Identification and functional characterization of a novel gene signature related to prognosis and metastasis in gastric cancer

Gastric cancer (GC) is the fifth leading cause of cancer incidence and mortality worldwide. Despite the recent advances in the molecular characterization of the disease and the development of novel therapeutic approaches, the prognosis of GC remains unfavorable. Moreover, the main prognostic factors are based on clinical features such as tumor stage or age, while the molecular determinants of GC progression are still not fully understood. In this thesis, we identified and validated novel genes associated with GC recurrence and metastasis using publicly available transcriptomics data, including the TCGA and ACRG cohorts, as well as an integrated dataset we developed comprising 1,908 GC samples. We first identified ANKRD6, ITIH3, SORCS3, NPY1R and CCDC178 as novel prognosis predictors using TCGA data. We confirmed that the association of these five genes individually and as a signature with poor prognosis, recurrence and aggressive molecular subtypes in the three datasets. Among them, ANKRD6 and ITIH3 showed increased expression in metastatic disease and were more strongly correlated with the epithelial-mesenchymal transition (EMT), suggesting an involvement with this program to promote GC progression. Moreover, functional and transcriptomic analyses in ANKRD6‑silenced cells confirmed the role of this gene in regulating EMT and promoting pro‑metastatic traits. Altogether, we identified ANKRD6, ITIH3, SORCS3, NPY1R and CCDC178 as novel genes associated with poor prognosis, recurrence and advanced disease in GC. In addition, we provided the first functional characterization of ANKRD6, demonstrating its role in GC progression.