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  • From Viral Detection to Oncogenic Evidence: A Targeted Scoping Review of Thresholds, Contamination Control, Validation, and Causality Assessment in Human Tumor Sequencing Studies

  • Seyedeh Paria Bahrani,1,*
    1. Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: Public tumor sequencing datasets allow large-scale screening for viral sequences, but detecting viral reads does not establish that a virus is present in tumor cells or drives oncogenesis. Documented errors illustrate this risk. HPV18 sequences found in non-cervical TCGA samples were attributed to HeLa cell contamination. In another TCGA analysis, an apparent HPV38 signal in 32 of 168 endometrial samples raised concerns about possible cross-contamination within a single sequencing batch. Existing reviews address virus discovery tools or barriers to discovering new human cancer viruses. This scoping review aimed to map how tumor-sequencing studies set positivity thresholds, control contamination, validate viral detections, and assess evidence of oncogenic involvement.
  • Methods: We conducted a targeted scoping review informed by the JBI framework, with reporting guided by PRISMA-ScR. On 11 October 2026, web-based searches of PubMed-indexed records, PubMed Central, and publisher websites were conducted to identify primary studies published between 2013 and 2025 that investigated viral sequences in human tumor DNA or RNA sequencing data, alongside relevant reviews. Eight primary studies and five reviews were identified. Primary studies were charted across five domains: detection approach, positivity threshold, contamination handling, independent validation, and evidence beyond detection, including viral integration, viral gene expression, or host response. Findings were synthesized descriptively.
  • Results: Detection approaches varied. Most studies aligned non-host reads to viral references, whereas the Pan-Cancer Analysis of Whole Genomes (PCAWG) integrated three pipelines and retained 389 consensus virus–tumor pairs supported by at least two pipelines. Positivity thresholds were not standardized: five studies used five different criteria, namely PMER above 1 with at least three reads, viral expression above 2 parts per million (p.p.m.) of library reads, at least 10 mapped reads, a comparison of any-read versus 1,000-read cut-offs, and at least 100 viral reads. Seven of eight studies addressed contamination using strategies such as vector-sequence filtering, sequencing-date or batch checks, and viral-genome masking to reduce false positives. Four of eight compared viral detection calls with an independent assay. In one study, in situ hybridization agreed with pipeline HPV calls in 8/8 positive and 44/44 negative head-and-neck samples. In addition, HBV detection using whole-genome sequencing showed 96.1% specificity and 84.0% sensitivity relative to PCR. Six of eight studies examined evidence beyond detection, including integration, viral expression, or host response. Nevertheless, viral sequences in tumor data alone were insufficient to establish an oncogenic role, and PCAWG authors noted that universal causality criteria for viral pathogens may be prone to errors. A 2026 consensus commentary on the tumor microbiota also highlighted the need for shared standards for reliable detection and for establishing causal pathways. Within the searched sources, we identified no review that systematically mapped thresholds, contamination control, validation, and causality evidence across studies investigating viruses in human tumor-sequencing data.
  • Conclusion: Detection thresholds, contamination-control strategies, and validation practices vary across human tumor-sequencing virus studies, complicating comparison and interpretation. In this targeted evidence map, seven of eight primary studies addressed contamination, but only four used independent validation. A structured evidence framework separating computational detection, confirmation of tumor-associated presence, molecular evidence, and functional or epidemiological support may improve reporting and reduce unsupported claims of viral oncogenicity. A broader systematic search is needed to establish the completeness of this evidence map.
  • Keywords: Oncogenic viruses; Tumor sequencing; Bioinformatics; Contamination control; Causality assessment

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