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Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
背景：对靶向癌症治疗的兴趣正在迅速增长。虽然已经开发并采用了许多癌症生物标志物和靶向治疗策略，在癌症的早期诊断和靶向治疗方面仍然存在显著的局限性和挑战.因此，迫切需要确定新的靶标并开发新的靶向药物。
方法：本研究采用顺式-孟德尔随机化（cis-MR）和共定位分析进行。我们分析了732种血浆蛋白的数据，以确定与8种位点特异性癌症相关的潜在药物靶标。使用UKBiobank数据集进一步验证了这些发现。然后，我们还构建了蛋白质-蛋白质相互作用网络,以检查已鉴定的蛋白质与现有癌症药物靶标之间的相互作用.
结果：这项MR分析揭示了五种血浆蛋白与前列腺癌之间的关联，五个患有乳腺癌，还有三个患有肺癌.随后，这些蛋白质被分为四个不同的目标组，重点关注1级和2级靶标，因为它们有更高的成为药物靶标的潜力。我们的研究表明，遗传预测的KDELC2（OR：0.89，95％CI0.86-0.93）和TNFRSF10B（OR：0.74，95％CI0.65-0.83）与前列腺癌呈负相关。此外，我们观察到CPNE1（OR：0.96，95％CI0.94-0.98）与乳腺癌之间呈负相关，而PDIA3（OR：1.19，95%CI1.10-1.30）被发现与乳腺癌风险相关。此外,我们还建议SPINT2(OR：1.05，95%CI1.03-1.06)，GSTP1（OR：0.82，95%CI0.74-0.90），和CTSS（OR：0.91，95％CI0.88-0.95）可能是前列腺癌的潜在治疗靶标。同样，GDI2（或：0.85，95%CI0.80-0.91），ISLR2（OR：0.87，95%CI0.82-0.93），和CTSF（OR：1.14，95％CI1.08-1.21）可能是乳腺癌的潜在目标。此外,我们确定了SFTPB(OR：0.93，95%CI0.91-0.95)，ICAM5（OR：0.95，95%CI0.93-0.97），和FLRT3（OR：1.10，95%CI1.05-1.15）作为肺癌的潜在靶标。值得注意的是,TNFRSF10B,发现GSTP1和PDIA3与前列腺癌或乳腺癌治疗中使用的当前药物的靶蛋白相互作用。
结论：这项综合分析强调了在三种位点特异性癌症中具有潜在作用的13种血浆蛋白。在这方面的持续研究可能揭示他们的治疗潜力，特别是KDELC2、TNFRSF10B、CPNE1和PDIA3为更有效的癌症治疗铺平了道路。
方法：本研究采用顺式-孟德尔随机化（cis-MR）和共定位分析进行。我们分析了732种血浆蛋白的数据，以确定与8种位点特异性癌症相关的潜在药物靶标。使用UKBiobank数据集进一步验证了这些发现。然后，我们还构建了蛋白质-蛋白质相互作用网络,以检查已鉴定的蛋白质与现有癌症药物靶标之间的相互作用.
结果：这项MR分析揭示了五种血浆蛋白与前列腺癌之间的关联，五个患有乳腺癌，还有三个患有肺癌.随后，这些蛋白质被分为四个不同的目标组，重点关注1级和2级靶标，因为它们有更高的成为药物靶标的潜力。我们的研究表明，遗传预测的KDELC2（OR：0.89，95％CI0.86-0.93）和TNFRSF10B（OR：0.74，95％CI0.65-0.83）与前列腺癌呈负相关。此外，我们观察到CPNE1（OR：0.96，95％CI0.94-0.98）与乳腺癌之间呈负相关，而PDIA3（OR：1.19，95%CI1.10-1.30）被发现与乳腺癌风险相关。此外,我们还建议SPINT2(OR：1.05，95%CI1.03-1.06)，GSTP1（OR：0.82，95%CI0.74-0.90），和CTSS（OR：0.91，95％CI0.88-0.95）可能是前列腺癌的潜在治疗靶标。同样，GDI2（或：0.85，95%CI0.80-0.91），ISLR2（OR：0.87，95%CI0.82-0.93），和CTSF（OR：1.14，95％CI1.08-1.21）可能是乳腺癌的潜在目标。此外,我们确定了SFTPB(OR：0.93，95%CI0.91-0.95)，ICAM5（OR：0.95，95%CI0.93-0.97），和FLRT3（OR：1.10，95%CI1.05-1.15）作为肺癌的潜在靶标。值得注意的是,TNFRSF10B,发现GSTP1和PDIA3与前列腺癌或乳腺癌治疗中使用的当前药物的靶蛋白相互作用。
结论：这项综合分析强调了在三种位点特异性癌症中具有潜在作用的13种血浆蛋白。在这方面的持续研究可能揭示他们的治疗潜力，特别是KDELC2、TNFRSF10B、CPNE1和PDIA3为更有效的癌症治疗铺平了道路。
