Recurrent Genomic Alterations of FHIT Gene with Impact on Lymphatic Metastasis in Early Oral Carcinoma

Abstract

Objectives: Determine the role of genetic factors related to the lymph node metastasis (LNM) in early oral squamous cell carcinoma (OSCC). Methods: Array-based comparative genomic hybridization with individual gene-level resolution using primary tumor materials from 14 early OSCC patients with (n = 7) or without (n = 7) cervical LNM. To confirm the genomic copy number alterations, immunohistochenical stain was conducted in 30 early OSCC specimens. Results: The number of recurrent (>25%) copy number alterations with LNM group is 34, whereas that without LNM group is 23 by array-based comparative genomic hybridization in the first cohort. We detected 10 recurrently altered regions (10 losses) associated with cervical LNM ( P < 0.05). Among them, loss of 3p14.2 for the FHIT gene was the most frequent one (5 out of 7 patients with LNM, 71.4%) and significantly associated with a worse disease specific survival ( P = 0.005). In the independent validation cohort of 30 early OSCC cases, loss of FHIT determined by an immunohistochemical analysis was associated with cervical LNM ( P = 0.032) and disease specific survival ( P = 0.045). Conclusions: Copy number alterations of FHIT are associated with LNM and poor prognosis, and risk stratification based on the copy-number status of this gene is useful to select the optimal treatment strategy in early OSCC patients.