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EV237/#833  Identifying therapeutic targets for ovarian cancer: a druggable genome-wide Mendelian randomization study
  1. Siyu Chen1 and
  2. Min Zheng2
  1. 1Sun Yat-sen University Cancer Center, Guangzhou, China
  2. 2Sun Yat-sen University Cancer Center, Gynecology, Guangzhou, China

Abstract

Introduction Ovarian cancer (OC) remains a major disease posing a threat to women’s health, but there is currently no completely effective treatment available. Here, we conducted Mendelian randomization (MR) study to identify novel therapeutic targets relevant to OC and then analyse their potential side effects.

Methods A two-sample MR integrating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) for 5716 druggable targets was performed to estimate the causal effects of actionable genes on OC. The GWAS data for OC were obtained from a generalized linear mixed model association of European ancestry. Colocalization analyses were further conducted to verify the candidate drugs that were identified from MR analyses. Additionally, we assessed the side effects of the identified actionable genes using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for actionable genes using virtual screening of the ZINC20 database.

Results We identified one significant MR association (HMOX1) and three suggestive MR associations (KIR3DL1, CCNC, H6PD) using eQTL genetic instruments, and genes (HMOX1, KIR3DL1, CCNC) were further confirmed by colocalization analyses (PPH4 > 0.8). The Phe-MR indicated that the three potential therapeutic targets for OC had no significant adverse effects. Based on receptor-based pharmacophore model, docking results, pharmacokinetic profile, molecular interactions with HMOX1, several compounds (ZINC000038143594 & ZINC000038559596) were retrieved as lead candidates to be further scrutinized in the in vitro assay and in vivo animal testing.

Conclusion/Implications This study provides genetic evidence supporting the potential therapeutic benefits of targeting HMOX1 for OC treatment and prioritizes approved druggable targets for OC.

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