The causal role of human papillomavirus infections in non‐anogenital cancers. It's time to ask for the functional evidence .

In 1982 the group of Harald zur Hausen discovered genomes of human papillomaviruses in cervical cancer biopsies and cell lines derived from them (reviewed in). It quickly became clear that human papillomavirus genomes can be found in the vast majority of cervical cancers but also in a substantial fraction of vaginal, vulvar, penile, anal, and oropharyngeal cancers. These findings stimulated a tremendous amount of activity to search for oncogenic HPV sequences in other nonanogenital cancers as well, including breast cancer, bladder cancer, colon cancer, and esophageal squamous cell carcinoma (ESCC) (reviewed in Halec et al., this issue and) . In particular, the prevalence of potentially oncogenic HPV genotypes in ESCC has been investigated in more than 100 original reports (reviewed in and). The reported prevalence of HPV genotypes in these studies ranged from 0 to 100 %, leaving the scientific community in the dark about the true role of oncogenic HPV types in the pathogenesis of ESCC. In the vast majority of these previously published reports, only the prevalence of HPV genome fragments was investigated while functional aspects of what causative role HPV genomes may play were largely neglected. Thus, it was difficult to discern whether these HPV genome fragments were just silent passengers or indeed encompassed active viral oncogenes to trigger the development of ESCC. The pathognomonic role of oncogenic HPV types in cervical and oropharyngeal cancers has been well established by a plethora of epidemiological studies linked to extensive functional analysis, clearly documenting that in these cancers the neoplastic phenotype is unequivocally linked to the genetic activity of the papillomavirus genes E6 and E7. The criteria now accepted to document the causative role of HPV genotypes in human cancers include the following three aspects: