title: Fine-mapping the 2q37 and 17q11.2-q22 loci for novel genes and sequence variants associated with a genetic predisposition to prostate cancer.
abstract: The 2q37 and 17q12-q22 loci are linked to an increased prostate cancer (PrCa) risk. No candidate gene has been localized at 2q37 and the HOXB13 variant G84E only partially explains the linkage to 17q21-q22 observed in Finland. We screened these regions by targeted DNA sequencing to search for cancer-associated variants. Altogether, four novel susceptibility alleles were identified. Two ZNF652 (17q21.3) variants, rs116890317 and rs79670217, increased the risk of both sporadic and hereditary PrCa (rs116890317: OR = 3.3-7.8, p = 0.003-3.3 × 10(-5) ; rs79670217: OR = 1.6-1.9, p = 0.002-0.009). The HDAC4 (2q37.2) variant rs73000144 (OR = 14.6, p = 0.018) and the EFCAB13 (17q21.3) variant rs118004742 (OR = 1.8, p = 0.048) were overrepresented in patients with familial PrCa. To map the variants within 2q37 and 17q11.2-q22 that may regulate PrCa-associated genes, we combined DNA sequencing results with transcriptome data obtained by RNA sequencing. This expression quantitative trait locus (eQTL) analysis identified 272 single-nucleotide polymorphisms (SNPs) possibly regulating six genes that were differentially expressed between cases and controls. In a modified approach, prefiltered PrCa-associated SNPs were exploited and interestingly, a novel eQTL targeting ZNF652 was identified. The novel variants identified in this study could be utilized for PrCa risk assessment, and they further validate the suggested role of ZNF652 as a PrCa candidate gene. The regulatory regions discovered by eQTL mapping increase our understanding of the relationship between regulation of gene expression and susceptibility to PrCa and provide a valuable starting point for future functional research.
authors.affiliation: BioMediTech, University of Tampere and Fimlab Laboratories, FI-33520, Tampere, Finland.
authors.forename: Virpi H
authors.initials: VH
authors.lastname: Laitinen
authors.forename: Tommi
authors.initials: T
authors.lastname: Rantapero
authors.forename: Daniel
authors.initials: D
authors.lastname: Fischer
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Vuorinen
authors.forename: Teuvo L J
authors.initials: TL
authors.lastname: Tammela
authors.forename: Tiina
authors.initials: T
authors.lastname: Wahlfors
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
mesh_terms: D016386:Chromosome Walking; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005387:Finland; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: D004268:DNA-Binding Proteins; C525993:ZNF652 protein, human
keywords: 17q11.2-q22; 2q37; genetic predisposition; prostate cancer risk; susceptibility loci