Genetic signature for tobacco/nut chewing HPV-negative early tongue cancer & prognostic biomarker for metastasis

14 Aug 2017

Genetic signature for tobacco/nut chewing HPV-negative early tongue cancer & prognostic biomarker for metastasis

By Dr Amit Dutt, Intermediate Fellow


In a recent report published in Oral Oncology, an official journal of the European Association of Oral Medicine, International Association of Oral Pathologists, we describe that distinct genomic alterations underlie tobacco/ nut chewing, Human papillomavirus (HPV)-negative early stage tongue tumors and identify a gene, Matrix Metalloproteinase (MMP10), as a potential prognostic biomarker to identify those likely to develop cancer metastases (spread of cancer from one organ to another).

Tongue squamous cell carcinoma (TSCC) is the most predominant form of oral cancer in developed countries and with varying incidence in developing countries wherein diverse etiological factors such as HPV infection and chewing betel-quid forms distinct underlying genetic alterations that remain uncharacterized to date. These factors lend to variability across populations, particularly in the Indian subcontinent wherein chewing betel-quid comprising of betel leaf (Piper betel), areca nut (Areca catechu) and slaked lime (predominantly calcium hydroxide) is a part of the tradition. While tobacco usage show a 5- to 25-fold increased risk of cancer, HPV infection defines clinical and molecularly distinct subgroups of head and neck squamous cell carcinoma (HNSCC) patients. Furthermore nodal metastases status, wherein tumor cells reach regional lymph nodes near the primary tumor, also play a decisive role for choice of treatment in about 27-40% of TSCC patients at an early stage. There’s an unmet need for prognostic biomarkers to stratify the patients who could be spared unnecessary surgery, lessening morbidity and cost of treatment. While several large-scale genome-sequencing efforts of advanced stage primary oral tumors have been described, systematic efforts to catalogue somatic gene alterations in tobacco/ nut chewing associated early stage HPV-negative tongue tumors has been lacking.

In our study, we present the first and most comprehensive glance at genomic alterations and mutational signature across 57 early stage cases derived from HPV-negative early stage tongue cancer patients habitual of chewing betel nuts, areca nuts, lime or tobacco by using 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.  Most significantly, we identify gene-sets involved in 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.

Genomic characterization of tobacco/nut chewing HPV-negative early stage tongue tumors identify MMP10 as a candidate to predict metastases.Pawan Upadhyay, Nilesh Gardi, Sanket Desai, Pratik Chandrani, Asim Joshi, Bhaskar Dharavath, Priyanca Arora, Munital Bal, Sudhir Nair, Amit DuttOral Oncology. August 2017. 



Banner Image Credit Wellcome Photo Library, Wellcome Images

Cancer of the tongue. Photomicrograph showing squamous cell carcinoma.