Elsevier

The Lancet Oncology

Volume 11, Issue 11, November 2010, Pages 1048-1056
The Lancet Oncology

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Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study

https://doi.org/10.1016/S1470-2045(10)70230-8Get rights and content

Summary

Background

Knowledge about the distribution of human papillomavirus (HPV) genotypes in invasive cervical cancer is crucial to guide the introduction of prophylactic vaccines. We aimed to provide novel and comprehensive data about the worldwide genotype distribution in patients with invasive cervical cancer.

Methods

Paraffin-embedded samples of histologically confirmed cases of invasive cervical cancer were collected from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Inclusion criteria were a pathological confirmation of a primary invasive cervical cancer of epithelial origin in the tissue sample selected for analysis of HPV DNA, and information about the year of diagnosis. HPV detection was done by use of PCR with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridisation line probe assay. Sequence analysis was done to characterise HPV-positive samples with unknown HPV types. Data analyses included algorithms of multiple infections to estimate type-specific relative contributions.

Findings

22 661 paraffin-embedded samples were obtained from 14 249 women. 10 575 cases of invasive cervical cancer were included in the study, and 8977 (85%) of these were positive for HPV DNA. The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58 with a combined worldwide relative contribution of 8196 of 8977 (91%, 95% CI 90–92). HPV types 16 and 18 were detected in 6357 of 8977 of cases (71%, 70–72) of invasive cervical cancer. HPV types 16, 18, and 45 were detected in 443 of 470 cases (94%, 92–96) of cervical adenocarcinomas. Unknown HPV types that were identified with sequence analysis were 26, 30, 61, 67, 69, 82, and 91 in 103 (1%) of 8977 cases of invasive cervical cancer. Women with invasive cervical cancers related to HPV types 16, 18, or 45 presented at a younger mean age than did those with other HPV types (50·0 years [49·6–50·4], 48·2 years [47·3–49·2], 46·8 years [46·6–48·1], and 55·5 years [54·9–56·1], respectively).

Interpretation

To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45.

Funding

Spanish grants from Instituto de Salud Carlos III, Agència de Gestió d'Ajuts Universitaris i de Recerca, Marató de TV3 Foundation, and unrestricted grants from GlaxoSmithKline Biologicals, Sanofi Pasteur MSD, and Merck.

Introduction

Invasive cervical cancer is the second most common cancer among women worldwide. 585 278 incident cases and 327 899 cases of attributable deaths are predicted for 2010.1 More than 80% of cases arise in developing countries; invasive cervical cancer accounts for 15% of cancers in women and ranks first or second among cancers in women in 13 of 23 regions in the world.1, 2 Infection with one of the few oncogenic human papillomavirus (HPV) types is a necessary cause of invasive cervical cancer.3, 4 More than 118 different HPV types have been isolated and sequenced, and about 40 of these are known to infect the genital tract and 12 are classified as carcinogens.5, 6

Distribution of HPV types in invasive cervical cancer has been reported for several countries.2, 7, 8, 9, 10, 11 However, no reliable information exists about the type-specific contribution of HPV in invasive cervical cancer in many, mostly developing, countries. Country or regional data for the prevalence of HPV types in cervical cancer have been used to estimate the contribution of the various HPV types in invasive cervical cancer. Although not much is known about HPV types that are classified phylogenetically as strongly linked to carcinogenesis, some epidemiological data are available for HPV α5 (26, 51, 69, 82), α6 (30, 53, 56, 66), and α7 (39, 59, 68, 70), excluding types 18 and 45 for which we have consolidated information.12

The present study is an international project in which we aim to provide information about HPV genotype distribution in samples of invasive cervical cancer from several countries with different incidences of this disease; investigate the contribution of rare HPV types and the type attribution in specimens with several HPV types; identify HPV types associated with specific histological types of cervical cancer; investigate the role of exclusively low-risk HPV types; and generate insight into the secular trends of HPV-type distribution in invasive cervical cancer. The prespecified hypothesis was that the distribution of the five most common HPV types would be consistent geographically for the main histological categories of invasive cervical cancer.

Section snippets

Study design

A retrospective cross-sectional study was designed and coordinated by the Institut Català d'Oncologia, Barcelona, Spain, and DDL Diagnostic Laboratory, Voorburg, Netherlands, to estimate the prevalence of HPV DNA types in women with invasive cervical cancer during 1949–2009. Paraffin-embedded specimens from cases (aged 16–97 years) with cervical cancer were obtained from hospital pathology archives in 38 countries—Europe (Bosnia-Herzegovina, Croatia, Czech Republic, France, Greece, Italy,

Results

After histological assessment of 22 661 blocks of archived paraffin-embedded tissues that were obtained from 14 249 women with cervical cancer, 10 575 cases of invasive cervical cancer were included in the study. Webappendix pp 5–7 lists the cases included in the study by region, country, period of sample collection, mean age at diagnosis, and histological group.

Most infections were present as single infections, with the lowest proportion of single infections detected in samples from Africa and

Discussion

We provide reference data for the distribution of HPV genotypes among women with invasive cervical cancer in 38 countries, and estimates of their relative contributions in five continents. The data confirm the universal contribution of the eight most common HPV types (16, 18, 31, 33, 35, 45, 52, and 58) to invasive cervical cancer and the predominant role of types 16, 18, and 45 in cervical adenocarcinoma. We also provide data for the HPV types that are phylogenetically classified as oncogenic,

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