Proportion of Transcriptionally Active Dna Virus Integrants: A Meta-Analysis

Abstract

Oncoviruses are collectively responsible for over 1,000,000 new cases of cancer per year; some can integrate into the host's chromosomes. The present work was aimed at assessing the proportion of transcriptionally active viral integrants through a systematic review of the scientific publications present on the MedLine database. From the articles screened, 628 viral integrants overall were retrieved, of which 530.84 were transcriptionally active (84.53%); among the clinical samples, 264 of 323 integrants were active (81.73%). The causes for the silencing were not addressed in the articles analyzed. These findings might highlight a possible risk factor for the insurgence of cancer since some oncovirus integrants could be reactivated by stimuli of disparate nature. Further studies should address such possibility. About 16% of all cancer cases have been identified having an infectious aetiology [1]. Hepatitis B virus (HBV), human papilloma virus (HPV), human herpes 4 virus (HHV-4, historically known as Epstein-Barr virus [EBV]) and human herpes 8 virus (HHV-8, previously Kaposi sarcoma herpes virus) are collectively responsible for 56.2% of the incident microbial-related cancer cases, corresponding to over 1,200,000 new cases per year [2].HBV, HPV and HHV-4 share the capability of integrating into the host's chromosomes whereas HHV-8 integrants have not been observed [3]. In addition, other DNA viruses with transformation potential can integrate: Merkel cell polyomavirus (MCPV), human herpes 6 virus (HHV-6) and, in a lesser extent, adenovirus (AdV) [4][5][6]. The infection with these viruses is associated with a wide range of cancer types: HBV with hepatocarcinoma; HPV with virtually all cases of cervical cancer and in a significant proportion of other tumors, for instance in the head and neck; HHV-4 with a number of malignancies, in particular Burkitt and Hodgkin lymphomas, in both immunologically deficient and competent patients; HHV-8 DNA has been retrieved in all Kaposi sarcoma lesions even in immunocompetent hosts; MCPV is recognized as the causative agent of the Merkel cell carcinoma; HHV-6 has been involved in lymphoproliferative diseases; and AdV has been shown to transform rodent cells [1,[7][8][9].All these viruses encode for proteins that disrupt the cell cycle and DNA damage repair response to sustain the viral replication. For example, HBV X, HPV E6/E7, HHV-8 LANA and MCPV large T proteins, all hinder the function of p53, a pivotal factor of the DNA damage response, and pRb, an oncosuppressor that prevents over-replication of the cellular DNA [10][11][12][13][14]. HHV-4 encodes for a plethora of early proteins with oncogenic potential; for instance, BARF1 and BCRF1 have antiapoptotic function and the viral DNAse enzyme can cause genomic instability, therefore induction of the lytic cycle can contribute to the development of malignant phenotypes [15]. Even during the lysogenic cycle, HHV-4 encodes for proteins and interfering RNAs that have oncogenic potential [16].Integration can disrupt the transcripti...