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Linear viral load increase of a single HPV‐type in women with multiple HPV infections predicts progression to cervical cancer
Author(s) -
Depuydt Christophe E.,
Thys Sofie,
Beert Johan,
Jonckheere Jef,
Salembier Geert,
Bogers Johannes J.
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30238
Subject(s) - viral load , cervical intraepithelial neoplasia , cervical cancer , immunostaining , medicine , cancer , hpv infection , staining , pathology , virology , immunology , biology , virus , immunohistochemistry
Persistent high‐risk human papillomavirus (HPV) infection is strongly associated with development of high‐grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type‐specific viral‐load measurements predict the natural history of the infection. In infections with multiple HPV‐types, the individual type‐specific viral‐load profile could distinguish progressing HPV‐infections from regressing infections. A case‐cohort natural history study was established using samples from untreated women with multiple HPV‐infections who developed CIN3+ ( n = 57) or cleared infections ( n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real‐time qPCR‐assay (18 HPV‐types). Using serial type‐specific viral‐load measurements (≥3) we calculated HPV‐specific slopes and coefficient of determination ( R 2 ) by linear regression. For each woman slopes and R 2 were used to calculate which HPV‐induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV‐types, each single HPV‐type generated similar increasing (0.27copies/cell/day) and decreasing (−0.27copies/cell/day) viral‐load slopes. In CIN3+, at least one of the HPV‐types had a clonal progressive course ( R 2 ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases ( n = 6), immunostaining detecting type‐specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion‐producing infections the RNA‐staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly‐formed virions. RNA‐hybridization patterns matched the calculated ongoing processes measured by R 2 and slope in serial type‐specific viral‐load measurements preceding the biopsy. In women with multiple HPV‐types, serial type‐specific viral‐load measurements predict the natural history of the different HPV‐types and elucidates HPV‐genotype attribution.