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.