SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit

Abstract

To understand the association of candidate tumour suppressor genes SH3GL2, p16^INK4a, p14^ARF, and p15^INK4b in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), we studied the deletion, mutation, and methylation of these genes in 61 dysplastic lesions and 94 HNSCC samples. In mild dysplasia, SH3GL2, p16^INK4a, and p14^ARF showed a higher frequency of overall alterations (60–70%) than in p15^INK4b (40%). However, in subsequent stages of tumour progression, the alteration frequency of these genes did not change significantly. One novel mutation in common exon 2 of p16^INK4ap14^ARF and three in exon 9 of SH3GL2 were seen. Concordance was seen in the expression of these genes with their molecular alterations. Deletions of INK4A-ARF and p15^INK4b have a significant poor patient outcome. The alterations of p16^INK4a, p14^ARF, and p15^INK4b were positively correlated with tobacco and inversely with HPV, while SH3GL2 alterations were independent of these factors. Based on aetiological factors, four tumour subtypes were recognized: HPV⁻tobacco⁻ (I), HPV⁺tobacco⁻ (II), HPV⁻tobacco⁺ (III), and HPV⁺tobacco⁺ (IV). Groups III and IV showed a high frequency of p16^INK4a/p14^ARF/p15^INK4b alterations with significant poor patient outcome in comparison to group II. Our findings suggest that deregulation of SH3GL2-associated signalling and p16^INK4a/p14^ARF/p15^INK4b-mediated G1–S/G2–M checkpoints of cell cycle are independent pathways for the development of early dysplastic lesions of the head and neck.