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Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers

Abstract

The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies.

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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. The 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. ABS is an NHMRC Senior Research Fellow, and GC-T is an NHMRC Senior Principal Research Fellow.

Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE)

DE is the PI of the study. DE, SP, and MC are funded by Cancer Research, UK Grants C1287/A10118 and C1287/A8874. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare Oliver, Debra Frost; North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory, Zosia Miedzybrodzka; Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison; West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Amy Taylor; 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, Emma McCann; St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: John Kennedy, David Barton; South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous; Peninsula Clinical Genetics Service. Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman; West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt; South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert, Caroline Langman. North West Thames Regional Genetics Service. Harrow: Huw Dorkins; Leicestershire Clinical Genetics Service; Leicester: Julian Barwell; Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller; Merseyside & Cheshire Clinical Genetics Service. Liverpool: Ian Ellis; Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Felicity Holt; North East Thames Regional Genetics Service, NE Thames: Alison Male, Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner; Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber; Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Anita Mitra; North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley; South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester; Wessex Clinical Genetics Service; Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Emma Tyler, Donna McBride. ACA is a Cancer Research UK Senior Cancer Research Fellow. CIMBA data management is supported by Cancer Research UK. The kConFab and EMBRACE genotyping was supported by an NHMRC Programme grant to GCT. MAGIC data collection and analysis was supported by R01-CA102776 to TRR.

Interdisciplinary Health Research International Team on Breast Cancer Susceptibility (INHERIT BRCAs)

Jacques Simard, Francine Durocher, Rachel Laframboise, Marie Plante, Centre Hospitalier Universitaire de Québec & Laval University, Québec, Canada; Peter Bridge, Jilian Parboosingh, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Québec, Canada; Bernard Lespérance, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada. Jacques Simard- J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This study was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program.

Modifiers and Genetics in Cancer (MAGIC)

This work was supported by the NIH grants R01-CA102776 and R01-CA083855 (to TRR). The MAGIC Consortium includes the following centers and individuals: Baylor- Charles A. Sammons Cancer Center (Joanne L, Blum, M.D. Ph.D.; Becky Althaus, R.N., C.G.C.; Gaby Ethington), Baylor College of Medicine (Claire Noll; Sharon Plon, M.D., Ph.D.), Beth Israel Deaconess Medical Center (Nadine Tung, M.D.), City of Hope National Medical Center (Sharon Sand; Jeffrey N. Weitzel, M.D.), Creighton University (Carrie Snyder, B.A.; Henry T. Lynch, M.D.; Patrice Watson, Ph.D.), Dana-Farber Cancer Institute (Kathryn Stoeckert; Judy E. Garber, M.D., M.P.H.), Duke University (Sydnee Crankshaw; Joellen Schildkraut, Ph.D.), Evanston Northwestern Healthcare Center for Medical Genetics (Suzanne M. O’Neill, Ph.D.; Christina Selkirk; Wendy S. Rubinstein, M.D., Ph.D.), Fox Chase Cancer Center (Mary B. Daly, M.D., Ph.D.; Andrew Godwin, Ph.D.), Queensland Institute of Medical Research (Georgia Chenevix-Trench), Georgetown University (Claudine Isaacs, M.D.), Jonsson Comprehensive Cancer Center at the University of California-Los Angeles (Joyce Seldon; Patricia A. Ganz, M.D.), Mayo Clinic College of Medicine (Linda Wadum; Fergus Couch, Ph.D.), University of Chicago (Shelly Cummings; Olufunmilayo Olopade, M.D.), University of California-Irvine (Susan L. Neuhausen, Ph.D.; Linda Steele), University of Pennsylvania Health System (Susan Domchek, M.D.; Katherine Nathanson M.D.; Tara Friebel, M.P.H.; Timothy Rebbeck, Ph.D.), University of Texas Southwestern (Gail Tomlinson, M.D.), University of Vienna (Christian Singer, M.D.), and Women’s College Hospital (Steven A. Narod, M.D.).

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Correspondence to Georgia Chenevix-Trench.

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Spurdle, A.B., Fahey, P., Chen, X. et al. Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 122, 281–285 (2010). https://doi.org/10.1007/s10549-009-0601-0

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Keywords

  • GST polymorphisms
  • BRCA1
  • BRCA2
  • Modifier gene