Anterior tongue cancer with no history of tobacco and alcohol use may be a distinct molecular and clinical entity.

Abstract

A small, albeit significant, number of head and neck squamous cell carcinoma (HNSCC) patients has no history of tobacco and alcohol use. Such non-habits associated HNSCCs may represent a distinct clinical entity and exhibit increased aggressiveness. The objective of the study was to understand differences in molecular etiology of habits, and non-habits associated tongue carcinomas. High-throughput gene expression profiling of 22 tumor samples was carried out. This was followed by quantitative real-time PCR validation of four of the identified differentially expressed genes. Eighteen genes were identified that correlate strongly with the habits- and non-habits distinction. Among the genes significantly overexpressed in the non-habits group are CCND1, a key cell-cycle regulator, DACT3, a modulator of the Wnt/beta-catenin pathway, and three genes associated with the Notch signaling pathway. CCND1 and DACT3 overexpression in non-habits associated tongue carcinomas were subsequently validated by quantitative real-time PCR in an independent cohort (n = 18) of patient samples. Gene expression data were integrated with publicly available protein interaction data to build a small protein interaction network containing five of 18 differentially expressed genes. This suggested that a functional 'network module' can be implicated in the subgroup distinction. All the tumors analyzed here were human papillomavirus (HPV) negative samples. An association between CCND1 overexpression in oral tumors and poor prognosis has previously been reported. Thus, CCND1 overexpression in non-habits associated anterior tongue carcinomas may contribute to their increased clinical aggressiveness.