PNNL

Abstract

Prostate cancer brings huge public health burden in men. A growing number of conventional 31 observational studies report associations of multiple circulating proteins with prostate cancer 32 risk. However, the existing findings may be subject to incoherent biases of conventional 33 epidemiologic studies. To better characterize their associations, herein, we evaluated 34 associations of genetically predicted concentrations of plasma proteins with prostate cancer 35 risk. We developed comprehensive genetic prediction models for protein levels in plasma. 36 After testing 1,838 proteins in 79,194 cases and 61,112 controls of European ancestry 37 included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 37 proteins 38 showed significant associations with prostate cancer risk, including 21 previously reported 39 proteins and 16 novel proteins. Of them, 20 proteins showed negative associations and 17 40 showed positive associations with prostate cancer risk. For 21 of the identified proteins, 41 somatic changes of gene deletion, insertion, or missense mutations were detected in prostate 42 cancer patients in The Cancer Genome Atlas. Genes encoding these proteins were 43 significantly involved in cancer-related pathways. We further identified drugs targeting the 44 identified proteins, which may serve as candidates for drug repurposing for treating prostate 45 cancer. In conclusion, this study identifies novel protein biomarker candidates for prostate 46 cancer risk, which may provide new perspectives on the etiology of prostate cancer and 47 improve its therapeutic strategies.