Abstract
BackgroundUp to 20% of cancers worldwide are thought to be associated with microbial pathogens, including bacteria and viruses. The widely used methods of viral infection detection are usually limited to a few a priori suspected viruses in one cancer type. To our knowledge, there have not been many broad screening approaches to address this problem more comprehensively.MethodsIn this study, we performed a comprehensive screening for viruses in nine common cancers using a multistep computational approach. Tumor transcriptome and genome sequencing data were available from The Cancer Genome Atlas (TCGA). Nine hundred fifty eight primary tumors in nine common cancers with poor prognosis were screened against a non-redundant database of virus sequences. DNA sequences from normal matched tissue specimens were used as controls to test whether each virus is associated with tumors.ResultsWe identified human papilloma virus type 18 (HPV-18) and four human herpes viruses (HHV) types 4, 5, 6B, and 8, also known as EBV, CMV, roseola virus, and KSHV, in colon, rectal, and stomach adenocarcinomas. In total, 59% of screened gastrointestinal adenocarcinomas (GIA) were positive for at least one virus: 26% for EBV, 21% for CMV, 7% for HHV-6B, and 20% for HPV-18. Over 20% of tumors were co-infected with multiple viruses. Two viruses (EBV and CMV) were statistically significantly associated with colorectal cancers when compared to the matched healthy tissues from the same individuals (p = 0.02 and 0.03, respectively). HPV-18 was not detected in DNA, and thus, no association testing was possible. Nevertheless, HPV-18 expression patterns suggest viral integration in the host genome, consistent with the potentially oncogenic nature of HPV-18 in colorectal adenocarcinomas. The estimated counts of viral copies were below one per cell for all identified viruses and approached the detection limit.ConclusionsOur comprehensive screening for viruses in multiple cancer types using next-generation sequencing data clearly demonstrates the presence of viral sequences in GIA. EBV, CMV, and HPV-18 are potentially causal for GIA, although their oncogenic role is yet to be established.
Highlights
We performed the systematic screening for potentially oncogenic viruses in nine cancer types from The Cancer Genome Atlas (TCGA) (Table 1), most of which were not previously known to be associated with viruses or have controversial reports in this regard [12,13]
Our results clearly demonstrate the presence of viral sequences in gastrointestinal adenocarcinomas (GIA)
Epstein-Barr virus (EBV) and CMV were statistically significantly associated with colorectal adenocarcinomas (CRAD)
Summary
Up to 20% of cancers worldwide are thought to be associated with microbial pathogens, including bacteria and viruses. Reported associations do not always mean that a virus is a direct cause of the cancer; they can be the result of contamination, viral infection without causal involvement (‘passenger’), and an indirect or direct causal relationship. The major disadvantage of these strategies is failure to detect viruses not previously known to be associated with a particular cancer type. We introduce a new and substantially different way of addressing this problem by utilizing next-generation sequencing (NGS) data to detect both human and nonhuman nucleic acids in tumor specimens. This approach does not require any prior knowledge of viruses involved and can identify all known viral genomes. Whole genome or transcriptome tumor sequencing data provides a unique resource for the development of new and powerful methodologies to detect and characterize viruses in cancers
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