Association of Prostate Cancer Risk Variants with Gene Expression in Normal and Tumor Tissue

Abstract

Background Numerous germline genetic variants are associated with prostate cancer risk, but their biological role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide. Methods We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N=160) and prostate tumor (N=264) tissue from participants of the Physicians’ Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test. Results In addition to confirming previously reported associations, we detected several new significant (p<0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, four genes (MSMB, NUDT11, NEFM, KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (p<2.5x10−6). Many more genes had a false discovery rate <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue. Conclusions The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biological and epidemiological studies. Impact Determining the biological role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention.

Association between RNASEL, MSR1, and ELAC2 single nucleotide polymorphisms and gene expression in prostate cancer risk

“…In the present study, we expected to prove that RNASEL, MSR1, KLK3, AR, and ELAC2 mRNA expression has a diagnostic value in patients with PCa by the exposed expression patterns in PCa in these genes [21]. Determining the biologic role of these variants-which would help better understanding PCa etiology-and identifying new targets for chemoprevention is essential [22].…”

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

“…lung cancer, meningiomas and breast cancer (Fevre-Montange, et al, 2009; Molina-Pinelo, et al, 2014; Pio, et al, 2010; Thakkar, et al, 2010). A very recent study found association of expression of MLPH (and some other genes) with nearby SNPs in prostate tissue (Penney, et al, 2015). In small lung cell cancer MLPH mRNA was identified as a target of differentially expressed miRNAs (Molina-Pinelo, et al, 2014).…”

MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer

“…Whole-transcriptome mRNA expression was available from a prior case–control study, including 404 men in PHS and HPFS with prostate cancer (14). The study design is described in detail in reference 14.…”