Elsevier

The Lancet

Volume 355, Issue 9222, 24 June 2000, Pages 2189-2193
The Lancet

Articles
Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study

https://doi.org/10.1016/S0140-6736(00)02401-6Get rights and content

Summary

Background

Infection with certain types of human papillomavirus (HPV), which is common among young women, increases the risk of cervical cancer. However, less than 1% of young women positive for oncogenic types of HPV develop cervical cancer. We investigated whether the amount of HPV DNA is a useful predictor of progression to cervical carcinoma in situ.

Methods

We estimated the amount of HPV 16 DNA by a PCR that uses the 5′-exonuclease (Taqman) method, in 478 women with cervical carcinoma in situ and 608 individually matched controls. To adjust for differences in the amount of genomic DNA between samples, we estimated the amount of a nuclear gene (β-actin). We studied multiple smears (total 3835 archived samples) from each woman, taken over periods of up to 26 years, that covered normal cytology to development of cervical cancer.

Findings

The risk of cervical carcinoma in situ increased with the amount of HPV 16 DNA. Analysis of the first smear from each woman, collected a mean of 7-8 years before cancer diagnosis, showed that women with the 20% highest amount of HPV 16 DNA were at a 60-fold higher risk of developing cervical carcinoma in situ than women negative for HPV 16. The first smear samples were classified as normal by squamous-cell cytology.

Interpretation

Analysis of the amount of HPV DNA can predict cancer risk at a stage when current screening methods are uninformative. Testing for the amount of HPV 16 DNA during gynaecological health checks might strikingly improve our ability to distinguish between infections that have a high or low risk of progressing into cervical cancer.

Introduction

Infection by certain types of human papillomavirus (HPV), especially HPV 16 and HPV 18, increases the risk of cervical cancer. Although HPV infection is common among young women, less than 1 % of those positive for oncogeneic types of HPV develop cervical cancer.1, 2 Therefore, the presence of HPV has a low predictive value. Several studies have suggested that the amount of HPV could be an important factor for progression from HPV infection to cervical cancer.3, 4, 5, 6, 7, 8, 9, 10 Without the availability of a method to estimate the amount of HPV in clinical samples, however, no study has been able to address the importance of viral load for cancer risk.

We did a nested case-control study of the relation between amount of HPV DNA and development of carcinoma in situ by analysis of archived cervical-smear samples.

Section snippets

Patients

We studied samples collected during routine gynaecological health checks from women with cervical cancer and individually matched controls from the general population.11 We selected women from a cohort who lived in Uppsala County, Sweden, between 1969 and 1995.11 To identify all eligible cases of cervical carcinoma in situ, we merged information from the organised screening programme, recorded from 1969 to 1995, with data from the National Cancer Registry. We included women who met the

Results

The nested case-control study included 504 cases and 662 controls. For some controls, only one smear was available during the follow-up period. Therefore, a second matched control for each of those was randomly chosen from the original pool of controls to increase the statistical power. 158 second controls were included. To confirm the cancer diagnosis of cases, the histological samples (complete cone or small biopsy) were reassessed by an experienced pathologist. After cytological and

Discussion

High amounts of HPV 16 DNA is a major risk factor for development of cervical carcinoma in situ. The amount of viral DNA could vary between individuals because of environmental factors,11, 17, 18, 19, 20 genetic factors, or both. Several environmental factors, such as smoking, use of oral contraceptives, and sequence variation in oncogenic HPV types have been purported to affect the risk of infection. The amount of viral DNA may also reflect inherent differences between individuals in response

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