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Rare variants in XRCC2 as breast cancer susceptibility alleles
  1. Florentine S Hilbers1,
  2. Juul T Wijnen1,2,
  3. Nicoline Hoogerbrugge3,
  4. Jan C Oosterwijk4,
  5. Margriet J Collee5,
  6. Paolo Peterlongo6,7,
  7. Paolo Radice6,7,
  8. Siranoush Manoukian8,
  9. Irene Feroce9,
  10. Fabio Capra6,10,
  11. Fergus J Couch11,
  12. Xianshu Wang11,
  13. Lucia Guidugli11,
  14. Kenneth Offit12,
  15. Sohela Shah12,
  16. Ian G Campbell13–15,
  17. Ella R Thompson13,14,
  18. Paul A James14,16,
  19. Alison H Trainer14,16,
  20. Javier Gracia17,
  21. Javier Benitez17,
  22. Christi J van Asperen2,
  23. Peter Devilee1
  1. 1Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Genetics, University Medical Center, University of Groningen, Groningen, The Netherlands
  5. 5Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  6. 6Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy
  7. 7Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  8. 8Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy
  9. 9Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy
  10. 10Cogentech Cancer Genetic Test Laboratory, Milan, Italy
  11. 11Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  12. 12Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA
  13. 13Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  14. 14Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  15. 15Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  16. 16Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  17. 17Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  1. Correspondence to Florentine S Hilbers, Department of Human Genetics, Leiden University Medical Centre, Albinusdreef 2, Leiden 2333 ZA, The Netherlands; f.s.m.hilbers{at}lumc.nl

Abstract

Background Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation.

Methods The coding regions and exon–intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms.

Results The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls.

Conclusions Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.

  • Cancer: breast
  • Genetic epidemiology
  • Genetics

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