1. INTRODUCTION
Smoking is a well-established risk factor for lung cancer, which is the leading cause of cancer-related deaths worldwide, including in Korea.1,2 Notably, the incidence of lung cancer in women who have never smoked is on the rise globally, and there is an increasing prevalence of adenocarcinoma (AD) compared to squamous cell carcinoma (SCC).3-5 Several studies have proposed that other etiological factors in addition to smoking contribute to the pathogenesis of lung cancer. These include infection with an oncogenic type of human papillomavirus (HPV), which is recognized as the primary cause of cervical cancer.6-8 Rezazadeh et al.9 reported an association between HPV infection and non-small cell lung cancer (NSCLC) (i.e., 20-25% of NSCLC patients).
Polyomaviruses, which belong to the family Polyomaviridae , are small nonenveloped DNA viruses that are widespread in nature and are suspected to be causative factors in various human tumors.10 Moreover, infection by these viruses may lead to a variety of disorders when they persist for a lifetime and undergo reactivation in immunocompromised hosts.11According to Feng et al. (2008), Merkel cell polyomavirus (MCPyV), which is an oncogenic etiology of Merkel cell carcinoma (MCC), is rare, aggressive and directly linked to human skin cancer.12Because MCC and small cell lung cancer (SCLC) share similar histological characteristics, specifically the presence of small cells similar to those found in neuroendocrine carcinoma, studies have explored the incidence of MCPyV infection in both SCLC and NSCLC.13-15 The MCPyV infection rate in NSCLC patients ranges from 4.7% to 38.5%.15,16-18 However, the prevalence of MCPyV in control lung tissues and adjacent normal lung tissues is either lower than that found in PCR-positive lung tissues18, or MCPyV is not detectable.13,19 Although Joe et al.20 investigated the correlation between HPV and MCPyV in NSCLC, a direct association between NSCLC and oncogenic HPV and MCPyV has not yet been clearly established.
The MCPyV genome is divided into three functional domains: an early gene region, including the large T antigen (LT), small T antigen (sT), 57kT antigen (57kT), alternative T antigen open reading frame (ALTO), and microRNA (miRNA); a noncoding control region (NCCR) containing the viral origin of replication (ORI); and late gene regions, including the capsid protein (VP1-3).21 MCPyV genotypes associated with the early region, LT and sT regions and the late region encoding viral protein 1 (VP1) play important roles in viral genome replication, transcription and tumorigenesis,22 and phylogenetic analyses based on these genes have enabled geographically related MCPyV genotype classification.23 In general, the LT and VP1 regions have been well studied, whereas knowledge of the NCCR region is relatively poor. In the JC polyomavirus (JCV) and BK polyomavirus (BKV), rearranged NCCR variants are known to be associated with human disease,24,25 but information on the MCPyV NCCR is limited.
Hashida et al.26 classified five genotypes from people with different racial backgrounds and geographic locations depending on the occurrence of NCCR rearrangement. Additionally, NCCR rearrangement analysis of the NCCR strain type has been used to assess whether NCCR genetic variability in this virus has an impact on its pathogenicity.27,28 Although it is possible to speculate on the correlation between genetic variability in NCCRs and disease, the pathogenesis and mechanisms underlying these mutations remain unknown.
Thus, the present study was designed to obtain additional data for use in resolving the inconsistencies and ambiguities discussed above and to explore aspects (i.e., analysis of the MCPyV NCCR) that have yet to be studied in Korea. The specific objectives of this study were as follows: to compare of the prevalence and frequency of MCPyV between NSCLC patients and adjacent nonlung cancer patients; to investigate the correlation between coinfection/infection with MCPyV and HPV in patients with NSCLC; and to analyze and compare specific genotypes in the Korean population through MCPyV DNA sequence analysis, particularly the classification of MCPyV NCCR genotypes and evaluation of MCPyV NCCR genetic variability, owing to the lack of MCPyV NCCR information.