Papadimitrakopoulou V, Izzo J, Lippman S M, Lee J S, Fan Y H, Clayman G, Ro J Y, Hittelman W N, Lotan R, Hong W K, Mao L
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Oncogene. 1997 Apr 17;14(15):1799-803. doi: 10.1038/sj.onc.1201010.
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.
头颈癌发生被认为是一个多步骤过程，在此过程中，遗传事件在暴露于致癌物的危险区域积累，导致明显的表型癌前变化，最终发展为浸润性癌。在头颈部鳞状细胞癌（HNSCC）中，已发现9号染色体p21区域频繁出现杂合性缺失（LOH），且p16（INK4a）通过不同机制失活。最近，我们报告9p21缺失在口腔癌前病变中也很常见。为了研究这些癌前病变中p16（INK4a）的潜在失活情况，我们通过免疫组织化学（IHC）分析了36例患者的74份活检标本中p16蛋白的表达。在17例患者（47%）的28份（38%）病变活检标本中发现p16表达缺失。在12例患者的19份病变活检标本中观察到9p21区域的标志物D9s171发生LOH，在12例可比病例中的11例（92%）以及19份病变活检标本中的15份（79%）中，其与IHC检测到的p16缺失相关。通过对10例D9s171发生LOH的个体的10份病变活检标本进行p16（INK4a）外显子2的直接测序，鉴定出一个位于密码子88的无义突变（GGA→TGA）。我们的数据表明，p16（INK4a）失活可能在头颈癌早期发展中起重要作用。
