PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS

Melissa C. Southey, David E. Goldgar, Robert Winqvist, Katri Pylkäs, Fergus J Couch, Marc Tischkowitz, William D Foulkes, Joe Dennis, Kyriaki Michailidou, Elizabeth J. Van Rensburg, Tuomas Heikkinen, Heli Nevanlinna, John L. Hopper, Thilo Dörk, Kathleen B.M. Claes, Jorge S. Reis-Filho, Zhi Ling Teo, Paolo Radice, Irene Catucci, Paolo PeterlongoHelen Tsimiklis, Fabrice A. Odefrey, James G Dowty, Marjanka K. Schmidt, Annegien Broeks, Frans B. Hogervorst, Senno Verhoef, Jane Carpenter, Christine Clarke, Rodney J. Scott, Peter A. Fasching, Lothar Haeberle, Arif B Ekici, Matthias W. Beckmann, Julian Peto, Isabel dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K. Bolla, Elinor J Sawyer, Ian P Tomlinson, Michael J. Kerin, Nicola Miller, Federik Marme, Barbara Burwinkel, Rongxi Yang, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Stig E Bojesen, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M. Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Hoda Anton-Culver, Susan L Neuhausen, Argyrios Ziogas, Christina A. Clarke, Hermann Brenner, Volker Arndt, Christa Stegmaier, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Natalia Antonenkova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Amanda B Spurdle, Els Wauters, Dominiek Smeets, Benoit Beuselinck, Giuseppe Floris, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Janet E Olson, Celine M Vachon, Vernon S. Pankratz, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Vessela Kristensen, Grethe Grenaker Alnæs, Wei Zheng, David J. Hunter, Sara Lindstrom, Susan E Hankinson, Peter Kraft, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Antoinette Hollestelle, Montserrat Garcia-Closas, Jonine D Figueroa, Stephen J Chanock, Jolanta Lissowska, Kamila Czene, Hatef Darabi, Mikael Eriksson, Diana M Eccles, Sajjad Rafiq, William J Tapper, Sue M Gerty, Maartje J Hooning, John W M Martens, J. Margriet Collée, Madeleine M A Tilanus-Linthorst, Per Hall, Jingmei Li, Judith S. Brand, Keith Humphreys, Angela Cox, Malcolm W R Reed, Craig Luccarini, Caroline Baynes, Alison M Dunning, Ute Hamann, Diana Torres, Hans Ulrich Ulmer, Thomas Rüdiger, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Anthony J Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Nuria álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Jacques Simard, Martine Dumont, Penny Soucy, Rosalind A Eeles, Kenneth Muir, Fredrik Wiklund, Henrik Gronberg, Johanna Schleutker, Børge G. Nordestgaard, Maren Weischer, Ruth C Travis, David Neal, Jenny L. Donovan, Freddie C Hamdy, Kay-Tee Khaw, Janet L. Stanford, William J. Blot, Stephen N. Thibodeau, Daniel J. Schaid, Joseph L. Kelley, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Katja Butterbach, Jong Hyuk Park, Radka P. Kaneva, Jyotsna Batra, Manuel R Teixeira, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Stefan P Renner, Arndt Hartmann, Alexander Hein, Matthias Ruebner, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Sandrina Lambretchs, Jennifer Anne Doherty, Mary Anne Rossing, Stefan Nickels, Ursula Eilber, Shan Wang-Gohrke, Kunle Odunsi, Lara E. Sucheston-Campbell, Grace Friel, Galina Lurie, Jeffrey L. Killeen, Lynne R. Wilkens, Marc T Goodman, Ingo B Runnebaum, Peter A. Hillemanns, Liisa M Pelttari, Ralf Butzow, Francesmary Modugno, Robert P. Edwards, Roberta B Ness, Kirsten B Moysich, Andreas du Bois, Florian Heitz, Philipp Harter, Stefan Kommoss, Beth Y. Karlan, Christine S Walsh, Jenny Lester, Allan Jensen, Susanne Krüger Kjaer, Estrid Høgdall, Bernard Peissel, Bernardo Bonanni, Loris Bernard, Ellen L Goode, Brooke L. Fridley, Robert A Vierkant, Julie M. Cunningham, Melissa C. Larson, Zachary C Fogarty, Kimberly R. Kalli, Dong Liang, Karen H. Lu, Michelle A T Hildebrandt, Xifeng Wu, Douglas A. Levine, Fanny Dao, Maria Bisogna, Ian Campbell, Graham G. Giles, kConFab Investigators, Australian Ovarian Cancer Study Group

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Abstract

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T > G and c.3113G > A, CHEK2 c.349A > G, c.538C > T, c.715G > A, c.1036C > T, c.1312G > T, and c.1343T > G and ATM c.7271T > G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G > A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T > G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A > G OR 2.26 (95% CI 1.29 to 3.95), c.1036C > T OR 5.06 (95% CI 1.09 to 23.5) and c.538C > T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T > G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G > T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Original languageEnglish
Pages (from-to)800-811
Number of pages12
JournalJournal of Medical Genetics
Volume53
Issue number12
DOIs
Publication statusPublished - Dec 2016
Externally publishedYes

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