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

Melissa Southey, David E. Goldgar, Robert Winqvist, Katri Pylkäs, Fergus J. Couch, Marc Tischkowitz, W. D. Foulkes, Joe Dennis, Kyriaki Michailidou, Elizabeth J. van Rensburg, Tuomas Heikkinen, Heli Nevanlinna, John Hopper, Thilo Dörk, Kathleen Claes, Jorge S. Reis-Filho, Z. L. Teo, Paolo Radice, Irene Catucci, Paolo PeterlongoHelen Tsimiklis, Fabrice Odefrey, James G. Dowty, Marjanka K. Schmidt, Annegien Broeks, Frans B. Hogervorst, S. 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 Tomlinson, Michael J. Kerin, Nicola Miller, Federik Marme, Barbara Burwinkel, Rongxi Yang, Pascal Guenel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Stig E. Bojesen, Sune F. Nielsen, Henrik Flyger, Javier Benitez, M. Pilar 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 N. 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 Vachon, Vernon S. Pankratz, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Fredrick R. Schumacher, Loic Le Marchand, Vessela Kristensen, Grethe Grenaker Alnaes, Wei Zheng, David J. Hunter, Sara Lindström, 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, Montse Garcia-Closas, Jonine D. Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Hatef Darabi, Mikael Eriksson, Diana Eccles, Sajjad Rafiq, William J. Tapper, Sue M. Gerty, Maartje J. Hooning, John W M Martens, J. Margriet Collée, M. M A Tilanus-Linthorst, Per Hall, Jingmei Li, Judith S. Brand, Keith Humphreys, Angela Cox, Malcolm W R Reed, Craig Luccarini, Caroline Baynes, Alison 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 E. 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 Eeles, Kenneth Muir, Fredrik Wiklund, Henrik Grönberg, Johanna Schleutker, Børge G. Nordestgaard, Maren Weischer, Ruth C. Travis, David E. Neal, J. L. Donovan, Freddie C. Hamdy, Kay Thee Khaw, J. L. Stanford, William J. Blot, Stephen Thibodeau, D. J. Schaid, Joseph L. Kelley, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Katja Butterbach, Jong Park, R. Kaneva, Jyotsna Batra, Manuel R. Teixeira, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, S. P. Renner, Arndt Hartmann, Alexander Hein, Matthias Ruebner, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Sandrina Lambretchs, Jennifer A. Doherty, Mary Anne Rossing, Stefan Nickels, Ursula Eilber, Shan Wang-Gohrke, Kunle Odunsi, Lara E. Sucheston-Campbell, Grace Friel, G. Lurie, Jeffrey L. Killeen, Lynne R. Wilkens, Marc T. Goodman, I. B. Runnebaum, Peter Hillemanns, Liisa M. Pelttari, Ralf Butzow, Francesmary Modugno, Robert P. Edwards, R. B. Ness, Kirsten B. Moysich, A. du Bois, Florian Heitz, Philipp Harter, Stefan Kommoss, Beth Y. Karlan, Christine S. Walsh, Jenny Lester, Allan Jensen, Susanne Krüger Kjær, Estrid Hogdall, Bernard Gilles Peissel, Bernardo Bonanni, Loris Bernard, Ellen L. Goode, Brooke L. Fridley, Robert A. Vierkant, Julie 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, Andrew Berchuck, Edwin S. Iversen, Jeffrey R. Marks, Lucy Akushevich, Daniel W. Cramer, Joellen M. Schildkraut, Kathryn L. Terry, Elizabeth M. Poole, M. Stampfer, Shelley S. Tworoger, Elisa V. Bandera, Irene Orlow, Sara H. Olson, Line Bjorge, Helga B. Salvesen, Anne M. Van Altena, Katja K H Aben, Lambartus Kiemeney, Leon F A G Massuger, Tanja Pejovic, Yukie Bean, Angela Brooks-Wilson, Linda E. Kelemen, Linda S. Cook, Nhu D. Le, Bohdan Gorski, Jacek Gronwald, Janusz Menkiszak, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Svend Aage Engelholm, Ed Dicks, Jonathan Tyrer, Ian Campbell, Iain A. McNeish, James Paul, Nadeem Siddiqui, Rosalind Glasspool, Alice S. Whittemore, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Hui Cai, Xiao Ou Shu, Rachel T. Teten, Rebecca Sutphen, John R. McLaughlin, S. A. Narod, Catherine M. Phelan, Alvaro N. Monteiro, David A. Fenstermacher, Hui Yi Lin, Jennifer B. Permuth, Thomas A. Sellers, Y. Ann Chen, Ya Yu Tsai, Zhihua Chen, Aleksandra Gentry-Maharaj, Simon A. Gayther, Susan J. Ramus, Usha Menon, Anna H. Wu, Celeste L. Pearce, David Van Den Berg, Malcolm C. Pike, Agnieszka Dansonka-Mieszkowska, Joanna Plisiecka-Halasa, Joanna Moes-Sosnowska, Jolanta Kupryjanczyk, Paul D P Pharoah, Honglin Song, Ingrid M. Winship, Georgia Chenevix-Trench, Graham G. Giles, Sean V. Tavtigian, Douglas F. Easton, Roger L. Milne

Research output: Contribution to journalArticle

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
JournalJournal of Medical Genetics
DOIs
Publication statusAccepted/In press - Sep 2 2016

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Southey, M., Goldgar, D. E., Winqvist, R., Pylkäs, K., Couch, F. J., Tischkowitz, M., Foulkes, W. D., Dennis, J., Michailidou, K., van Rensburg, E. J., Heikkinen, T., Nevanlinna, H., Hopper, J., Dörk, T., Claes, K., Reis-Filho, J. S., Teo, Z. L., Radice, P., Catucci, I., ... Milne, R. L. (Accepted/In press). PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-103839