For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Oncology Vol 3 January 2002 11 Persistent human papillomavirus infection and cervical neoplasia Alex Ferenczy and Eduardo Franco The development of cervical cancer is preceded by precursor lesions (cervical intraepithelial neoplasia). Evidence-based epidemiological and molecular data suggest that persistent infections with human papillomavirus (HPV) types that carry a high oncogenic risk are the intermediate endpoints, leading to both intraepithelial and invasive cervical neoplasia. Integration of highly oncogenic HPVs into host-cell chromosomes is followed by binding of HPV E6 and E7 oncoproteins to tumour-suppressor genes p53 and RB, respectively. This process results in impaired tumour-suppressor-gene function, involving DNA repair, decreased apoptosis, and eventual cell immortalisation. Mutations causing chromosomal alterations, loss of heterozygosity, and proto-oncogene and telomerase activation in immunopermissive individuals have important roles in virus-induced cervical carcinogenesis. The so-called non-European variants of HPV 16 and 18 may increase the degradation potential of p53. HPV 16 is polymorphic and, although the evidence is controversial, the Arg/Arg genotype of p53 could have greater susceptibility to HPV-E6 degradation than the other genotypes. The coincident interplay between the non- European genomic variants of HPV 16/18 and p53 Arg/Arg may explain, at least in part, the persistence of HPV infection and tumour progression in women with cervical neoplasia. Further epidemiological and molecular research is needed, to gain insight into HPV- mediated cervical carcinogenesis. The evidence highlights the need to develop appropriate prophylactic HPV vaccines and diagnostic and screening tests. Lancet Oncol 2002; 3: 11–16 Cervical cancer is one of the most frequent diseases in women, and causes considerable morbidity. Indeed, after breast cancer, it is the most common cancer in women worldwide. Age-adjusted incidence rates vary from about 10 per 100 000 per year in many industrialised nations to more than 40 per 100 000 per year in developing countries. Four of five new cases and most deaths from cervical cancer occur in the developing world (Figure 1). 1 The estimated global incidence of invasive cancer is about 371 000 cases per year, and 5-year survival ranges from 44% to 66% for all clinical stages. 2 In recent years, strong pathological and cell and molecular evidence has been accumulated to implicate human papillomavirus (HPV) as the primary surrogate for the development of cervical neoplasia (Figure 2). In this review, we focus on advances in our understanding of the epidemiology and molecular biology of virus host–cell interactions, as related to HPV-mediated cervical carcinogenesis. The epidemiological evidence Epidemiological studies have shown that the number of sexual male partners a woman has is directly related to her risk of developing cervical cancer and its precursors, cervical Reviews AF is Professor of Pathology and Obstetrics & Gynecology at McGill University and the Sir Mortimer B Davis Jewish General Hospital, Montréal, Québec, Canada. EF is Professor of Epidemiology and Oncology and Director of the Division of Cancer Epidemiology, McGill University, Montréal, Québec, Canada Correspondence: Alex Ferenczy, MD, Department of Pathology, SMBD-Jewish General Hospital, 3755 Côte Ste. Catherine Road, Montréal, Québec, Canada, H3T 1E2. Tel: +1 514 340 7526. Fax: +1 514 340 7542. Email: aferen@po-box.mcgill.ca Figure 1. Cervical carcinoma and hydronephrosis. (a) A large cancerous growth (viewed from the front) has essentially replaced the entire cervix. (b) The most frequent cause of death due to cervical carcinoma, ie hydroureter and hydronephrosis due to tumour obstruction of ureters.