<i>PALB2</i>, <i>CHEK2</i> and <i>ATM</i> rare variants and cancer risk: data from COGS
Melissa C. Southey(The University of Melbourne), David E Goldgar(Huntsman Cancer Institute), Robert Winqvist(University of Oulu), Katri Pylkäs(University of Oulu), Fergus J. Couch(Mayo Clinic in Arizona), Marc Tischkowitz(University of Cambridge), William D. Foulkes(McGill University Health Centre), Joe Dennis(University of Cambridge), Kyriaki Michailidou(University of Cambridge), Elizabeth J. van Rensburg(University of Pretoria), Tuomas Heikkinen(University of Helsinki), Heli Nevanlinna(University of Helsinki), John L. Hopper(The University of Melbourne), Thilo Dörk(Medizinische Hochschule Hannover), Kathleen Claes(Ghent University Hospital), Jorge S. Reis‐Filho(Memorial Sloan Kettering Cancer Center), Zhi L. Teo(The University of Melbourne), Paolo Radice(Fondazione IRCCS Istituto Nazionale dei Tumori), Irene Catucci(IFOM), Paolo Peterlongo(IFOM), Helen Tsimiklis(The University of Melbourne), Fabrice Odefrey(The University of Melbourne), James G. Dowty(The University of Melbourne), Marjanka K. Schmidt(The Netherlands Cancer Institute), Annegien Broeks(The Netherlands Cancer Institute), Frans B.L. Hogervorst(The Netherlands Cancer Institute), Senno Verhoef(The Netherlands Cancer Institute), Jane Carpenter(The University of Sydney), Christine L. Clarke(The University of Sydney), Rodney J. Scott(University of Newcastle Australia), Peter A. Fasching(University of California, Los Angeles), Lothar Haeberle(Friedrich-Alexander-Universität Erlangen-Nürnberg), Arif B. Ekici(Friedrich-Alexander-Universität Erlangen-Nürnberg), Matthias W. Beckmann(Universitätsklinikum Erlangen), Julian Peto(London School of Hygiene & Tropical Medicine), Isabel dos‐Santos‐Silva(London School of Hygiene & Tropical Medicine), Olivia Fletcher(Institute of Cancer Research), Nichola Johnson(Institute of Cancer Research), Manjeet K. Bolla(University of Cambridge), Elinor J. Sawyer(King's College London), Ian Tomlinson(Centre for Human Genetics), Michael J. Kerin(Ollscoil na Gaillimhe – University of Galway), Nicola Miller(Ollscoil na Gaillimhe – University of Galway), F. Marmé(Heidelberg University), Barbara Burwinkel(German Cancer Research Center), Rongxi Yang(German Cancer Research Center), Pascal Guénel(Université Paris-Sud), Thérèse Truong(Université Paris-Sud), F. Ménégaux(Université Paris-Sud), Marie Sanchez(Université Paris-Sud), Stig E. Bojesen(University of Copenhagen), Sune F. Nielsen(University of Copenhagen), Henrik Flyger(Herlev Hospital), Javier Benı́tez(Spanish National Cancer Research Centre), M. Pilar Zamora(Hospital Universitario La Paz), José Ignacio Arias Pérez(Hospital Monte Naranco), Primitiva Menéndez(Hospital Monte Naranco), Hoda Anton‐Culver(University of California, Irvine), Susan L. Neuhausen(City of Hope), Argyrios Ziogas(University of California, Irvine), Christina A. Clarke(The University of Sydney), Hermann Brenner(German Cancer Research Center), Volker Arndt(German Cancer Research Center), Christa Stegmaier(Krebsregister Saarland), Hiltrud Brauch(German Cancer Research Center), Thomas Brüning(Institute for Prevention and Occupational Medicine), Yon‐Dschun Ko(Johanniter-Krankenhaus Bonn), Taru Muranen(University of Helsinki), Kristiina Aittomäki(Helsinki University Hospital), Carl Blomqvist(Helsinki University Hospital), Natalia Bogdanova(Medizinische Hochschule Hannover), Natalia Antonenkova(N.N. Alexandrov National Cancer Centre), Annika Lindblom(Karolinska Institutet), Sara Margolin(Karolinska Institutet), Arto Mannermaa(University of Eastern Finland), Vesa Kataja(University of Eastern Finland), Veli‐Matti Kosma(University of Eastern Finland), Jaana M. Hartikainen(University of Eastern Finland), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), kConFab Investigators(The University of Melbourne), Australian Ovarian Cancer Study Group(KU Leuven), Els Wauters(KU Leuven), Dominiek Smeets(Universitair Ziekenhuis Leuven), Benoit Beuselinck(Universitair Ziekenhuis Leuven), Giuseppe Floris(German Cancer Research Center), Jenny Chang‐Claude(German Cancer Research Center), Anja Rudolph(German Cancer Research Center), Petra Seibold(Universität Hamburg), Dieter Flesch‐Janys(Universität Hamburg), Janet E. Olson(Mayo Clinic in Florida), Celine M. Vachon(Mayo Clinic in Florida), V. Shane Pankratz(The Alfred Hospital), Catriona McLean(University of Southern California), Christopher A. Haiman(University of Southern California), Brian E. Henderson(University of Southern California), Fredrick R. Schumacher(University of Southern California), Loı̈c Le Marchand(University of Hawaiʻi at Mānoa), Vessela Kristensen(Oslo University Hospital), Grethe Grenaker Alnæs(Oslo University Hospital), Wei Zheng(Harvard University), David J. Hunter(Harvard University), Sara Lindström(Brigham and Women's Hospital), Susan E. Hankinson(Brigham and Women's Hospital), Peter Kraft(Mount Sinai Hospital), Irene L. Andrulis(Mount Sinai Hospital), Julia A. Knight(Mount Sinai Hospital), Gord Glendon(Mount Sinai Hospital), Anna Marie Mulligan(University Health Network), Arja Jukkola‐Vuorinen(Oulu University Hospital), Mervi Grip(Oulu University Hospital), Saila Kauppila(Oulu University Hospital), Peter Devilee(Leiden University Medical Center), Robert A.E.M. Tollenaar(Leiden University Medical Center), Caroline Seynaeve(Erasmus MC Cancer Institute), Antoinette Hollestelle(Institute of Cancer Research), Montserrat García‐Closas(Institute of Cancer Research), Jonine D. Figueroa(National Cancer Institute), Stephen J. Chanock(National Cancer Institute), Jolanta Lissowska(Karolinska Institutet), Kamila Czene(Karolinska Institutet), Hatef Darabi(Karolinska Institutet), Mikael Eriksson(Karolinska Institutet), Diana M Eccles(University of Southampton), Sajjad Rafiq(University of Southampton), William Tapper(University of Southampton), Sue Gerty(Erasmus MC Cancer Institute), Maartje J. Hooning(Erasmus MC Cancer Institute), John W.M. Martens(Erasmus MC), J. Margriet Collée(Erasmus MC), Madeleine M.A. Tilanus‐Linthorst(Erasmus MC), Per Hall(Karolinska Institutet), Jingmei Li(Karolinska Institutet), Judith S. Brand(Karolinska Institutet), Keith Humphreys(Karolinska Institutet), Angela Cox(University of Sheffield), Malcolm Reed(University of Cambridge), Craig Luccarini(University of Cambridge), Caroline Baynes(University of Cambridge), Alison M. Dunning(German Cancer Research Center), Ute Hamann(German Cancer Research Center), Diana Torres(German Cancer Research Center), Hans Ulrich Ulmer(Städtisches Klinikum Karlsruhe), Thomas Rüdiger(Städtisches Klinikum Karlsruhe), Anna Jakubowska(Pomeranian Medical University), Jan Lubiński(Postgraduate School of Molecular Medicine), Katarzyna Jaworska(Postgraduate School of Molecular Medicine), Katarzyna Durda(Mayo Clinic in Florida), Susan Slager(Mayo Clinic in Florida), Amanda E. Toland(Roswell Park Comprehensive Cancer Center), Christine B. Ambrosone(Roswell Park Comprehensive Cancer Center), Drakoulis Yannoukakos(Institute of Cancer Research), Anthony J. Swerdlow(Institute of Cancer Research), Alan Ashworth(Institute of Cancer Research), Nick Orr(Institute of Cancer Research), Michael E. Jones(Institute of Cancer Research), Anna González‐Neira(Spanish National Cancer Research Centre), Guillermo Pita(Spanish National Cancer Research Centre), M. Rosario Alonso(Spanish National Cancer Research Centre), Núria Álvarez(Spanish National Cancer Research Centre), Daniel Herrero(Spanish National Cancer Research Centre), Daniel C. Tessier(McGill University and Génome Québec Innovation Centre), Daniel Vincent(McGill University), François Bacot(Centre hospitalier universitaire de Québec), Jacques Simard(Centre hospitalier universitaire de Québec), Martine Dumont(Centre hospitalier universitaire de Québec), Penny Soucy(Royal Marsden NHS Foundation Trust), Rosalind A. Eeles(Royal Marsden NHS Foundation Trust), Kenneth Muir(Karolinska Institutet), Fredrik Wiklund(Karolinska Institutet), Henrik Grönberg(University of Turku), Johanna Schleutker(University of Turku), Børge G. Nordestgaard(University of Copenhagen), Maren Weischer(University of Copenhagen), Ruth C. Travis(University of Cambridge), David E. Neal(University of Cambridge), Jenny Donovan(Nuffield Orthopaedic Centre), Freddie C. Hamdy(University of Cambridge), Kay‐Tee Khaw(University of Washington), Janet L. Stanford(University of Washington), William J. Blot(Mayo Clinic in Arizona), Stephen N. Thibodeau(Mayo Clinic in Arizona), Daniel J. Schaid(University of Pittsburgh), Joseph L. Kelley(University of Pittsburgh), Christiane Maier(Brigham and Women's Hospital), Adam S. Kibel(Brigham and Women's Hospital), Cezary Cybulski(University of Utah), Lisa Cannon‐Albright(German Cancer Research Center), Katja Butterbach(German Cancer Research Center), Jong Moon Park(Medical University of Sofia), Radka Kaneva(Queensland University of Technology), Jyotsna Batra(Queensland University of Technology), Manuel R. Teixeira(Institute of Cancer Research), Zsofia Kote‐Jarai(Institute of Cancer Research), Ali Amin Al Olama(University of Cambridge), Sara Benlloch(University of Cambridge), Stefan P. Renner(Universitätsklinikum Erlangen), Arndt Hartmann(Universitätsklinikum Erlangen), Alexander Hein(Universitätsklinikum Erlangen), Matthias Ruebner(Universitätsklinikum Erlangen), Diether Lambrechts(Dartmouth College), Els Van Nieuwenhuysen(Dartmouth College), Ignace Vergote(Dartmouth College), Sandrina Lambretchs(Dartmouth College), Jennifer A. Doherty(Dartmouth College), Mary Anne Rossing(German Cancer Research Center), Stefan Nickels(German Cancer Research Center), Ursula Eilber(German Cancer Research Center), Shan Wang‐Gohrke(Roswell Park Comprehensive Cancer Center), Kunle Odunsi(Roswell Park Comprehensive Cancer Center), Lara Sucheston‐Campbell(Roswell Park Comprehensive Cancer Center), Grace Friel(University of Hawaiʻi at Mānoa), Galina Lurie(University of Hawaiʻi at Mānoa), Jeffrey Killeen(University of Hawaiʻi at Mānoa), Lynne R. Wilkens(University of Hawaiʻi at Mānoa), Marc T. Goodman(Cedars-Sinai Medical Center), Ingo B. Runnebaum(Medizinische Hochschule Hannover), Peter Hillemanns(University of Helsinki), Liisa M. Pelttari(University of Helsinki), Ralf Bützow(University of Pittsburgh), Francesmary Modugno(University of Pittsburgh), Robert P. Edwards(University of Pittsburgh), Roberta B. Ness(Roswell Park Comprehensive Cancer Center), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Andreas du Bois(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Florian Heitz(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Philipp Harter(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Stefan Kommoss(Cedars-Sinai Medical Center), Beth Y. Karlan(Cedars-Sinai Medical Center), Christine Walsh(Cedars-Sinai Medical Center), Jenny Lester(Cedars-Sinai Medical Center), Allan Jensen(Rigshospitalet), Susanne K. Kjær(University of Copenhagen), Estrid Høgdall(University of Copenhagen), Bernard Peissel(Fondazione IRCCS Istituto Nazionale dei Tumori), Bernardo Bonanni(European Institute of Oncology), Loris Bernard(Mayo Clinic in Florida), Ellen L. Goode(University of Kansas Medical Center), Brooke L. Fridley(University of Kansas Medical Center), Robert A. Vierkant(Mayo Clinic in Arizona), Julie M. Cunningham(Mayo Clinic in Arizona), Melissa C. Larson(Mayo Clinic in Florida), Zachary C. Fogarty(Mayo Clinic), Kimberly R. Kalli(Mayo Clinic), Dong Liang(The University of Texas MD Anderson Cancer Center), Karen H. Lu(The University of Texas MD Anderson Cancer Center), Michelle A.T. Hildebrandt(The University of Texas MD Anderson Cancer Center), Xifeng Wu(Memorial Sloan Kettering Cancer Center), Douglas A. Levine(Memorial Sloan Kettering Cancer Center), Fanny Dao(Memorial Sloan Kettering Cancer Center), Maria Bisogna(Memorial Sloan Kettering Cancer Center), Andrew Berchuck(Duke University), Edwin S. Iversen(Duke University), Jeffrey R. Marks(Duke Medical Center), Lucy Akushevich(Brigham and Women's Hospital), Daniel W. Cramer(Brigham and Women's Hospital), Joellen M. Schildkraut(Brigham and Women's Hospital), Kathryn L. Terry(Brigham and Women's Hospital), Elizabeth M. Poole(Brigham and Women's Hospital), Meir J. Stampfer(Brigham and Women's Hospital), Shelley S. Tworoger(Rutgers, The State University of New Jersey), Elisa V. Bandera(Rutgers, The State University of New Jersey), Irene Orlow(Memorial Sloan Kettering Cancer Center), Sara H. Olson(Memorial Sloan Kettering Cancer Center), Line Bjørge(Haukeland University Hospital), Helga B. Salvesen(Radboud University Nijmegen), Anne M. van Altena(Radboud University Nijmegen), Katja K.H. Aben(Radboud University Nijmegen), Lambertus A. Kiemeney(Radboud University Nijmegen), Leon F.A.G. Massuger(Radboud University Nijmegen), Tanja Pejović(Oregon Health & Science University), Yukie T. Bean(BC Cancer Agency), Angela Brooks‐Wilson(BC Cancer Agency), Linda E. Kelemen(Medical University of South Carolina), Linda S. Cook(BC Cancer Agency), Nhu D. Le(BC Cancer Agency), Bohdan Górski(International Hereditary Cancer Center), Jacek Gronwald(International Hereditary Cancer Center), Janusz Menkiszak(Rigshospitalet), Claus Høgdall(University of Copenhagen), Lene Lundvall(University of Copenhagen), Lotte Nedergaard(University of Copenhagen), Svend Aage Engelholm(University of Copenhagen), Ed Dicks(University of Cambridge), Jonathan P. Tyrer(University of Cambridge), Ian Campbell(Peter MacCallum Cancer Centre), Iain A. McNeish(Beatson West of Scotland Cancer Centre), James Paul(Beatson West of Scotland Cancer Centre), Nadeem Siddiqui(Glasgow Royal Infirmary), Rosalind Glasspool(Glasgow Royal Infirmary), Alice S. Whittemore(Stanford University), Joseph H. Rothstein(Stanford University), Valerie McGuire(Stanford University), Weiva Sieh(Vanderbilt University), Hui Cai(Vanderbilt University), Xiao‐Ou Shu(Vanderbilt University), Rachel Threet Teten(University of South Florida), Rebecca Sutphen(University of South Florida), John R McLaughlin(University of Toronto), Steven A. Narod(University of Toronto), Catherine M. Phelan(Moffitt Cancer Center), Álvaro N.A. Monteiro(Moffitt Cancer Center), David Fenstermacher(Moffitt Cancer Center), Hui‐Yi Lin(Moffitt Cancer Center), Jennifer B. Permuth(Moffitt Cancer Center), Thomas A. Sellers(Moffitt Cancer Center), Y. Ann Chen(Moffitt Cancer Center), Ya-Yu Tsai(Moffitt Cancer Center), Zhihua Chen(Moffitt Cancer Center), Aleksandra Gentry‐Maharaj(University of Southern California), Simon A. Gayther(University of Southern California), Susan J. Ramus(University of Southern California), Usha Menon(University of Southern California), Anna H. Wu(University of Southern California), Celeste Leigh Pearce(University of Southern California), David Van Den Berg(University of Southern California), Malcolm C. Pike(University of Southern California), Agnieszka Dansonka‐Mieszkowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Joanna Plisiecka-Hałasa(The Maria Sklodowska-Curie National Research Institute of Oncology), Joanna Moes-Sosnowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Jolanta Kupryjańczyk(University of Cambridge), Paul D.P. Pharoah(University of Cambridge), Honglin Song(The Royal Melbourne Hospital), Ingrid Winship(The Royal Melbourne Hospital), Georgia Chenevix‐Trench(The University of Melbourne), Graham G. Giles(The University of Melbourne), Sean V. Tavtigian(University of Cambridge), Doug Easton(The University of Melbourne), Roger L. Milne(The University of Melbourne)
Cited by 217Open Access
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: ) 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.
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