Multiple HPV infection in cervical cancer screened by HPVDNAChip™

Abstract

This study determined the distribution of high-risk HPV type infection in cervical cancer using newly developed oligonucleotide chips (HPVDNAChips™). The study subjects included 80 cases of cervical neoplasia and 746 controls with a normal Pap smear. For HPV genotyping, the commercially available HPVDNAChips™ was used. The risk of cervical cancer was increased in women with a family history of cervical cancer (adjusted OR=2.3, 95% CI: 0.92–6.17) and in smokers (adjusted OR=3.2, 95% CI: 1.45–7.06). There was also a trend of increased risk with the number of full term pregnancies $\text{(P}{}_{\mathrm{<mtext>for</mtext><mspace\; xmlns="true"\; sp="0.25"\; width="2px"\; linebreak="nobreak"\; is="true"></mspace><mtext>trend</mtext>}}\text{<0.001).}$ There were only 7.2% (54 of 746) infected high-risk HPV types in the control, whereas 54.5% (six of 11) and 76.5% (52 of 68) were infected in the CIN and cervical cancer, respectively. Multiple HPV infection was observed in 0.5% (three of 592) of the control group but in 9.1% (seven of 77) of cases. Multivariate analysis revealed that subjects infected with multiple HPV types had a 31.8-fold (95% CI: 7.50–134.75) higher risk of cervical cancer, while the single HPV type had a 19.9-fold increased risk (95% CI: 10.90–36.18) $\text{(P}{}_{\mathrm{<mtext>for</mtext><mspace\; xmlns="true"\; sp="0.25"\; width="2px"\; linebreak="nobreak"\; is="true"></mspace><mtext>trend</mtext>}}\text{<0.001).}$ These results show that the detection and typing of HPV infection by HPVDNAChip™ can be a useful in clinical applications because it provides information on multiple infections and the types of HPV in addition to HPV infection status.

Introduction

Cervical cancer is the second most common cancer only to breast cancer in terms of both incidence and mortality worldwide. In Korea, cervical cancer is the third most common female cancer, which accounts for 13.0% of female malignancies [1].

More than 70 types of human papillomavirus have been identified to date and are closely associated with benign and malignant lesions of mucocutaneous epithelia [2]. They have several interesting biological properties, such as host species specificity, preferential site tropism of infection (mucosal or cutaneous), and different pathologies according to genomic diversity [3]. More than 20 genotypes of HPV have been found to infect genitalia and are classified as high or low-risk genotypes based on their oncogenic potentials [4]. Epidemiologic and experimental evidence shows that human papillomaviruses play a major causal role in the development of cervical cancer [5], [6]. By using the polymerase chain reaction, about 90% of cervical cancers have been found to contain DNAs of high-risk HPV-16 or -18, usually the former [2].

Previous studies have shown that HPV-6 and -11 are associated with benign anogenital lesions, whereas HPV-16 and -18 are associated with cervical cancer [7]. Therefore, the association between HPV infections and anogenital lesions is more complicated than expected. HPV types such as HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68 are thought to be high-risk types because they have been identified in high grade intraepithelial lesions or in invasive cervical cancer, whereas HPV-6, -11, -40, -42, -43, -44, and -55 are considered as low-risk types [7], [10]. Geographical differences in HPV types have been reported to exist between countries, and even within the countries such as United States [9], [10]. Therefore, the HPV types prevalent in Japan may differ from those in Western countries [8], [11].

Although a number of studies on the etiologic factors of cervical cancer carried out in Western Europe and North America have suggested that reproductive factors and sexual behavior play important roles in the occurrence cervical cancer, there are few studies to determine the etiological factors of cervical cancer in Korea [12], [13]. As a result of a hospital-based case-control study, Yoo et al. [14] found that the risk factors of cervical cancer in Korea are similar with those found in other countries such as Western Europe and North America.

The HPVDNAChip™ (version 2.0, Biomedlab Co., Seoul, Korea) was recently developed. It is an oligonucleotide chip that enables the rapid and easy detection and genotyping of 15 high-risk and seven low-risk HPV types simultaneously. Using this oligonucleotide chip, we conducted this case-control study in Korea to elucidate the distribution of high-risk HPV type infection in cervical cancer and to examine the prevalence of infection of a single HPV type or of multiple HPV types to clarify the association between HPV infection pattern and cervical cancer. The associations between HPV infection and various risk factors of cervical cancer were also examined.