PAPILLOMAVIRUS INFECTIONS - A MAJOR CAUSE OF HUMAN CANCERS

The papillomavirus family represents a remarkably heterogeneous group of viruses. At present, 77 distinct genotypes have been identified in humans and partial sequences have been obtained from more than 30 puta tive novel genotypes. Geographic differences in base composition of in dividual genotypes are generally small and suggest a low mutation rate and thus an ancient origin of today's prototypes The relatively small size of the genome permitted an analysis of individual gene functions and of interactions of viral proteins with host cell components, Prol iferating cells contain the viral genome in a latent form, large scale viral DNA replication, as well as translation and functional activity of late viral proteins, and viral particle assembly are restricted to differentiating layers of skin and mucosa. In humans papillomavirus i nfections cause a variety of benign proliferations: warts, epithelial cysts, intraepithelial neoplasias, anogenital, oro-laryngeal and -phar yngeal papillomas, keratoacanthomas and other types of hyperkeratoses. Their Involvement in the etiology of some major human cancers is of p articular interest: specific types (HPV 16, 18 and several others) hav e been identified as causative agents of at least 90% of cancers of th e cervix and are also linked to more than 50% of other anogenital canc ers. These HPV types are considered as 'high risk' infections. Their E 6/E7 oncoproteins stimulate cell proliferation by activating cyclins E and A, and interfere with the functions of the cellular proteins RB a nd p53. The latter interaction appears to be responsible for their mut agenic and aneuploidizing activity as an underlying principle for the progression of these HPV-containing lesions and the role of high risk HPV types as solitary carcinogens. In non-transformed human keratinocy tes transcription and function of viral oncoproteins is controlled by intercellular and intracellular signalling cascades, their interruptio n emerges as a precondition for immortalization and malignant growth. Recently, novel and known HPV types have also been identified in a hig h percentage of non-melanoma skin cancers (basal and squamous cell car cinomas). Similar to observations in patients with a rare hereditary c ondition, epidermodyplasia verruciformis, characterized by an extensiv e verrucosis and development of skin cancer, basal and squamous cell c arcinomas develop preferentially in light-exposed sites. This could su ggest an interaction between a physical carcinogen (UV-part of the sun light) and a 'low risk' (non-mutagenic) papillomavirus infection. Repo rts on the presence of HPV infections in cancers of the oral cavity, t he larynx, and the esophagus further emphasize the importance of this virus group as proven and suspected human carcinogens.