(514.7) Prognostic Potential of a PSAT1-Associated Gene Signature in Identifying High-Risk Patients in Early-Stage EGFR-Mutant Lung Cancer

Poster Board Number: A386

Rumeysa Biyik-Sit (University of Louisville), Brian Clem (University of Louisville)

De novo cellular production of serine may contribute to tumor growth by providing precursors for macromolecular production and one-carbon metabolism. Accordingly, multiple cancers exhibit increased expression of serine biosynthetic enzymes. For example, elevated PSAT1 (phosphoserine aminotransferase 1), which catalyzes the second step in converting 3-phosphohydroxypyruvate to phosphoserine, is associated with poorer clinical outcomes. Several reports have implicated PSAT1 in the proliferation, migration, invasion, and chemo-resistance of malignant cells. Our previous study found that PSAT1 translocated into the nucleus within EGFR-activated NSCLC cells and was associated with poorer clinical outcomes of patients with EGFR-mutant lung cancer, suggesting a relevant function for PSAT1 in EGFR-driven tumorigenesis. In this study, we designed a bioinformatic approach to identify a PSAT1-associated gene signature for EGFR-mutant lung cancer (Fig. 1). Since PC9 cells are frequently utilized as an EGFR-mutant lung cancer model, we speculated that a subset of PSAT1-regulated genes independently contributes to EGFR-driven lung tumorigenesis. For this, we transcriptionally profiled PSAT1 silenced PC9 cells. Analysis of the RNASeq identified 490 genes ( 279-down, 211-up) that were differentially expressed upon PSAT1 silencing (PSAT1-mediated DEG). We next performed a comparative analysis between PSAT1-mediated DEG and publicly available microarray datasets obtained from EGFR-mutant patient tumors. Twenty-five genes (13-down, 12-up) were differentially expressed in all EGFR-mutant lung cancer datasets. These were classified as a PSAT1-associated gene signature for EGFR-mutant lung tumors and used to assess the relationship between this gene signature and both relapse-free (RFS) and overall survival (OS) by the survival prediction tool from BRB-ArrayTools. Thirteen and seventeen genes from the 25-gene signature were found to predict the OS and RFS rates of EGFR-mutant lung cancer, respectively. However, this signature failed to predict patient outcomes for either wild-type or KRAS-mutant lung tumors. Furthermore, the expression profile of RFS high-risk patients with stage I EGFR-mutant tumor phenocopies the high-risk stage II tumor, supporting the prognostic power of PSAT1-mediated gene signature for these EGFR-mutant tumors. As early-stage cancers dominate the gene signature obtained from human EGFR-mutant lung tumors, analysis of genes involved in late-stage tumor progression and metastasis is limited. Therefore, differentially expressed genes between parental PC9-P and brain-metastatic PC9-BrM3 were extracted from the Nguyen et al. study (2009). Comparative analysis with RNA-seq data found a potential PSAT1-associated metastatic gene signature. In summary, our genomic approach yielded a PSAT1-associated gene signature with prognostic value in EGFR-mutant NSCLC patient outcomes.

P20GM103436 (KBRIN) and W81XWH-19-1-0445 (DoD-LCRP) to Dr. Brian Clem



Figure 1. Strategic flow chart to identify PSAT1-associated gene signatures from PSAT1-mediated DEG that are differentially expressed in human EGFR mutant lung tumors.