Abstract
Purpose Network analysis methods can potentially quantify cancer disturbances in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs), and to rank key genes associated with prognosis.
Methods Copy number alterations (CNAs) from targeted and whole exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein-protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier-Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan-Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups.
Results The network curvature analysis stratified patients at high risk of mortality with p=0.00047 in Kaplan-Meier analysis. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer.
Conclusion Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.
Competing Interest Statement
D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech; and personal/consultancy fees from Merck, Synlogic Therapeutics, GSK, Bristol Myers Squibb, Genentech, Xencor, Memgen, and Agenus. These are all outside of the scope of the submitted work. J.R.-F. reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro. These are all outside the scope of the submitted work. B.W. reports ad hoc membership of the advisory board of Repare Therapeutics, outside the scope of the submitted work. J.D. is a shareholder in PaigeAI. This is outside the scope of the submitted work. Y.L. reports research funding from Astra Zeneca and GSK/Tesaro outside the scope of the submitted work. None of the other authors report a potential COI.