title: A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia.
abstract: Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity.
authors.affiliation: Divisions of Cancer Epidemiology and Genetics and Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20852, USA. schiffmm@mail.nih.gov
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.forename: Ana Cecilia
authors.initials: AC
authors.lastname: Rodriguez
authors.forename: Zigui
authors.initials: Z
authors.lastname: Chen
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Rolando
authors.initials: R
authors.lastname: Herrero
authors.forename: Allan
authors.initials: A
authors.lastname: Hildesheim
authors.forename: Rob
authors.initials: R
authors.lastname: Desalle
authors.forename: Brian
authors.initials: B
authors.lastname: Befano
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Mahboobeh
authors.initials: M
authors.lastname: Safaeian
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.forename: Jorge
authors.initials: J
authors.lastname: Morales
authors.forename: Diego
authors.initials: D
authors.lastname: Guillen
authors.forename: Mario
authors.initials: M
authors.lastname: Alfaro
authors.forename: Martha
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Diane
authors.initials: D
authors.lastname: Solomon
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001499:Bayes Theorem; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000235:genetics*; D010802:Phylogeny; D011446:Prospective Studies; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000821:virology*