Viral Analysis: Early Detection of HCC

A test that analyzes patients' exposure to viruses can detect hepatocellular carcinoma (HCC) before standard diagnostic techniques, a study reveals (Cell 2020;182:317–28). The approach may allow earlier detection of HCC, enabling more patients to receive potentially lifesaving treatments such as surgery and transplantation.

For patients who are at risk of HCC, current guidelines recommend twice-yearly screening with ultrasound, often combined with tests for the tumor biomarker alpha-fetoprotein. However, most HCCs are not diagnosed until they have reached an advanced stage.

Xin Wei Wang, PhD, of the NCI and colleagues suspected that a patient's history of viral infections could reveal HCC earlier. Based on previous research, they hypothesized that viruses alter the immune system, thus decreasing or increasing its ability to combat HCC tumors. A variety of viruses—not just the ones that cause hepatitis B and C and promote liver tumors—could affect risk, Wang notes.

To detect viral exposures, the scientists used a method developed by other researchers called VirScan, which checks blood for antibodies against nearly 94,000 epitopes from almost all known human viruses. First, the team analyzed blood samples from a case-control study that included 899 participants who had HCC, were at risk for it, or were healthy. The researchers used 90% of the samples to discover patterns of viral infection and 10% of the samples to validate those results. They found that exposure to 61 viral strains could discriminate patients with HCC from at-risk and healthy individuals. Moreover, the technique could distinguish patients with HCC from healthy controls with about 90% accuracy for the discovery samples and about 70% accuracy for the validation samples.

However, the results indicate that not all 61 viruses affect HCC risk by promoting cancer. Exposure to hepatitis B or C viruses, two influenza strains, and cytomegalovirus correlated with increased HCC risk. By contrast, patients with HCC were less likely to have been infected by 43 of the viruses, including respiratory syncytial virus. Thus, the absence of these viruses appears to increase the likelihood of developing the disease, suggesting that they may play a protective role. “It is worth speculating that cancer-prone individuals may perceive viral epitopes differently compared to healthy individuals,” the authors wrote, adding that additional research on the relationship between viruses and an individual's genomics and immune profile is needed to understand mechanisms of antitumor immunity.

The scientists also evaluated their approach by studying a different group of 173 at-risk individuals who were tracked for up to 20 years; 44 developed HCC. Wang and colleagues tested blood samples collected before diagnosis for exposure to the 61 viral strains. The results suggest that this method of testing could uncover a patient's cancer a median of 8.8 years earlier than conventional screening techniques. “This is a proof-of-concept study,” Wang says. “The real test,” he adds, will be to evaluate whether the method can reduce mortality in a randomized clinical trial.

Researchers who weren't connected to the study are enthusiastic about the prospects for viral profiling. Augusto Villanueva, MD, PhD, of the Icahn School of Medicine at Mt. Sinai in New York, NY, says that the approach is immunologically sound and praises its novelty. “It's a breath of fresh air,” he says. A clinical trial now needs to determine whether it allows earlier detection of HCC, he says.

Jonathan Schwartz, MD, of the Montefiore Medical Center at Albert Einstein College of Medicine in New York, NY, adds that “if this could be validated prospectively, it could be a game changer” for HCC screening. –Mitch Leslie

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