Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers

Abstract

Background The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs. Methods The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein–protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications. Results This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86–0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65–0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94–0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10–1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03–1.06), GSTP1 (OR: 0.82, 95% CI 0.74–0.90), and CTSS (OR: 0.91, 95% CI 0.88–0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80–0.91), ISLR2 (OR: 0.87, 95% CI 0.82–0.93), and CTSF (OR: 1.14, 95% CI 1.08–1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91–0.95), ICAM5 (OR: 0.95, 95% CI 0.93–0.97), and FLRT3 (OR: 1.10, 95% CI 1.05–1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment. Conclusions This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

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

“…Despite, the application of MR in identifying plasma proteins as drug targets in breast cancer is still sporadic. For instance, one study performed MR analysis on a single cohort of 732 plasma proteins, where GDI2 and CTSF were identified as potential targets for breast cancer ( Ren et al, 2023 ), aligning with our research. However, it is important to note that this study also focused on pan-cancer research and lacked association analysis.…”

Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma

“…ALAD is significantly decreased in breast and hepatocellular carcinoma, and its reduced expression is correlated with an unfavorable prognosis in patients [ 67 , 68 ]. Yh Yang et al also found a significant association between ICAM5 and LUAD risk, suggesting its potential as a target for lung cancer [ 69 , 70 ]. MDGA2 is a tumor suppressor in gastric carcinogenesis, and its hypermethylation is an independent prognostic factor in gastric cancer patients [ 71 ].…”

PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression

“…Contemporary zeniths in research, namely cancer immunotherapy, which includes checkpoint inhibitors and adoptive cellular therapy, strategize to recalibrate the immune system for the identification and eradication of neoplastic cells. A luminary target within this therapeutic domain for addressing prostate carcinoma is the PDIA3 protein [ 26 , 27 ]. The realms of biotechnology and microbial studies ceaselessly advance in devising innovative curatives for an array of carcinomas, CRC included, proffering a glimmer of solace for those besieged by this scourge.…”