title: Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.
abstract: Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Pomerantz
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Flavin
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Schafer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
mesh_terms: D002448:Cell Adhesion; D049109:Cell Proliferation; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D056918:Nuclear Receptor Coactivators / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein