title: A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.
abstract: Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Williams
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Minnkyong
authors.initials: M
authors.lastname: Lee
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Andreas
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Shashank J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Suiyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Settara
authors.initials: S
authors.lastname: Chandrasekharappa
authors.affiliation: Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, United States of America.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, United States of America.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics*; D000818:Animals; D039521:CD11c Antigen / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics; D016914:Ribonuclease H / Q000235:genetics
chemical_list: D039521:CD11c Antigen; C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C586147:LPCAT2 protein, human; C091139:ribonuclease HII; D016914:Ribonuclease H