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A role for XRCC2 gene polymorphisms in breast cancer risk and survival
  1. Wei-Yu Lin1,
  2. Nicola J Camp2,
  3. Lisa A Cannon-Albright2,
  4. Kristina Allen-Brady2,
  5. Sabapathy Balasubramanian3,
  6. Malcolm W R Reed3,
  7. John L Hopper4,
  8. Carmel Apicella4,
  9. Graham G Giles5,
  10. Melissa C Southey6,
  11. Roger L Milne4,7,
  12. Jose I Arias-Pérez8,
  13. Primitiva Menéndez-Rodríguez8,
  14. Javier Benítez9,
  15. Magdalena Grundmann10,
  16. Natalia Dubrowinskaja10,
  17. Tjoung-Won Park-Simon10,
  18. Thilo Dörk10,
  19. Montserrat Garcia-Closas11,
  20. Jonine Figueroa12,
  21. Mark Sherman12,
  22. Jolanta Lissowska13,
  23. Douglas F Easton14,15,
  24. Alison M Dunning14,15,
  25. Preetha Rajaraman16,
  26. Alice J Sigurdson16,
  27. Michele M Doody16,
  28. Martha S Linet16,
  29. Paul D Pharoah14,15,
  30. Marjanka K Schmidt17,
  31. Angela Cox1
  1. 1Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, UK
  2. 2Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
  3. 3Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Sheffield, UK
  4. 4Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population Health, The University of Melbourne, Carlton, Victoria, Australia
  5. 5Cancer Epidemiology Centre, The Cancer Council Victoria, Victoria, Australia
  6. 6Department of Pathology, The University of Melbourne, Victoria, Australia
  7. 7Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  8. 8Hospital Monte Naranco, Oviedo, Spain
  9. 9Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  10. 10Hannover Medical School, Clinics of Obstetrics and Gynaecology, Hannover, Germany
  11. 11Sections of Epidemiology and Genetics, Institute of Cancer Research, Belmont Sutton, Surrey, UK
  12. 12Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, Rockville, Maryland, USA
  13. 13Department of Cancer Epidemiology and Prevention, The M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
  14. 14Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  15. 15Department of Oncology, University of Cambridge, Cambridge, UK
  16. 16Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, Maryland, USA
  17. 17Netherlands Cancer Institute, Amsterdam, The Netherlands
  1. Correspondence to Dr Angela Cox, Institute for Cancer Studies, Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK; a.cox{at}shef.ac.uk

Abstract

Background The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.

Methods The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).

Results The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10−4, minor allele frequency (MAF)=0.23). This SNP yielded an ORrec of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-ORrec of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).

Conclusions These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

  • Single nucleotide polymorphism
  • XRCC2
  • breast cancer risk
  • breast cancer survival
  • cancer: breast
  • epidemiology
  • genetic epidemiology
  • cancer: prostate
  • clinical genetics
  • cancer: colon
  • molecular genetics
  • other oncology
  • cancer: urological

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Footnotes

  • Funding The SBCS study was funded by the Breast Cancer Campaign (grants 2000:146 and 2004 Nov 49), and Yorkshire Cancer Research core funding. The UBCS was supported by the Susan G. Komen Breast Cancer Foundation (BCTR0706911 to NJC) and the Avon Foundation (02-2009-080 to NJC). Data collection in Utah was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah. The Australian Breast Cancer Family Study was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (CFR) and principal investigators. The University of Melbourne (U01 CA69638) contributed data to this study. The content of this manuscript does not necessarily reflect the views or the policies of the National Cancer Institute or any of the collaborating centres in the CFR, nor does mention of trade names, commercial products or organisations imply endorsement by the US government or the CFR. JLH is a National Health and Medical Research Council Australia Fellow. MCS is a National Health and Medical Research Council Senior Research Fellow. JLH and MCS are both group leaders of the Victoria Breast Cancer Research Consortium. The CNIO-BCS work was partly funded by the Red Temática de Investigación Cooperativa en Cáncer, the Asociación Española Contra Cáncer and grants from the Fondo de Investigación Santiario (PI081583 to RLM and PI081120 to JB). SEARCH is funded by Cancer Research UK (C490/A10124) and the Cambridge NIHR Biomedical Research Centre. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by Sheffield Research Ethics Committee (UK) and other institutional review boards as appropriate for each contributing study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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