Despite improvements in surgical and perioperative adjuvant therapy, gastric adenocarcinoma carries a 75% case-fatality rate and approximately 40% of Western patients die of recurrent disease. As an important regulator of centriolar duplication, cell motility, and invasion, polo-like kinase 4 (PLK4) has been identified as an oncogene which affects tumourigenesis, cancer metastasis, and response to chemotherapy. Change in PLK4 expression has been identified in numerous human cancers, but Plk4’s role in gastric adenocarcinoma is not well defined; I hypothesized that Plk4 or its interactors could be intimately involved in gastric cancer metastasis and progression. The high degree of molecular heterogeneity in gastric adenocarcinoma and variability in patient outcomes highlight the importance of utilizing patient cohorts to identify novel therapeutic targets. As such, I performed a comprehensive clinical chart review of 238 consecutive gastric adenocarcinoma patients who underwent a curative-intent resection. Recurrence remained a major cause of death in this patient cohort and was only predicted by pathologic staging. Our laboratory had previously identified a number of high-confidence functional interactors of Plk4, and, for each interactor, I determined the mRNA expression in tumour vs paired normal mucosa in our patient cohort. From this interrogation, I identified low expression of FAM46C, a Plk4 inhibitor and tumour suppressor in multiple myeloma, as a novel predictor of inferior disease-specific survival and recurrence at locoregional or distant sites. In vitro experiments demonstrate that FAM46C expression is cytotoxic to gastric cancer cells and suppresses cell migration. RNA-sequencing of patients’ gastric tumour and normal mucosa further reveal that ion-channel related pathways are significantly dysregulated in low-FAM46C tumours, but not in high-FAM46C tumours, implying a novel relationship between FAM46C and ion channels. Targeted evaluation revealed a correlation between the expression of FAM46C and KCNQ1, the main potassium recycler in parietal cells, both in vitro and in patient samples. FAM46C-depleted gastric cancer cells were also better able to survive in a high KCl concentration environment. These findings provide support for FAM46C as a tumour suppressor and therapeutic target in gastric adenocarcinoma patients, and potentially reveal a new role for FAM46C in regulating KCNQ1-mediated evasion of apoptosis and epithelial-to-mesenchymal transition.Ph.D
