Integrated analysis linksTP53, NOTCH, SLC38Aand 11p with survival in patients with oral tongue squamous cell carcinoma

Abstract

15Head and neck squamous cell carcinoma (HNSCC) are a heterogeneous group of cancers 16 affecting multiple subsites, including oral cavity. Oral or anterior tongue tumors (OTSCC) are an 17 aggressive group of squamous cell carcinomas, characterized by their early spread to lymph nodes 18 and higher rate of regional failure compared to other oral cavity cancers. There is a rise in the 19 incidence of oral tongue cancer among younger population (<50yrs); many of who lack the typical 20 associated risk factors of alcohol and/or tobacco exposure. In order to carry out an ensemble 21 learning and prediction method with multiple parameters classifying survival, we generated data, on 22 somatic mutations in genes from exome sequencing, immediate upstream and downstream flanking 23 nucleotides of the somatic mutations, DNA methylation, loss of heterozygosity (LOH), copy 24 number variations (CNV), gene expression, significant pathways altered and Human Papilloma 25 Virus (HPV) infection, from 50 OTSCC patients. Results of our analysis identified somatic 26 mutations in NOTCH2 and/or TP53, and/or LOH in 11p to associate with better disease free 27 survival in HPV positive patients (P = 0.0254) and not in HPV negative patients (P = 0.414). We 28 validated the latter in patients without HPV infection from TCGA cohort (P = 0.369, N = 17 for 29 2 TCGA_ OralTongue; P = 0.472, N = 67 for all TCGA_HNSCC patients). Integrated analysis, 30 including pathways, linked survival with apoptosis and aberrant methylation in SLC38A8 (P = 31 0.0129). 32 33 Author Summary 34 Oral tongue squamous cell carcinomas (OTSCC) are a homogenous group of head and neck 35 tumors characterized with aggressive behavior among younger patients. In this report, we have 36 analysed genetic variants, expression and DNA methylation changes across 50 oral tongue primary 37 tumors along with the Human Papilloma Virus (HPV) infection status in those tumors to identify 38 factors associated with disease free survival. Our data identified somatic mutations in the genes 39 NOTCH2, TP53 and LOH in 11p, to be significantly associated with better disease free survival in 40 HPV positive patients (P = 0.0254), but not in HPV negative patients (P = 0.414). We validated the 41 latter using patients without HPV infection from TCGA (P = 0.369, N = 17 for 42 TCGA_OralTongue; P = 0.472, N = 67 for all TCGA_HNSCC patients). Integrated analysis linked 43 survival with apoptosis and aberrant methylation in SLC38A8 (P = 0.0129).44 45 48 cause of cancer worldwide [1]. In India, they account for almost 30% of all cancer cases [2]. Studies 49 on molecular biology of HNSCC in the past 5yrs have largely been concentrated on cataloging 50various genetic changes in many cancer types using high-throughput sequencing assays and 51 computational methods [3][4][5][6][7]. Unlike other oral cavity subsites, squamous cell carcinomas of 52 oral/anterior tongue tend to be associated more with younger patients [8, 9], early spread to lymph 53 nodes [8] and a higher regional failure compared t...

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes

“…The method employed here follows the method described before (32). Briefly, the algorithm performs both backward elimination of variables and selection based on the importance spectrum.…”