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To understand the association of candidate tumour suppressor genesSH3GL2,p16INK4a,p14ARF, andp15INK4bin 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,p16INK4a, andp14ARFshowed a higher frequency of overall alterations (60–70%) than inp15INK4b(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 ofp16INK4a/p14ARFand three in exon 9 ofSH3GL2were seen. Concordance was seen in the expression of these genes with their molecular alterations. Deletions ofINK4A-ARFandp15INK4bhave a significant poor patient outcome. The alterations ofp16INK4a,p14ARF, andp15INK4bwere positively correlated with tobacco and inversely with HPV, whileSH3GL2alterations 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 ofp16INK4a/p14ARF/p15INK4balterations with significant poor patient outcome in comparison to group II. Our findings suggest that deregulation of SH3GL2-associated signalling and p16INK4a/p14ARF/p15INK4b-mediated G1–S/G2–M checkpoints of cell cycle are independent pathways for the development of early dysplastic lesions of the head and neck. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.