Abstract
ObjectivesNodal metastases status among early stage tongue squamous cell cancer patients plays a decisive role in the choice of treatment, wherein about 70% patients can be spared from surgery with an accurate prediction of negative pathological lymph node status. This underscores 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 that were analyzed using in-house computational tools. Additionally, gene expression meta-analyses were carried out for 253 tongue cancer samples. The candidate genes were validated using qPCR and immuno-histochemical analysis in an extended set of 50 early primary tongue cancer samples. 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.
Highlights
Tongue cancer is the most predominant form of oral cancer in developed countries with a varying incidence in developing countries [1]
human papilloma virus (HPV)-negative tumors are driven by amplification at 11q13, EGFR and FGFR loci; focal deletions at NSD1, FAT1, NOTCH1, SMAD4 and CDKN2A loci; and, point mutations in TP53, CDKN2A, FAT1, PIK3CA, NOTCH1, KMT2D, and NSD1 [6,7]
We present a portrait of somatic alterations in HPV negative early tongue cancer using integrative genomic approach to identify marker to stratify those likely to develop metastases
Summary
Tongue cancer is the most predominant form of oral cancer in developed countries with a varying incidence in developing countries [1]. The major etiological factors associated with tongue cancer include tobacco related products, alcohol and human papilloma virus (HPV) infections [2] These factors lend to variability across populations, in the Indian subcontinent wherein chewing betel-quid comprising betel leaf (Piper betel), areca nut. While tobacco usage shows a 5– 25-fold increased risk of cancer [4], HPV infection defines clinical and molecularly distinct subgroups of head and neck squamous cell carcinoma (HNSCC) patients [5] Such as, HPV-negative tumors are driven by amplification at 11q13, EGFR and FGFR loci; focal deletions at NSD1, FAT1, NOTCH1, SMAD4 and CDKN2A loci; and, point mutations in TP53, CDKN2A, FAT1, PIK3CA, NOTCH1, KMT2D, and NSD1 [6,7]. HPV-positive tumors harbor TRAF3, ATM deletion, E2F1 amplification, FGFR2/3 and KRAS mutations
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