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

Authors:
Ali Amin Olama, PhD
Ali Amin Olama, PhD
University Of Cambridge
Dr.
Cambridge | United Kingdom
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
Melissa C Southey David E Goldgar Robert Winqvist Katri Pylkäs Fergus Couch Marc Tischkowitz William D Foulkes Joe Dennis Kyriaki Michailidou Elizabeth J van Rensburg Tuomas Heikkinen Heli Nevanlinna John L Hopper Thilo Dörk Kathleen Bm Claes Jorge Reis-Filho Zhi Ling Teo Paolo Radice Irene Catucci Paolo Peterlongo Helen 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 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 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 A E M Tollenaar Caroline Seynaeve Antoinette Hollestelle Montserrat Garcia-Closas Stephen J Chanock Jolanta Lissowska Kamila Czene Hatef Darabi Mikael Eriksson Diana M Eccles Sajjad Rafiq 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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

J Med Genet 2016 12 5;53(12):800-811. Epub 2016 Sep 5.

Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.

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), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10) 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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Source
http://dx.doi.org/10.1136/jmedgenet-2016-103839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200636PMC
December 2016
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