PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
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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 Guénel;
Thérèse Truong;
Florence Menegaux;
Marie Sanchez;
Stig Bojesen;
Sune F Nielsen;
Henrik Flyger;
Javier Benitez;
M Pilar Zamora;
Jose Ignacio Arias Perez;
Primitiva Menéndez;
Hoda Anton-Culver;
Susan 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;
kConFab Investigators;
Australian Ovarian Cancer Study Group;
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 Schumacher;
Loic Le Marchand;
Vessela Kristensen;
Grethe Grenaker Alnæs;
Wei Zheng;
David J Hunter;
Sara Lindstrom;
Susan E Hankinson;
Peter Kraft;
Irene Andrulis;
Julia A Knight;
Gord Glendon;
Anna Marie Mulligan;
Arja Jukkola-Vuorinen;
Mervi Grip;
Saila Kauppila;
Peter Devilee;
Robert AEM Tollenaar;
Caroline Seynaeve;
Antoinette Hollestelle;
Montserrat Garcia-Closas;
Jonine 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 WM Martens;
J Margriet Collée;
Madeleine Tilanus-Linthorst;
Per Hall;
Jingmei Li;
Judith S Brand;
Keith Humphreys;
Angela Cox;
Malcolm WR 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 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 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 Thibodeau;
Daniel J Schaid;
Joseph L Kelley;
Christiane Maier;
Adam S Kibel;
Cezary Cybulski;
Lisa Cannon-Albright;
Katja Butterbach;
Jong Park;
Radka 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 A 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 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 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 AT Hildebrandt;
Xifeng Wu;
Douglas A Levine;
Fanny Dao;
Maria Bisogna;
Andrew Berchuck;
Edwin S Iversen;
Jeffrey R Marks;
Lucy Akushevich;
Daniel W Cramer;
Joellen Schildkraut;
Kathryn L Terry;
Elizabeth M Poole;
Meir Stampfer;
Shelley S Tworoger;
Elisa V Bandera;
Irene Orlow;
Sara H Olson;
Line Bjorge;
Helga B Salvesen;
Anne M van Altena;
Katja KH Aben;
Lambertus A Kiemeney;
Leon FAG Massuger;
Tanja Pejovic;
Yukie Bean;
Angela Brooks-Wilson;
Linda E Kelemen;
Linda S Cook;
Nhu D Le;
Bohdan Górski;
Jacek Gronwald;
Janusz Menkiszak;
Claus K Høgdall;
Lene Lundvall;
Lotte Nedergaard;
Svend Aage Engelholm;
Ed Dicks;
Jonathan Tyrer;
Ian Campbell;
Iain 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;
Steven A Narod;
Catherine M Phelan;
Alvaro N Monteiro;
David 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 Dp Pharoah;
Honglin Song;
Ingrid Winship;
Georgia Chenevix-Trench;
Graham G Giles;
Sean V Tavtigian;
Doug F Easton;
Roger L Milne;
(2016)
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
Journal of medical genetics, 53 (12).
pp. 800-811.
ISSN 0022-2593
DOI: 10.1136/jmedgenet-2016-103839
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.
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