Abstract 2134: Bioinformatic analysis of the tumor biomarker thymidine kinase 1: Elucidating its cancer gene network and membrane expression across all cancers

Abstract

Abstract The purpose of this study was to analyze the regulatory gene cancer network of the tumor biomarker Thymidine Kinase 1 (TK1) across all cancers and identify the genes with meaningful correlations that interact and drive tumorigenesis along with TK1. In addition, we sought to find a feasible mechanism for TK1 membrane expression in cancer cells. Using data from The Cancer Genome Atlas (TCGA), the pathway commons protein interaction database, the Biogrid database and the R graphite library, we analyzed the correlation of mRNA expression levels of all proteins that were involved in TK1 metabolic pathways or physically interacted with TK1. By searching the pathway commons protein interaction database and data drawn from the graphite library in R, we found that 1495 proteins were involved with TK1 metabolism. Using Dijkstra's algorithm we found that 294 proteins had 1-2 degrees of interaction with TK1. Analysis of the Biogrid database showed that 191 proteins physically interact with TK1. The genes with higher average Pearson's correlation values across all 25 cancers had the following functions: cell cycle regulation, DNA synthesis, replication and repair, transcription factors (E2F family), transport of mono and dicarboxylate for energy production pathways, transport of nucleosides, pyrimidine metabolism, DNA methylation of tumor suppressor genes, mRNA stabilization, aging, regulation of cell proliferation, control of cyclin kinases, apoptosis, and formation of channels on cell membranes. Among the genes that had significant correlation values with TK1 (P<0.001) were: RRM2(2), CDK1, CDK2, CDK4(0), CDC20(0), CDC25A, MKI67(0), MCM3, E2Fs, CD6, PXMP2, DTYMK(1), BRCA1, EZH2(0), NUDT1(3), SLC29A2(2), SLC25A10(2), SLC16A3(3), SLC25A19(3), PRIM1, CARHSP1(0), NKIRAS2(0), METTL23(0) CENPB(0), FAF1(0), COPS6 (0), TRIM28 (0), MSH2(0), AAMP (0). Further analysis revealed that 476 of the proteins from the common pathways and Biogrid had transmembrane (tm) domains. Although it had a moderate correlation value, SEZ6L protein, which is overexpressed on the cell membrane of lung, colon and gastric cancers was a physical interactor of TK1. Additional analysis showed that the nucleoside transporter SLC29A2, that transports both adenosine and thymidine, had a tm domain and 2 degrees of interaction with TK1. Like the purinosome, we hypothesize that TK1 in malignant cells may be complexing with other pyrimidine synthesis proteins. Moreover, the physical interaction with other proteins containing tm domains could provide a path for TK1 membrane expression. Overexpression, secretion and membrane association of TK1 may be an evolutionary advantage that supply enough enzymes to modify the nucleotide pool balance necessary for DNA replication in tumor proliferating cells. Future directions will focus on the TK1 protein-protein interactions found in this analysis. Citation Format: Edwin J. Velazquez, David M. Bellini, Rachel A. Skabelund, Tyler B. Humpherys, Jonathan R. Skidmore, Brett E. Pickett, Stephen R. Piccolo, Kim L. O'Neill. Bioinformatic analysis of the tumor biomarker thymidine kinase 1: Elucidating its cancer gene network and membrane expression across all cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2134.