Cristiano Ferlini, MD, PhD, had a hunch. What could be learned if tissue samples from The Cancer Genome Atlas database were mapped for viral—instead of human—microRNA (miRNA) expression?

Quite a lot, as it turns out. Not only is viral microRNA consistently higher in cancerous tissues, “viral microRNA expression is associated with significantly worse clinical outcome among patients with early stage malignancy,” Dr. Ferlini, the Rudy and Sally Ruggles endowed chief of cancer research at the Western Connecticut Health Network (WCHN) Biomedical Research Institute in Danbury, CT, and colleagues wrote in PLoS One.1

The study, which “represents the first comprehensive clinical investigation of viral miRNA expression in a wide array of solid malignancies,” analyzed expression of viral miRNA from Epstein-Barr virus (EBV), herpes simplex virus (HSV)-1, HSV-2, Kaposi’s sarcoma-associated herpesvirus (KSHV), and cytomegalovirus (CMV) in 600 patients where both noncancerous and cancer tissues were available for comparison.

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Included were bladder, breast, head and neck squamous, chromophobe, renal clear cell and papillary clear cell, liver, hepatocellular, lung adenocarcinoma and squamous cell, prostate, stomach, papillary thyroid, and uterine corpus endometrial carcinoma.

Of the 21.3 billion sequences successfully mapped, “we detected a significant number of viral miRNAs in both tissue types with greater than 96% derived from EBV,” they wrote. In their analysis, the disease with the highest EBV miRNA expression was stomach adenocarcinoma, for which EBV previously has been well-documented as having an oncogenic role.

More than 90% of adults harbor the EBV. In an interview with Cancer Therapy Advisor, Dr. Ferlini and Paul N. Fiedler, MD, chairman of the Department of Pathology and Laboratory Medicine at WCHN, explained that their findings suggest cancer and EBV share some of the same immune system mechanisms, working in tandem to defeat anticancer immunity in some, but not all, patients.

“It’s a mutual benefit,” Dr. Ferlini said. “The cancer helps the virus to be activated, and the virus is helping the cancer to get the immune system repressed.”

And, when EBV is activated, “those patients have a worse prognosis among the subset of patients with early-stage disease,” Dr. Fiedler said. “We’re not saying EBV is causative in the oncogenic sense, but we are saying that expression and reactivation modifies the course of the disease.”

“What’s really important in this paper is we are moving this to very early stage cancer,” said Dr. Ferlini. “If we can start to treat early stage in a personalized way, identify those who will have problems even after successful surgery, that can be really important for the overall survival of these patients.”

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Dr. Fiedler added, “in the dataset, we had not only gene expression, but microRNA expression, and these microRNAs were correlated in a highly statistical fashion with immune genes that are very relevant in cancer biology.”

While vaccine efforts have sought to ameliorate EBV, to date, only seroconversion can be prevented. Understanding the “noxious” interplay between EBV and cancer and their attendant effects on the immune system, notably in the PD1/PDL-1 pathway, may assist in identifying which patients may benefit best from novel therapeutic strategies that incorporate antiviral agents and/or pathway-specific inhibitors.

In the future, cancer treatment may be guided by a patient’s EBV status, or a vaccine may prevent not only EBV but abrogate aggressive early stage disease by modulating the immune system postsurgery.


  1. Pandya D, Mariani M, He S, et al. Epstein-Barr virus microRNA expression increases aggressiveness of solid malignancies. PLoS ONE. 2015;10(9): e0136058. doi:10.1371/journal.pone.0136058.