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

Publication date: October 2017
Source:Oral Oncology, Volume 73
Author(s): Pawan Upadhyay, Nilesh Gardi, Sanket Desai, Pratik Chandrani, Asim Joshi, Bhaskar Dharavath, Priyanca Arora, Munital Bal, Sudhir Nair, Amit Dutt
ObjectivesNodal metastases status among early stage tongue squamous cell cancer patients plays a decisive role for choice of treatment, wherein about 70% patients may be spared from surgery with accurate prediction of negative pathological lymph node status. However, there is an unmet need for prognostic biomarkers to stratify the patients who are likely to develop metastases.Materials and methodsWe performed high throughput sequencing of fifty four samples derived from HPV negative early stage tongue cancer patients habitual of chewing betel nuts, areca nuts, lime or tobacco using whole exome (n=47) and transcriptome (n=17) sequencing. Additionally the relevant alterations were validated using orthologous methods in extended early stage TSCC cohort.Results and conclusionSomatic analysis revealed a classical tobacco mutational signature C:G>A:T transversion in 53% patients that were mutated in TP53, NOTCH1, CDKN2A, HRAS, USP6, PIK3CA, CASP8, FAT1, APC, and JAK1. Similarly, significant gains at genomic locus 11q13.3 (CCND1, FGF19, ORAOV1, FADD), 5p15.33 (SHANK2, MMP16, TERT), and 8q24.3 (BOP1); and, losses at 5q22.2 (APC), 6q25.3 (GTF2H2) and 5q13.2 (SMN1) were observed in these samples. Furthermore, an integrated gene-expression analysis of 253 tongue tumors suggested an upregulation of metastases-related pathways and over-expression of MMP10 in 48% tumors that may be crucial to predict nodal metastases in early tongue cancer patients. In overall, we present the first descriptive portrait of somatic alterations underlying the genome of tobacco/nut chewing HPV-negative early tongue cancer, and identify MMP10 asa potential prognostic biomarker to stratify those likely to develop metastases.



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