FREQUENT INACTIVATION OF P16(INK4A) IN ORAL PREMALIGNANT LESIONS

Head and neck carcinogenesis is believed to be a multistep process, wh ereby genetic events accumulate in the carcinogen-exposed field at ris k, resulting in distinct phenotypic premalignant changes that eventual ly evolve into invasive cancer, Frequent loss of heterozygosity (LOH) at the chromosome 9p21 region and inactivation of p16(INK4a) by differ ent mechanisms have been described in head and neck squamous cell carc inoma (HNSCC), Recently, we reported that loss of 9p21 is also frequen t in oral premalignant lesions. To investigate potential inactivation of p16(INK4a) in these premalignant lesions, we analysed 74 biopsies f rom 36 patients by immunohistochemistry (MC) for expression of the p16 protein. Loss of p16 expression was found in 28 (38%) of the lesion b iopsies from 17 patients (47%). LOH at the D9s171, a marker in the 9p2 1 region, was observed in 19 lesion biopsies from 12 cases and correla ted with absence of p16 by IHC in 11 (92%) of the 12 comparable cases and 15 (79%) of 19 lesion biopsies, By direct sequencing of ten lesion biopsies from ten individuals with LOH at D9s171 for p16(INK4a) exon 2, one non-sense mutation at codon 88 (GGA-->TGA) was identified, Our data suggest that inactivation of p16(INK4a) may play an important rol e in early head and neck cancer development.