Frequent inactivation of SLIT2 and ROBO1 signaling in head and neck lesions: clinical and prognostic implications.

The protein SLIT2 and its receptor ROBO1 regulate different cellular processes, such as proliferation, apoptosis, and migration. In this study our aim is to understand the alterations of these genes during development of head and neck squamous cell carcinoma (HNSCC). First, molecular alterations of the genes were analyzed in 30 dysplastic lesions, 128 primary HNSCC samples, and 1 HNSCC cell line. Then alterations were correlated with mRNA expression (n = 22) and protein expression (n = 29). Finally, the alterations were correlated with different clinicopathologic parameters and clinical outcomes of the patients. ROBO1 had a comparatively high frequency of deletion (28.5%-54.2%) from dysplastic lesions and subsequent clinical stages than did SLIT2 (16.6-27%). On the contrary, SLIT2 had a high frequency (56.6%-81.2%) of promoter methylation from dysplastic lesions onward compared with ROBO1 (20%-32.8%). Interestingly, alterations of SLIT2 and ROBO1 were high in dysplastic lesions (80%), followed by comparable frequencies (92.5%-95.3%) in subsequent stages of tumor. Alterations of these genes showed concordance with their mRNA/protein expression and significant association with poor patient outcome. Our data suggest that inactivation of SLIT2 and/or ROBO1 is one of the early events in development of dysplastic lesions of head and neck and has prognostic importance.