The viral landscape in metastatic solid cancers 

Researchers from Norwegian University of Science and Technology and colleagues have recently systematically catalogued the presence of viral DNA (and RNA) in whole genome and transcriptome sequencing data of nearly 5.000 metastatic cancer patients in the Hartwig Medical Database. The researchers identified 25 unique viral genera across 32 different cancer types. In total 747 tumor samples were virus positive. The top three most prevalent taxa (comprising 70% of the viral hits) were HPV (Human Papillomavirus), EBV (Epstein-Barr Virus) and HHV – consistent with their well-known causal association with particular cancer types ([1]).  

Read the paper

The viruses were typically found in their associated organs, such as HBV (Hepatitis B virus) which was significantly enriched in liver cancers. In several cases they also find tumor that have moved through the body that still carry their original viruses and their footprints, for example their findings indicate that HPV will spread with primary cancer cells and are not a result of the metastases being located in typically HPV-positive regions (like the reproductive organs). An example from the study was the detection of HPV type 16 in patients with metastatic Colorectal Cancers (CRC), an association not previously observed in large pan-cancer datasets. 

The researchers also looked for viral presence in the blood samples from the same individuals. Viral sequences were detected in blood samples from 336 patients with 29 unique cancer types and dominated by viruses of the Anelloviridae family – species that did not have a clear association to a particular tumor type and are generally believed not to be directly related to human disease. Interestingly HPV could be detected in the blood for 20% of HPV positive cervical cancers and 40% of HPV positive anus cancers – suggesting a potential blood-based biomarker for HPV positive cancers. 

Furthermore, researchers exploited the transcriptomics data in the Hartwig Medical Database to look for specific transcriptional programs activated in the host in HPV positive samples. Notably, expression of APOBEC genes was higher in HPV positive samples. APOBEC (Apolipoprotein B mRNA Editing Catalytic Polypeptide-like) is a family of cytidine deaminases that are implicated in protection from viruses but also have been described for their mutational footprint across a wide range of cancers (see also (https://pubmed.ncbi.nlm.nih.gov/38552621/ for APOBEC signatures in the Hartwig Medical Database). Indeed, APOBEC-related signatures were also increased in HPV positive samples. Overall HPV positive samples had higher somatic mutation rates and higher number of extrachromosomal DNA elements.   

APOBEC signature in the DNA is characterized by C to G changes at TCA/TCT tri nucleotides (see figure below). 

This research sheds more light on the etiology of virus-associated cancers by direct and indirect mutational processes activated in the host. Activation of host immune responses by viruses – as shown by the authors – may also have implications for the success of immune therapies against cancer. Furthermore, detection of viral presence in blood and/or tissue can aid diagnosis, e.g. for cancers of unknown primary (CUPs) and could have implications for treatment responses.  

The research described could not have been possible without a systematic collection of WGS-data and transcriptome across a broad range of metastatic tumors, as has been made available by Hartwig Medical Foundation.