Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control.
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.
Wiest
Tina
T
Molekularbiologisches Labor, Universitäts-Hals-Nasen-Ohrenklinik, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Schwarz
Elisabeth
E
Enders
Christel
C
Flechtenmacher
Christa
C
Bosch
Franz X
FX
D001483:Base Sequence; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000276:immunology / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D016158:Genes, p53; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D027383:Papillomaviridae / Q000302:isolation & purification; D050725:Papillomavirus E7 Proteins; D012367:RNA, Viral / Q000096:biosynthesis; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C068651:E6 protein, Human papillomavirus type 16; D015514:Oncogene Proteins, Fusion; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012367:RNA, Viral; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16