Identification of a central network hub of key prognostic genes based on correlation between transcriptomics and survival in patients with metastatic solid tumors.

Background: Dysregulated pathways in cancer may be hub addicted. Identifying these dysregulated networks for targeting might lead to novel therapeutic options.
Objective: Considering the hypothesis that central hubs are associated with increased lethality, identifying key hub targets within central networks could lead to the development of novel drugs with improved efficacy in advanced metastatic solid tumors.
Design: Exploring transcriptomic data (22,000 gene products) from the WINTHER trial ( N  = 101 patients with various metastatic cancers), in which both tumor and normal organ-matched tissue were available.
Methods: A retrospective in silico analysis of all genes in the transcriptome was conducted to identify genes different in expression between tumor and normal tissues (paired t -test) and to determine their association with survival outcomes using survival analysis (Cox proportional hazard regression algorithm). Based on the biological relevance of the identified genes, hub targets of interest within central networks were then pinpointed. Patients were grouped based on the expression level of these genes ( K -mean clustering), and the association of these groups with survival was examined (Cox proportional hazard regression algorithm, Forest plot, and Kaplan-Meier plot).
Results: We identified four key central hub genes- PLOD3, ARHGAP11A, RNF216 , and CDCA8 , for which high expression in tumor tissue compared to analogous normal tissue had the most significant correlation with worse outcomes. The correlation was independent of tumor or treatment type. The combination of the four genes showed the highest significance and correlation with the poorer outcome: overall survival (hazard ratio (95% confidence interval (CI)) = 10.5 (3.43-31.9) p  = 9.12E-07 log-rank test in a Cox proportional hazard regression model). Findings were validated in independent cohorts.
Conclusion: The expression of PLOD3, ARHGAP11A, RNF216 , and CDCA8 constitute, when combined, a prognostic tool, agnostic of tumor type and previous treatments. These genes represent potential targets for intercepting central hub networks in various cancers, offering avenues for novel therapeutic interventions.
Competing Interests: V.L., C.B., and F.W. are full-time employees of the Worldwide Innovative Network (WIN) Association—WIN Consortium. WIN Association—WIN Consortium is the owner of the patent family entitled Digital Display. The inventors are V.L. and S.M. E.Ra. receives consulting and is a shareholder of SCOR Health Science, GenoScience Pharma, and Stromacare, is a shareholder of Axoltis, is a Scientific Director of Institut des Vaisseaux et du Sang (IVS), is a member of the Board of Directors of Institut National du Cancer (INCa France). S.M. receives consultancy from WIN Association—WIN Consortium. A.O. receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim, and AstraZeneca. M.D. reports consulting or advisory role: Amgen, AstraZeneca, Bayer, Daiichi Sankyo, GlaxoSmithKline, Ipsen, Merck Serono, MSD, Pierre Fabre, Roche, Servier, Sotio, and Zymeworks. Speakers’ bureau: Amgen, AstraZeneca, Bayer, Merck KgaA, MSD, Pierre Fabre, Pfizer, Roche, Servier, and Terumo. G.B. collaborates in formal clinical trial contracts, IITs, and in joint grants funded by Canadian and Quebec governments with Roche, Merck, Novartis, Astra-Zeneca, Bayer, Esperas, Aurka, Caprion, MRM. U.L. reports advisory board roles at Bayer, Pfizer, and Novartis. Research grants: BMS, Roche, Pfizer, Lilly, Incyte, and GSK. R.L.S. is the Chairman of the WIN Association—WIN Consortium. He declares Research Support: and continues to serve as the PI of the ASCO TAPUR trial. ASCO receives research grants from the following companies in support of this trial: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Seagen, TAIHO. He does not personally receive any compensation from these companies; receives Consulting: he is a consultant to the following companies: Aadi Bioscience*Brylogyx, Cellworks*, Clarified Precision Medicine*, EQRx*, Illumina*, Scandion Oncology* ZephyrAI*, and receive compensation from those designated (*) in the last 2 years. Board Service: He is a member of the Board of Directors of the following companies and receives compensation from each: Clarified Precision Medicine and Leap Therapeutics. R.K. is Chief Medical Officer of the WIN Association—WIN Consortium. She has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, MedImmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. I.B.N., A.T.R., J.R., F.C.N., and E.Ru. report no competing interests. All authors have read the policy of conflicts of interests.
(© The Author(s), 2024.)