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No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

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Abstract

The p27kip1 protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53–0.99; P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99–2.18; P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.

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Acknowledgments

kConFab—The Kathleen Cuningham Consortium for Research into Familial Breast Cancer: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. EMBRACE—M.C., S·P., and EMBRACE are funded by Cancer Research-UK. The following are EMBRACE collaborating centers. Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Alexandra Bignell and Debra Frost. North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole and Carole McKeown. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark Rogers and Emma McCann. St James’s Hospital, Dublin and National Centre for Medical Genetics, Dublin: Peter Daly and David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous and Michael Steel. Peninsula Clinical Genetics Service. Exeter: Carole Brewer and Julia Rankin.West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson and Victoria Murday. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt and Gabriella Pichert. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Richard Trembath.Yorkshire Regional Genetics Service, Leeds: Tim Bishop and Carol Chu. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D. Gareth Evans and Fiona Lalloo. North East Thames Regional Genetics Service, NE Thames: Alison Male, James Mackay, and Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas and John Burn. Oxford Regional Genetics Service, Oxford: Lucy Side, Lisa Walker and Sarah Durell. Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles. North Trent Clinical Genetics Service, Sheffield: Jackie Cook and Oliver Quarrell. South West Thames Regional Genetics Service, London: Shirley Hodgson. Wessex Clinical Genetics Service. Southampton: Diana Eccles and Anneke Lucassen. UPENN—Breast Cancer Research Foundation (KLN), QVC Network and the Fashion Footwear Association of New York, Marjorie B. Cohen Foundation, National Cancer Institute Cancer Genetics Network [HHSN216200744000C] (SMD). The genotyping was supported by an NHMRC Programme grant to GCT. ABS was funded by an NHMRC Career Development Award, AJD is a recipient of a Cancer Council of Victoria Postdoctoral fellowship, DD is an NHMRC Senior Research Fellow. ACA is funded by Cancer Research UK, DFE is a Principal Research Fellow of Cancer Research UK, GAM is the Weary Dunlop Fellow of the Cancer Council of Victoria, and GC-T is an NHMRC Senior Principal Research Fellow.

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Authors and Affiliations

  1. Queensland Institute of Medical Research, Brisbane, Australia

    Amanda B. Spurdle, David Duffy, Xiaoqing Chen, Jonathan Beesley & Georgia Chenevix-Trench

  2. Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Rd, Herston, 4006, Australia

    Amanda B. Spurdle

  3. Peter MacCallum Cancer Centre, Melbourne, Australia

    Andrew J. Deans & Grant A. MacArthur

  4. Department of Dermatology, University of Utah, Salt Lake City, UT, USA

    David E. Goldgar

  5. Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Douglas F. Easton, Antonis C. Antoniou, Susan Peock & Margaret Cook

  6. Department of Medicine and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, USA

    Katherine L. Nathanson & Susan M. Domchek

  7. Department of Medicine, St Vincents Hopsital, Melbourne, Australia

    Grant A. MacArthur

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  1. Amanda B. Spurdle
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  2. Andrew J. Deans
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  14. Georgia Chenevix-Trench
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kConFaB

EMBRACE Study Collaborators

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Correspondence to Amanda B. Spurdle.

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Spurdle, A.B., Deans, A.J., Duffy, D. et al. No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 115, 307–313 (2009). https://doi.org/10.1007/s10549-008-0083-5

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  • DOI: https://doi.org/10.1007/s10549-008-0083-5

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