Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility

Abstract

Background: Predicting protein levels from genotypes for proteome-wide association studies (PWAS) may provide insight to the mechanisms underlying cancer susceptibility. Methods: We performed PWAS of breast, endometrial, ovarian, and prostate cancers and their subtypes in several large European ancestry discovery consortia (effective sample size: 237,483 cases/317,006 controls) and tested the results for replication in an independent European ancestry GWAS (31,969 cases/410,350 controls). We performed PWAS using the cancer GWAS summary statistics and two sets of plasma protein prediction models, followed by colocalization analysis. Results: Using Atherosclerosis Risk in Communities (ARIC) models, we identified 93 protein-cancer associations (FDR < 0.05). We then performed a meta-analysis of the discovery and replication PWAS, resulting in 61 significant protein-cancer associations (FDR < 0.05). Ten of 15 protein-cancer pairs that could be tested using Trans-omics for Precision Medicine (TOPMed) protein prediction models replicated with the same directions of effect in both cancer GWAS (p<0.05). To further support our results, we applied Bayesian colocalization analysis and found colocalized SNPs for SERPINA3 protein levels and prostate cancer (Posterior Probability, PP=0.65) and SNUPN protein levels and breast cancer (PP=0.62). Conclusions: We used proteome-wide association studies (PWAS) to identify potential biomarkers of hormone-related cancer risk. SNPs in SERPINA3 and SNUPN did not reach genome-wide significance for cancer in the original GWAS, highlighting the power of PWAS for novel locus discovery, with the added advantage of providing directions of protein effect. Impact: PWAS and colocalization are promising methods to identify potential molecular mechanisms underlying complex traits.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis

“…This disruption of cellular homeostasis contributes to the initiation and progression of tumorigenesis, particularly in the context of leukemia ( 30 ). A recent proteome association study has further confirmed the association between SNUPN and breast cancer, which was in consistent with our finding ( 31 ).…”

Elucidating the susceptibility to breast cancer: an in-depth proteomic and transcriptomic investigation into novel potential plasma protein biomarkers

“…Recent advancements in molecular technologies and techniques have shown significant potential in utilizing plasma protein biomarkers such as Adipsin and CA15-3 for early detection and quantification for diagnostic and therapeutic applications in breast cancer ( Afzal et al, 2022 ; Rajkumar et al, 2022 ; Veyssière et al, 2022 ). A recent high-throughput study identified 61 proteins associated with various cancers ( Gregga et al, 2023 ). While this study provided valuable insights into pan-cancer associations, it did not explore causation.…”