Among those studying HERV and RCC is Shridar Ganesan MD, PhD, professor of medicine and pharmacology, and associate director for translational research at Rutgers Cancer Institute of New Jersey in New Brunswick. In a 2018 paper, Dr Ganesan and colleagues reported that overexpression of a subset of ERVs was linked with immune checkpoint activation in patients with clear-cell renal cell carcinoma (ccRCC).2

Dr Ganesan said the PCAWG Consortium study correlated well with his own research. “Importantly, the authors noted that increased expression of ERVs in ccRCC is associated with worse outcomes, which confirms similar observations made by our group.” He said the finding suggests that ERV expression in some cancers, including ccRCC, may reflect “underlying perturbation of the chromatin landscape in these tumors that may have significant impact on tumor biology and tumor immunology.”

He added, “Overall, the work by the PCAWG Consortium is an elegant comprehensive analysis of the presence of exogenous viral pathogens and expression of endogenous retroviral elements in cancer.”

Dr Mao expressed similar enthusiasm for the scale and scope of the PCAWG Consortium study. “This is the largest and comprehensive series of tumor genome and transcriptome analysis,” he said. “This study tells us of an alternative mechanism for carcinogenesis that is independent of mutations of key oncogene and tumor suppressor genes.”

While these data may be encouraging for bench researchers, they are not ready for the bedside, noted Robert Dreicer, MD, urologic medical oncologist and deputy director of the University of Virginia Cancer Center in Charlottesville. Offering a clinical perspective of this study, he said, “I think it is an important piece of work; an incredibly detailed summary of the really complex world of viral association in human cancer.” He added, “This was observational; it is not ready for clinical utility.”

For future study and translation of data into clinical practice, Dr Dreicer suggested exploring the following questions regarding HERV expression and poor survival results in kidney cancer:

  • Is this a bystander effect?
  • Is this something you only see in patients who tend to do worse?
  • Is this representative of the population at large?
  • How prevalent is it — 1 out of 1000 patients, or is it very common?
  • If it is common, is it differentially expressed?
  • Is it associated with clinical factors we can use?

Dr Mao agreed with this observation about clinical utility — while impressive, this study is “not meant to be a Rosetta stone,” he said. “It is just a sketch of the terrain of human cancer genome, with a focus on virus genetic sequence. It gives you some footprints of viruses in the genomic landscape; it is heroic laborious work well done.” But, he added, many questions remain unanswered, especially in regard to individual cancer type.

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“The study tells you the story of a static moment — invaders (viruses) in a community (genome) — but it does not tell you the aftermath, the impact of viral infection in terms of cascade of transcription dysregulation, genomic stability, epigenetic regulation, DNA methylation, chromatin organization and beyond, cellular response, extracellular/tumor microenvironment inflammatory reaction, [or] host immune response. These are left for the imagination,” said Dr Mao.

In addition to this study, which was first published online in February 2020 in Nature Genetics, an additional 23 papers have been published in Nature and its affiliated journals — each borne out of the PCAWG project. According to Dr Ristić, “These papers provide numerous new and exciting insights into the molecular drivers of cancer.” 

References

  1. Zapatka M, Borozan I, Brewer DS, et al. The landscape of viral associations in human cancers. Nat Genet. 2020;52(3):320-330.
  2. Panda A, de Cubas AA, Stein M, et al. Endogenous retrovirus expression is associated with response to immune checkpoint blockage in clear cell renal cell carcinoma. JCI Insight. 2018;3(16):e121522.