Accurate detection and identification of Human Papillomavirus genotypes in archival cervical specimens by broad-spectrum PCR and reverse hybridization and the long-term risk identifies risk for development of cervical carcinoma.

W.G.V. Quint a, Yolanda van der Graafb, Anco Molijna, Heleen Doornewaardb, Bernhard Kletera, Leen-Jan van Doorna, Jan G. van den Tweelb

a Delft Diagnostic Laboratory, Delft, and b University Medical Center Utrecht, the Netherlands.

Persistent HPV infection is associated with development of cervical neoplasia. The HPV-associated risk for cervical neoplasia in women with normal smears was calculated. 347 cases and controls was studied in a prospective population-based nested case-control study. Cases (n = 77) participated in a cancer screening program and had cytologically normal smears >2 years (range 2-12 years, mean 5.3 years) prior to the diagnosis of CIN3 or cervical cancer. Controls (n = 270) also had a confirmed normal smear at baseline but did not develop cervical neoplasia. DNA was isolated from the smears and was tested for the presence of HPV DNA by the broad-spectrum SPF10 PCR primers and genotyped by the reverse hybridization line probe assay (LiPA). HPV DNA was present in 71% of the base-line smears of the 77 cases, and in 12% of the 270 controls. The age-adjusted odds ratio for the development of CIN 3 or cervical cancer was 19.2 (95% CI 10.3-35.7) for HPV positivity in general, 5.0 (95% CI 1.4 - 18.2) for low risk HPV genotypes, 24 (95%CI 12.4-46.4) for high risk HPV genotypes and 104.8 (95% CI 29.5-3872.7) for HPV 16. Follow-up smears were available in 49 cases and in 37 (97.4%) of the 38 cases that were HPV-DNA positive at base line, HPV infection persisted. The presence of HPV in cytologically normal Pap smears was associated with a significantly increased risk of invasive cervical cancer. Therefore, detection of HPV DNA is useful for triage of women with cytologically normal smears.

KEY WORDS: genotyping, cancer risk, predictive value.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.