Integrated analysis links TP53, NOTCH, SLC38A and 11p with survival in patients with oral tongue squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) are a heterogeneous group of cancers affecting multiple subsites, including oral cavity. Oral or anterior tongue tumors (OTSCC) are an aggressive group of squamous cell carcinomas, characterized by their early spread to lymph nodes and higher rate of regional failure compared to other oral cavity cancers. There is a rise in the incidence of oral tongue cancer among younger population (<50yrs); many of who lack the typical associated risk factors of alcohol and/or tobacco exposure. In order to carry out an ensemble learning and prediction method with multiple parameters classifying survival, we generated data, on somatic mutations in genes from exome sequencing, immediate upstream and downstream flanking nucleotides of the somatic mutations, DNA methylation, loss of heterozygosity (LOH), copy number variations (CNV), gene expression, significant pathways altered and Human Papilloma Virus (HPV) infection, from 50 OTSCC patients. Results of our analysis identified somatic mutations in NOTCH2 and/or TP53, and/or LOH in 11p to associate with better disease free survival in HPV positive patients (P = 0.0254) and not in HPV negative patients (P = 0.414). We validated the latter in patients without HPV infection from TCGA cohort (P = 0.369, N = 17 for TCGA_ OralTongue; P = 0.472, N = 67 for all TCGA_HNSCC patients). Integrated analysis, including pathways, linked survival with apoptosis and aberrant methylation in SLC38A8 (P = 0.0129).\n\nAuthor SummaryOral tongue squamous cell carcinomas (OTSCC) are a homogenous group of head and neck tumors characterized with aggressive behavior among younger patients. In this report, we have analysed genetic variants, expression and DNA methylation changes across 50 oral tongue primary tumors along with the Human Papilloma Virus (HPV) infection status in those tumors to identify factors associated with disease free survival. Our data identified somatic mutations in the genes NOTCH2, TP53 and LOH in 11p, to be significantly associated with better disease free survival in HPV positive patients (P = 0.0254), but not in HPV negative patients (P = 0.414). We validated the latter using patients without HPV infection from TCGA (P = 0.369, N = 17 for TCGA_OralTongue; P = 0.472, N = 67 for all TCGA_HNSCC patients). Integrated analysis linked survival with apoptosis and aberrant methylation in SLC38A8 (P = 0.0129).