Abstract 2969: Genetically predicted blood protein biomarkers and prostate cancer risk: an analysis in over 140,000 European descendants
Authors: Wu Lang , Shu Xiang , Bao Jiandong , Guo Xingyi ,   the PRACTICAL, CRUK, BPC3, CAPS, PEGASUS consortia, Kote-Jarai Zsofia , Haiman Christopher A. , Eeles Rosalind A. , Zheng Wei 
Published: August 2018

Prostate cancer (PrCa) is the second most frequently diagnosed malignancy among males in many countries. Several protein markers measured in blood have been found to be associated with PrCa risk. However, most previous studies assessed only a small number of biomarkers or included a small sample size. To search for novel protein biomarkers for PrCa risk, we performed a large study in 79,194 prostate cancer cases and 61,112 controls of European ancestry included in PRACTICAL/ELLIPSE consortia by using genetic instruments.

Protein quantitative trait loci (pQTLs) for 1,478 plasma proteins identified in a large study of 3,301 European descendants were used as instruments to evaluate associations between genetically predicted protein levels and PrCa risk. For proteins showing a significant association with PrCa risk, we further evaluated whether genetically predicted mRNA expression levels of the corresponding genes were associated with PrCa risk, by using mRNA expression prediction models for blood, prostate and cross tissue built using data of the Genotype-Tissue Expression Project.

We identified 31 proteins showing an association of their predicted levels with PrCa risk at a false discovery rate &lt; 0.05, including 22 encoded by genes located more than 500 Kb away from any reported PrCa risk variants. These include proteins encoded by GSTP1, whose methylation was identified as a potential biomarker for PrCa detection, and MSMB, SPINT2, and CTSS, which were previously implicated as potential target genes of PrCa risk variants identified in genome-wide association studies. Eighteen of the proteins showed an inverse association and 13 showed a positive association. Among the 23 of the genes with mRNA expression prediction models built, seven showed an mRNA-PrCa association at p &lt; 0.05 with a same direction of effect as the protein-PrCa association. For 28 of the identified genes, somatic changes of short indels, splice site, nonsense, or missense mutations were detected in PrCa patients in The Cancer Genome Atlas (enrichment p&lt;0.0001). Pathway enrichment analysis showed that these genes were significantly enriched in cancer related pathways, including STAT3 Pathway, Glutathione Redox Reactions I, Glutathione-mediated Detoxification, Endoplasmic Reticulum Stress Pathway, and tRNA Splicing.

Our study has identified multiple proteins significantly associated with PrCa risk. Further research is needed to evaluate potential utility of the identified proteins in early detection of PrCa.

Citation Format: Lang Wu, Xiang Shu, Jiandong Bao, Xingyi Guo, the PRACTICAL, CRUK, BPC3, CAPS, PEGASUS consortia, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles, Wei Zheng. Genetically predicted blood protein biomarkers and prostate cancer risk: an analysis in over 140,000 European descendants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2969.