Genomic characterization of tobacco/ nut chewing HPV-negative early stage tongue tumors identify MMP10 as a candidate to predict metastases

Clinical collaborator: Dr. Sudhir Nair (ACTREC/ TMH)

Tongue squamous cell carcinoma (TSCC) is the most predominant form of oral cancer in developed countries with varying incidence in developing countries wherein diverse etiological factors such as chewing betel-quid comprising betel leaf, areca nut and slaked lime forms distinct underlying genetic alterations that remain uncharacterized to date. In about 27-40% early stage TSCC patients (pT1 or pT2) represent with lymph node metastasis. They are treated by surgery. Among patients with clinically node negative status, about 30% are known to have occult metastases that are very difficult to be diagnosed. As a recourse the physicians commonly recommend preventive neck lymph node surgery to reduce the risk of cancer recurrence and spread for all patients. This underscores an unmet need for  identification of prognostic bio-markers to stratify the patients who are likely to develop metastases.

Here, we present first and most comprehensive glance to genomic alterations and mutational signature across 57 early stage (pT1 and pT2) derived from HPV-negative early stage tongue cancer patients habitual of chewing betel nuts, areca nuts, lime or tobacco using by whole exome and whole transcriptome sequencing followed by validation using orthologous methods. We present several lines of distinct features underlie this study attributing to unique aetiology, subsite, and specific population, which have been previously described for HNSCC The mutational profile of large fraction of patients display high frequency (53%) of C:G > A:T transversion in exome sequencing data—a hallmark of tobacco usage—reflecting tobacco as the most predominant etiological agent. We present the first report to describe EGFR amplification in TSCC mutually exclusive to 11q13.3 (CCND1, FGF19, ORAOV1, FADD) amplification among HPV-negative early TSCC tumors. Most significantly, we identify gene-sets involved in EMT processes with significant overexpression of MMP10 in 48% early stage TSCC tumors (n=50) as a potential candidate prognostic biomarker in early stage tongue cancer patients to predict nodal metastases.