianchini, L. F., additional, Papah, M. B., additional, and Ojoo, R. O., additional

Published
2014
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38. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Author

Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, Lubinski, J, Jakubowska, A, Rozkrut, D, Antoniou, A, Hamann, U, Scott, RJ, McGuffog, L, Healy, S, Sinilnikova, OM, Rennert, G, Lejbkowicz, F, Flugelman, A, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, Marga, Paligo, M, Aretini, P, Kantala, J, Aroer, B, von Wachenfeldt, A, Liljegren, A, Loman, N, Herbst, K, Kristoffersson, U, Rosenquist, R, Karlsson, P, Stenmark-Askmalm, M, Melin, B, Nathanson, KL, Domchek, SM, Byrski, T, Huzarski, T, Gronwald, J, Menkiszak, J, Cybulski, C, Serrano, P, Osorio, A, Cajal, TR, Tsitlaidou, M, Benitez, J, Gilbert, M, Rookus, M, Aalfs, CM, Kluijt, I, Boessenkool-Pape, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Blok, MJ, Nelen, MR, van den Ouweland, Ans, Seynaeve, Caroline, van der Luijt, RB, Devilee, P, Easton, DF, Peock, S, Frost, D, Platte, R, Ellis, SD, Fineberg, E, Evans, DG, Lalloo, F, Eeles, R, Jacobs, C, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Godwin, A, Bove, B, Stoppa-Lyonnet, D, Caux-Moncoutier, V, Belotti, M, Tirapo, C, Mazoyer, S, Barjhoux, L, Boutry-Kryza, N, Pujol, P, Coupier, I, Peyrat, JP, Vennin, P, Muller, D, Fricker, JP, Venat-Bouvet, L, Johannsson, O, Isaacs, C, Schmutzler, R, Wappenschmidt, B, Meindl, A, Arnold, N, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Preisler-Adams, S, Simard, J, Soucy, P, Durocher, F, Chenevix-Trench, G, Beesley, J, Chen, X, Rebbeck, T, Couch, F, Wang, X, Lindor, N, Fredericksen, Z, Pankratz, VS, Peterlongo, P, Bonanni, B, Fortuzzi, S, Peissel, B, Szabo, C, Mai, PL, Loud, JT, and Lubinski, J

Abstract

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1 CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK

Published
2012

39. Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

Author

Osorio, A., Milne, R. L., Alonso, R., Pita, G., Peterlongo, P., Teule, A., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Lasa, A., Konstantopoulou, I., Hogervorst, F. B., Verhoef, S., van Dooren, M. F., Jager, A., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Vreeswijk, M., Waisfisz, Q., Van Roozendaal, C. E., Ligtenberg, M. J., Easton, D. F., Peock, S., Cook, M., Oliver, C. T., Frost, D., Curzon, B., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Adlard, J., Eccles, D., Ong, K-R, Douglas, F., Downing, S., Brewer, C., Walker, L., Nevanlinna, H., Aittomaki, K., Couch, F. J., Fredericksen, Z., Lindor, N. M., Godwin, A., Isaacs, C., Caligo, M. A., Loman, N., Jernstrom, H., Barbany-Bustinza, G., Liljegren, A., Ehrencrona, Hans, Stenmark-Askmalm, M., Feliubadalo, L., Manoukian, S., Peissel, B., Zaffaroni, D., Bonanni, B., Fortuzzi, S., Johannsson, O. T., Chenevix-Trench, G., Chen, X-C, Beesley, J., Spurdle, A. B., Sinilnikova, O. M., Healey, S., McGuffog, L., Antoniou, A. C., Brunet, J., Radice, P., Benitez, J., Osorio, A., Milne, R. L., Alonso, R., Pita, G., Peterlongo, P., Teule, A., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Lasa, A., Konstantopoulou, I., Hogervorst, F. B., Verhoef, S., van Dooren, M. F., Jager, A., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Vreeswijk, M., Waisfisz, Q., Van Roozendaal, C. E., Ligtenberg, M. J., Easton, D. F., Peock, S., Cook, M., Oliver, C. T., Frost, D., Curzon, B., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Adlard, J., Eccles, D., Ong, K-R, Douglas, F., Downing, S., Brewer, C., Walker, L., Nevanlinna, H., Aittomaki, K., Couch, F. J., Fredericksen, Z., Lindor, N. M., Godwin, A., Isaacs, C., Caligo, M. A., Loman, N., Jernstrom, H., Barbany-Bustinza, G., Liljegren, A., Ehrencrona, Hans, Stenmark-Askmalm, M., Feliubadalo, L., Manoukian, S., Peissel, B., Zaffaroni, D., Bonanni, B., Fortuzzi, S., Johannsson, O. T., Chenevix-Trench, G., Chen, X-C, Beesley, J., Spurdle, A. B., Sinilnikova, O. M., Healey, S., McGuffog, L., Antoniou, A. C., Brunet, J., Radice, P., and Benitez, J.

Abstract

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Published
2011
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40. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

Author

Cox, D.G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M.H., Mai, P.L., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Caligo, M.A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S.S., Borg, A., Karlsson, P., Askmalm, M.S., Bustinza, G.B., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Benitez, J., Hamann, U., Rookus, M.A., Ouweland, A.M. van den, Ausems, M.G., Aalfs, C.M., Asperen, C.J. van, Devilee, P., Gille, H.J., Peock, S., Frost, D., Evans, D.G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A.K., Remon, M.A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M.C., Terry, M.B., Singer, C.F., Dressler, A.C., Tea, M.K., Hansen, T.V., Johannsson, O., Piedmonte, M., Rodriguez, G.C., Basil, J.B., Blank, S., Toland, A.E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S.A., Moysich, K.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A.B., Neuhausen, S.L., Ding, Y.C., Couch, F.J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O.M., Ligtenberg, M.J.L., Hoogerbrugge, N., et al., Cox, D.G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M.H., Mai, P.L., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Caligo, M.A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S.S., Borg, A., Karlsson, P., Askmalm, M.S., Bustinza, G.B., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Benitez, J., Hamann, U., Rookus, M.A., Ouweland, A.M. van den, Ausems, M.G., Aalfs, C.M., Asperen, C.J. van, Devilee, P., Gille, H.J., Peock, S., Frost, D., Evans, D.G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A.K., Remon, M.A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M.C., Terry, M.B., Singer, C.F., Dressler, A.C., Tea, M.K., Hansen, T.V., Johannsson, O., Piedmonte, M., Rodriguez, G.C., Basil, J.B., Blank, S., Toland, A.E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S.A., Moysich, K.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A.B., Neuhausen, S.L., Ding, Y.C., Couch, F.J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O.M., Ligtenberg, M.J.L., Hoogerbrugge, N., and et al.

Abstract

Item does not contain fulltext, Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Published
2011

41. Exploring the link between MORF4L1 and risk of breast cancer

Author

Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Maxwell, CM, Ramírez, MJ, Easton, DF, Oliver, CT, Evans, DG, Chu ,C, Ong, KR, Morrison, PJ, Putignano, AL, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Asperen, CJ, Ausems, MG, van Os, TA, Blok, MJ, Meijers Heijboer, HE, Hogervorst, FB, Goldgar, DE, John, EM, Daly, MB, Domchek, SM, Nathanson, KL, Rebbeck, TR, Johannsson, OT, Couch, FJ, Pientka, FK, Caligo, MA, Godwin, AK, Imyanitov, EN, Sinilnikova, OM, Bignon, YJ, Peyrat, JP, Ferrer, SF, Collonge Rame, MA, McGuffog, L, Pereira Smith, OM, Antoniou, AC, Pujana, MA, ROVERSI, GAIA, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Maxwell, CM, Ramírez, MJ, Easton, DF, Oliver, CT, Evans, DG, Chu ,C, Ong, KR, Morrison, PJ, Putignano, AL, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Asperen, CJ, Ausems, MG, van Os, TA, Blok, MJ, Meijers Heijboer, HE, Hogervorst, FB, Goldgar, DE, John, EM, Daly, MB, Domchek, SM, Nathanson, KL, Rebbeck, TR, Johannsson, OT, Couch, FJ, Pientka, FK, Caligo, MA, Godwin, AK, Imyanitov, EN, Sinilnikova, OM, Bignon, YJ, Peyrat, JP, Ferrer, SF, Collonge Rame, MA, McGuffog, L, Pereira Smith, OM, Antoniou, AC, Pujana, MA, and ROVERSI, GAIA

Abstract

Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) =

Published
2011

42. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer

Author

Håkansson S, Johannsson O, Johansson U, Sellberg G, Loman N, Anne-Marie Gerdes, Holmberg E, Dahl N, Pandis N, Kristoffersson U, Olsson H, and Borg A

Subjects
endocrine system diseases, skin and connective tissue diseases, Research Article
Abstract

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.

Published
1997

43. Erratum: The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Author

Antoniou, A C, primary, Cunningham, A P, additional, Peto, J, additional, Evans, D G, additional, Lalloo, F, additional, Narod, S A, additional, Risch, H A, additional, Eyfjord, J E, additional, Hopper, J L, additional, Southey, M C, additional, Olsson, H, additional, Johannsson, O, additional, Borg, A, additional, Pasini, B, additional, Radice, P, additional, Manoukian, S, additional, Eccles, D M, additional, Tang, N, additional, Olah, E, additional, Anton-Culver, H, additional, Warner, E, additional, Lubinski, J, additional, Gronwald, J, additional, Gorski, B, additional, Tryggvadottir, L, additional, Syrjakoski, K, additional, Kallioniemi, O-P, additional, Eerola, H, additional, Nevanlinna, H, additional, Pharoah, P D P, additional, and Easton, D F, additional

Published
2008
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