Wiest Tina, Schwarz Elisabeth, Enders Christel, Flechtenmacher Christa, Bosch Franz X
Molekularbiologisches Labor, Universitäts-Hals-Nasen-Ohrenklinik, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Oncogene. 2002 Feb 28;21(10):1510-7. doi: 10.1038/sj.onc.1205214.
We have identified parameters which define a causal role of HPV16 in head and neck cancer. Twenty-eight tumours which were typed positive for HPV16 DNA, were comprehensively analysed for expression of the viral oncogenes E6 and E7, the status of the p53 gene, and the protein status of pRb and p16(INK4a). In a subset of cases, we have searched for integrated viral DNA, and have determined the genomic status of the E6 gene. Expression of E6/E7 was found in 12 tumours most of which were derived from the oropharynx, whereas p53 mutations were present in 13 tumours from various sites. The tumours either carried p53 mutations but did not express E6/E7, or they did express E6/E7 but were p53-wild-type. Coexistence of E6/E7 expression with a mutated p53 was found in only one case. Strikingly, in most p53-mutated tumours without E6/E7 expression, we found the E6 gene to be disrupted. E6/E7 expression was associated with reduced pRb and overexpressed p16(INK4a). Viral-cellular fusion transcripts were found in two cases. Our data demonstrate that HPV16 DNA-positivity in head and neck cancers is not indicative of a causal role. A causal role of HPV16 in head and neck cancer is defined by: E6/E7 expression, viral integration with an intact E6 gene, and perturbation of pRb cell cycle control. Mostly, the p53 gene is wild-type.
我们已经确定了一些参数，这些参数定义了人乳头瘤病毒16型（HPV16）在头颈癌中的因果作用。对28例HPV16 DNA检测呈阳性的肿瘤进行了全面分析，检测病毒癌基因E6和E7的表达、p53基因状态以及视网膜母细胞瘤蛋白（pRb）和p16（INK4a）的蛋白状态。在部分病例中，我们寻找了整合的病毒DNA，并确定了E6基因的基因组状态。在12例肿瘤中发现了E6/E7的表达，其中大多数来源于口咽，而在来自不同部位的13例肿瘤中存在p53突变。这些肿瘤要么携带p53突变但不表达E6/E7，要么表达E6/E7但p53为野生型。仅在1例病例中发现E6/E7表达与p53突变共存。引人注目的是，在大多数无E6/E7表达的p53突变肿瘤中，我们发现E6基因被破坏。E6/E7表达与pRb减少和p16（INK4a）过表达相关。在2例病例中发现了病毒-细胞融合转录本。我们的数据表明，头颈癌中HPV16 DNA阳性并不意味着其具有因果作用。HPV16在头颈癌中的因果作用由以下因素定义：E6/E7表达、病毒整合且E6基因完整以及pRb细胞周期控制受到干扰。大多数情况下，p53基因为野生型。
