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PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
Southey, Melissa C; Goldgar, David E; Winqvist, Robert; Pylkäs, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L; Dörk, Thilo; Claes, Kathleen Bm; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A; Dowty, James G; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Yang, Rongxi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie.
Affiliation
  • Southey MC; Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
  • Goldgar DE; Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • Winqvist R; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Nordlab Oulu, Oulu, Finland.
  • Pylkäs K; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Nordlab Oulu, Oulu, Finland.
  • Couch F; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Tischkowitz M; Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, and the Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrooke's Hospital.
  • Foulkes WD; Program in Cancer Genetics, Department of Human Genetics and Oncology, Lady Davis Institute, and Research Institute, McGill University Health Centre, McGill University, Montreal, Canada.
  • Dennis J; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, UK.
  • Michailidou K; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, UK.
  • van Rensburg EJ; Department of Genetics, University of Pretoria, South Africa.
  • Heikkinen T; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
  • Nevanlinna H; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
  • Hopper JL; Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
  • Dörk T; Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • Claes KB; Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
  • Reis-Filho J; Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Teo ZL; Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
  • Radice P; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
  • Catucci I; IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
  • Peterlongo P; IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
  • Tsimiklis H; Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
  • Odefrey FA; Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
  • Dowty JG; Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
  • Schmidt MK; Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Broeks A; Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Hogervorst FB; Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Verhoef S; Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
  • Carpenter J; Australian Breast Cancer Tissue Bank, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia.
  • Clarke C; Centre for Cancer Research, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia.
  • Scott RJ; Division of Molecular Medicine, Pathology North, Newcastle and University of Newcastle, NSW, Australia.
  • Fasching PA; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Haeberle L; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA.
  • Ekici AB; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Beckmann MW; Unit of Biostatistics, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
  • Peto J; Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
  • Dos-Santos-Silva I; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Fletcher O; Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
  • Johnson N; Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
  • Bolla MK; Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
  • Sawyer EJ; Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
  • Tomlinson I; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, UK.
  • Kerin MJ; Division of Cancer Studies, NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, London, UK.
  • Miller N; Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, UK and Oxford NIHR Biomedical Research Centre, Headington, OX3 7LE.
  • Marme F; Surgery, Lambe Institute for Translational Science, NUIGalway, University Hospital Galway, Galway, Ireland.
  • Burwinkel B; Surgery, Lambe Institute for Translational Science, NUIGalway, University Hospital Galway, Galway, Ireland.
  • Yang R; Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
  • Guénel P; National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
  • Truong T; Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
  • Menegaux F; Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Sanchez M; Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
J Med Genet ; 53(12): 800-811, 2016 12.
Article in En | MEDLINE | ID: mdl-27595995
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Breast Neoplasms / Nuclear Proteins / Genetic Predisposition to Disease / Tumor Suppressor Proteins / Ataxia Telangiectasia Mutated Proteins / Checkpoint Kinase 2 / Mutation Type of study: Clinical_trials / Etiology_studies / Observational_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: J Med Genet Year: 2016 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Breast Neoplasms / Nuclear Proteins / Genetic Predisposition to Disease / Tumor Suppressor Proteins / Ataxia Telangiectasia Mutated Proteins / Checkpoint Kinase 2 / Mutation Type of study: Clinical_trials / Etiology_studies / Observational_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: J Med Genet Year: 2016 Document type: Article Affiliation country: Australia