16 Chapter 1 Harald zur Hausen and his team 27, HPV has been the subject of extensive research. HPV is a small, non-enveloped deoxyribonucleic acid (DNA) virus that belongs to the family of Papillomaviridae 28. The circular, double-stranded viral genome is approximately 8000 base pairs in length (Figure 1.3) 28, and consists mainly of three functional parts: an early region that encodes for proteins of E1, E2, E4–E7 genes required for viral replication; a late region that encodes for proteins of L1 and L2 genes necessary for viral assembly; and an upstream regulatory region (URR) between E6 and L1, important for viral gene transcription regulation and DNA replication. HPVs are strictly epitheliotropic and can be subdivided into mucosal and cutaneous types according to their affinity for one of these epithelia 29. So far, more than 400 different types of HPV have been identified on the basis of DNA sequence data showing genomic differences 30. Based on the nucleotide sequences of E6, E7 and L1, papillomavirus (PV) types are defined. Genotypes are classified into phylogenetic genera and numbered species 5. Approximately 40 HPV types are known to infect the genital mucosa 31. These mucosal HPV types typically cluster to the alpha-HPV genus. Mucosal HPVs can be further subdivided into low-risk (lr) and high-risk (hr) types, according to their oncogenic potential. The International Agency for Research on Cancer (IARC) Working Group defined HPV types as to its carcinogenicity to humans based on frequency of occurrence in cases of cervical cancer and available biological data: IARC Group 1 carcinogenic to humans, IARC Groups 2A and 2B probably and possibly carcinogenic to humans, respectively, and IARC Group 3 not classifiable as to carcinogenicity in humans. HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 are carcinogenic (Group 1), and HPV68, 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85 and 97 are probably/possibly carcinogenic (Group 2A/2B) 32. Group 2A/2B accounts for a minority of cervical cancers (~3%) 33. Oncogenic potential differs greatly between hrHPV types. HPV16 is the most common and most carcinogenic HPV type, responsible for over 60% of cervical carcinomas worldwide; followed by HPV18, which accounts for another 10% 34. HPV18 is especially common in ACC 35, 36. HPV31, 33, 45, 52 and 58 account for an additional 19% of cervical cancers 37. Besides being responsible for cervical carcinogenesis, hrHPV types, particularly HPV16, also play a causal role in the development of a subset of other types of cancers (in particular vulvar and vaginal, anal, penile and oropharyngeal) 38-43. On the other hand, lrHPV types, such as HPV6 and HPV11, are associated with the development of benign lesions like genital warts and cervical low-grade premalignant lesions.
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