PILOT--MOLECULAR PREDICTORS OF ORAL CANCER DEVELOPMENT

许多口腔鳞状细胞癌发生在癌前阶段，在组织学上以不同程度的上皮异常增生为特征。然而，在很大比例的病例中，口腔上皮异型增生的患者不会进展为口腔癌，并且通过传统的临床或组织学方法无法预测哪些病变会进展。本病例对照研究的目的是评估口腔上皮异型增生中CDKN2A基因失活模式的改变是否可以预测口腔癌的进展。CDKN2A基因编码两种不同的选择性剪接转录本。P16Ink4a(外显子α，2，3)通过CDK-4和-6作为关键的G1细胞周期抑制因子发挥作用。P14/ARF(外显子1β，2，3)调节MDM2介导的肿瘤抑制基因p53的降解。从口腔癌组织病理学核心中，我们确定了两组患有口腔癌前病变的患者。一组已经进展为口腔癌，另一组经过多年的随访仍处于癌前阶段。从每个患者的同一口腔内部位连续进行活组织检查，并记录包括吸烟情况在内的临床信息。这是非常难收集的材料，因此提供了一个独特的机会来检查体内的多步致癌过程。我们将使用分子研究，然后比较CDKN2A(p16/INK4a和p14/ARF)基因失活和蛋白表达在进展为口腔癌和未进展为癌症的上皮不典型增生组织中的时间和模式。这些研究的结果将确定这种关键的肿瘤抑制基因的变化，这是口腔癌前病变向癌症转化所必需的。此外，它们还提供了分子分析来预测个体患者发展为口腔癌的可能性。

Many oral squamous cell carcinomas are preceded by a precancerous stage characterized histologically by varying degrees of epithelial dysplasia. However, in a large proportion of cases, patients with oral epithelial dysplasia do not progress to oral cancer and prediction which lesions will progress is not possible by conventional clinical or histological methods. The objective of the present case control study is to evaluate whether changes in patterns of inactivation of the CDKN2A gene present in oral epithelial dysplasia may predict progression to oral cancer. The CDKN2A gene locus encodes two different transcripts derived from alternative splicing. P16 INK4A (exons alpha,2,3) acts as a critical G1 cell cycle inhibitor via CDK-4 and -6. P14/ARF (exons 1beta,2,3) acts to modulate MDM2 mediate degradation of the tumour suppressor gene p53. From the Oral Cancer Histopathology Core we have identified two groups of 2o patients with precancerous oral lesions. One group has progressed to oral cancer and the other has remained in the precancerous stage after many years of follow-up. Sequential biopsies have been obtained from the same intra-oral site in each patient and clinical in formation including smoking status recorded. This is exceptionally difficult material to collect and thus provides a unique opportunity to examine multistep carcinogenesis in vivo. We will use molecular studies and then compare the timing and patterns of CDKN2A (p16/INK4A and p14/ARF) gene inactivation and protein expression in sequential biopsies of epithelial dysplasias that have progressed to oral cancer with those that have not progressed to cancer. Results from these studies will determine changes in this critical tumour suppressor gene necessary for the transformation of oral precancerous lesions to cancer. Moreover, they offer the possibility of molecular assays to predict progression to oral cancer for the individual patient.