title: Variant NKX3.1 and Serum IGF-1: Investigation of Interaction in Prostate Cancer.
abstract: NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians' Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1 genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1 and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1 genotype does not modify the association between serum IGF-I levels and prostate cancer risk.
authors.affiliation: Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Muhlbradt
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Cancer Epidemiology Centre, Cancer Control Research Institute, Cancer Council Victoria, Carlton South, Victoria, Australia ; Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ortner
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hayes
authors.affiliation: Cancer Epidemiology Centre, Cancer Control Research Institute, Cancer Council Victoria, Carlton South, Victoria, Australia ; Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Hoa N
authors.initials: HN
authors.lastname: Hoang
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Meir
authors.initials: M
authors.lastname: Stampfer
authors.affiliation: Cancer Epidemiology Centre, Cancer Control Research Institute, Cancer Council Victoria, Carlton South, Victoria, Australia ; Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Giles
authors.affiliation: Division of Cancer Prevention, Department of Oncology, Lady Davis Research Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
keywords: IGF-1; IGFBP-3; NKX3.1; prostate cancer