Identification of a Gene-Expression-Based Surrogate of Genomic Instability during Oral Carcinogenesis

SIMPLE SUMMARY: New personalized cancer prevention strategies may decrease the mortality of oral cancer that can arise from oral potentially malignant disorders (OPMD). A major cancer hallmark is the acquisition of multiple deletions or amplifications of genomic material fragments leading to genomic instability (GI). Our goal was to identify a set of genes whose expression was associated with GI. A total of 20 genes correlated with GI were identified in two independent datasets of head and neck cancer (including oral cancer). We computed a score of those genes, referred to as the GIN score, in with each sample from multiple validation datasets. We show that the GIN score: (i) was correlated with GI, (ii) increased at different stages of oral carcinogenesis from normal mucosa to oral cancer, and (iii) was associated with malignant transformation of OPMD. The GIN score is a promising biomarker for identifying patients suffering from OPMD with high risk of oral cancer. ABSTRACT: Background: Our goal was to identify a gene-expression-based surrogate of genomic instability (GI) associated with the transformation of oral potentially malignant disorder (OPMD) into oral squamous cell carcinoma (OSCC). Methods: GI was defined as the fraction of genome altered (FGA). Training sets included the CCLE and TCGA databases. The relevance of the enrichment score of the top correlated genes, referred to as the GIN score, was evaluated in eight independent public datasets from the GEO repository, including a cohort of patients with OPMD with available outcome. Results: A set of 20 genes correlated with FGA in head and neck SCC were identified. A significant correlation was found between the 20-gene based GIN score and FGA in 95 esophagus SCC (r = 0.59) and 501 lung SCC (r = 0.63), and in 33 OPMD/OSCC (r = 0.38). A significantly increased GIN score was observed at different stages of oral carcinogenesis (normal–dysplasia –OSCC) in five independent datasets. The GIN score was higher in 10 OPMD that transformed into oral cancer compared to 10 nontransforming OPMD (p = 0.0288), and was associated with oral-cancer-free survival in 86 patients with OPMD (p = 0.0081). Conclusions: The GIN score is a gene-expression surrogate of GI, and is associated with oral carcinogenesis and OPMD malignant transformation.