BOD - Revision - Lent - Edwards - Cancer Lecture 42 - The Causes of Cancer - Viruses? 2 > Squamous carcinoma cervix = arises within metaplastic squamous epithelium > almost all cases associated with human papillomavirus (HPV) · DNA virus > 8kB genome · HPV sexually transmitted > transient, subclinical infections of squamous epithelium that resolve with no treatment > cause wart and flat lesions · Cervix: HPV particularly high affinity for metaplastic squamous epithelium > infects basal squamous cells · Viral genes: stimulate cell proliferation, immortalisation, reduce apoptosis, and confer genetic instability > loss of growth control + facilitate acquisition of additional mutations > cancer progression HPV instead degrades p53: the HPV protein E6 binds to a cellular protein called the E6ffiassociated protein > forming a complex which causes the rapid and specific ubiquitination of p53 " Small genomes > proteins Apoptosis, downregulate MHC class 1 HPV contains a protein, E7, which can bind to Rb in much the same way * Viral DNA integrated into host genome > broken gene E2 > dysregulates E6, 7 > they are permanently on at a high level E5: cyclin activation; EDGF + PDGF activation · Cervical intraepithelial neoplasia 1 (CIN1): changes confined to lower oneffithird of epithelium * Most transient cases will proceed no further than this before regressing * Persistent infection: higherffirisk variants HPVffi16 or HPVffi18 + high viral load > cellular changes may progress to involve lower twoffithirds epithelium = CIN 2 · Nuclear atypia: nuclear enlargement, darker staining nucleoli (hyperchromasia), coarse chromatin granules, and higher nuclearffitofficytoplasmic ratios * in conjunction with perinuclear clearing ("halo") makes a cell a "koilocyte" · Detected in sections of cervical neoplasms by chromogenic in situ hybridisation (ISH) * ISH = hybridisation that uses a labelled complementary DNA or RNA strand (or "probe") to localise a specific DNA or RNA sequence in a section of tissue · HPV vaccination: UK > girls 12ffi13 years > protects against four strains of HPV: types 6, 11, 16 and 18 * Types 16 and 18 = 70% cases of cervical cancer in Europe * HPV6 and HPV11 > genital warts and laryngeal papillomatosis Decrease in incidence of tumours shows that virus is causative effect · Vaccine for boys too? * Arguments for change: Protects against genital warts and several highffirisk HPV infectionffirelated cancers (anogenital and head and neck cancers) " Strengthens herd immunity, preventing transmission to a sexual partner
# Arguments for status quo: link between other cancers and HPV is not as strong as that with cervical cancer " Some herd immunity will already be conferred by vaccinating women, albeit not as much " The financial cost of extending the programme EpsteinffiBarr Virus: · Develop cancer if immunosuppressed, · Infects Bfficells and nasopharyngeal epithelium > different cell types > primary infection in epithelium > latent in Bfficells · Multifactorial tumour progression: diet, genetics, geographical, pollution · Chinese populations: causes nasopharyngeal carcinoma · Malariaffiendemic areas: infected children > may develop aggressive Bfficell Burkitt's lymphoma · Genetic