title: Frequent inactivation of p16INK4a in oral premalignant lesions.
abstract: Head and neck carcinogenesis is believed to be a multistep process, whereby genetic events accumulate in the carcinogen-exposed field at risk, resulting in distinct phenotypic premalignant changes that eventually evolve into invasive cancer. Frequent loss of heterozygosity (LOH) at the chromosome 9p21 region and inactivation of p16(INK4a) by different mechanisms have been described in head and neck squamous cell carcinoma (HNSCC). Recently, we reported that loss of 9p21 is also frequent in oral premalignant lesions. To investigate potential inactivation of p16(INK4a) in these premalignant lesions, we analysed 74 biopsies from 36 patients by immunohistochemistry (IHC) for expression of the p16 protein. Loss of p16 expression was found in 28 (38%) of the lesion biopsies from 17 patients (47%). LOH at the D9s171, a marker in the 9p21 region, was observed in 19 lesion biopsies from 12 cases and correlated 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 role in early head and neck cancer development.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
authors.forename: V
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: J
authors.initials: J
authors.lastname: Izzo
authors.forename: S M
authors.initials: SM
authors.lastname: Lippman
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: Y H
authors.initials: YH
authors.lastname: Fan
authors.forename: G
authors.initials: G
authors.lastname: Clayman
authors.forename: J Y
authors.initials: JY
authors.lastname: Ro
authors.forename: W N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: R
authors.initials: R
authors.lastname: Lotan
authors.forename: W K
authors.initials: WK
authors.lastname: Hong
authors.forename: L
authors.initials: L
authors.lastname: Mao
mesh_terms: D001706:Biopsy; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007972:Leukoplakia, Oral / Q000235:genetics*; D009062:Mouth Neoplasms / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation; D011230:Precancerous Conditions / Q000737:chemistry / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm