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Genetic Variation in the Growth Hormone Synthesis Pathway in Relation to Circulating Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Breast Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study

¹ IARC, Lyon, France; ² Institut Gustave Roussy, Villejuif, France; ³ German Cancer Research Center, Heidelberg, Germany; ⁴ German Institute of Human Nutrition, Potsdam, Germany; ⁵ University of Athens Medical School, Athens, Greece; ⁶ CSPO-Scientific Institute of Tuscany, Florence, Italy; ⁷ Cancer Registry, Azienda Ospedaliera "Civile M.P. Arezzo," Ragusa, Italy; ⁸ Imperial College, London, United Kingdom; ⁹ University of Torino, Turin, Italy; ¹⁰ National Cancer Institute, Milan, Italy; ¹¹ National Institute of Public Health and the Environment, Bilthoven, the Netherlands; ¹² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; ¹³ Catalan Institute of Oncology, Barcelona, Spain; ¹⁴ Instituto de Salud Pública, SNS-O, Pamplona, Spain; ¹⁵ Servicio de Epidemiología, Consejería de Sanidad y Consumo, Murcia, Spain; ¹⁶ Public Health Directorate, Consejería de Sanidad y Servicios Sociales de Asturias, Oviedo, Spain; ¹⁷ Public Health Division of Gipuzkoa, Health Department of the Basque Country, San Sebastián, Spain; ¹⁸ School of Public Health of Andalucia, Granada, Spain; ¹⁹ Cancer Research UK, Epidemiology Unit, University of Oxford, Oxford, United Kingdom; and ²⁰ Medical Research Council Dunn Human Nutrition Unit, Welcome Trust/Medical Research Council Building; ²¹ Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, United Kingdom

Requests for reprints: Rudolf Kaaks, Hormones and Cancer Team, International Agency for Research on Cancer, 150 cours Albert-Thomas, F-69372 Lyon, France. Phone: 33-4-72738553; Fax: 33-4-72738361. E-mail: kaaks{at}iarc.fr

Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk.

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