The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers
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Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan® allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93–1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82–1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84–1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66–1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
KeywordsBreast cancer Ovarian cancer-Klotho BRCA Modifier gene
This research was supported in part by grants from the Israel Cancer Association to EF for the Israeli consortium of inherited breast cancer; The CIMBA data management and analysis is supported by Cancer Research, UK (C12292/A11174). ACA is a Cancer Research, UK Senior Cancer Research Fellow. GCT and ABS are supported by Fellowships from the Australian National Health and Medical Research Council. 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. The kConFab clinical Follow Up Study has been funded by NHMRC, the National Breast Cancer Foundation and Cancer Australia. kConFab general acknowledgements: 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 for their contributions to this resource, and the many families who contribute to kConFab; Georgetown Center (CI) received support from the Familial Cancer Registry and the Tissue Culture Shared Registry at Georgetown University (NIH/NCI Grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. Susan L Neuhasen’s support was received from NIH Grant R01CA74415 (to SLN), SLN was partially supported by the Morris and Horowitz Families Endowed Professorship; The MAYO study was supported by NIH Grant CA128978, the Breast Cancer Research Foundation and the Komen Foundation for the Cure; The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation; SWE BRCA collaborators—Per Karlsson, Margareta Nordling, Annika Bergman, and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Maria Soller, Helena Jernström, Katja Harbst, and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza, and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin, and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist, and Niklas Dahl, Uppsala University Hospital; Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Susan Peock, Debra Frost, Steve D. Ellis, Elena Fineberg, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Marc Tischkowitz, Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Emma Killick, Sue Martin, Gillian Rea, Anjana Kulkarni. 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, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR Grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385; The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) GC-HBOC is supported by a Grant of the German Cancer Aid (Grant 109076) and the Centre of Molecular Medicine Cologne, Germany (CMMC); University of Kansas Medical Center (KUMC) would like to thank JoEllen Weaver for her help collecting patient data and samples. A.K.G. was funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund while at FCCC. The author acknowledges support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor; UPENN funding- Breast Cancer Research Foundation (to KLN), Susan G. Komen for the Cure, MacDonald Women’s Cancer Risk Evaluation Program (to SMD); MSKCC was supported by grants to KO by the Breast Cancer Research Foundation, The Starr Cancer Consortium, The Robert and Kate Niehaus Clinical Cancer Initiative, and the Schreiber Family Research Fund; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F. B. L. Hogervorst, S. Verhoef, M. Verheus, L. J. van‘t Veer, F. E. van Leeuwen, M. A. Rookus, J. P. Knol-Bout; Erasmus Medical Center, Rotterdam, NL: M. Collée, A. M. W. van den Ouweland, A. Jager, M. J. Hooning, M. M. A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C. J. van Asperen, J. T. Wijnen, M. P. Vreeswijk, R. A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M. J. Ligtenberg, N. Hoogerbrugge, C. M. Kets; University Medical Center Utrecht, Utrecht, NL: M. G. Ausems, R. B. van der Luijt; Amsterdam Medical Center, NL: C. M. Aalfs, T. A. van Os; VU University Medical Center, Amsterdam, NL: J. J. P. Gille, Q. Waisfisz, H. E. J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E. B. Gomez-Garcia, K. E. P. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H. F. Vasen. The HEBON study is supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW Grant 91109024.
Conflict of interest
All authors declare that they have no conflict of interest.
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