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Researchers find unsuspected DNA virus associated with HCC

Adeno-associated virus type 2, a type of DNA virus, was associated with oncogenic insertional mutagenesis in human hepatocellular carcinoma cells, according to data published in Nature Genetics.

Researchers, including Jessica Zucman-Rossi, MD, PhD, professor and hospital practitioner at Paris Descartes University, and director of Unit 1162 at the Institut National de la Santé et de la Recherche Médicale in France, analyzed tumor cells of 193 patients with hepatocellular carcinoma. The analysis was designed to screen the cells for the telomerase reverse transcriptase (TERT) gene, thought to be a common and frequent genetic alteration in HCC cells. However, the researchers identified a 208-bp insertion of adeno-associated virus type 2 (AAV2).

Jessica Zucman-Rossi

“Early studies showed that during infection, the AAV2 DNA integrates into the human genome, where it remains quiescent until a new parvovirus infection occurs,” the researchers wrote. “To investigate the functional consequences of viral integration, we generated a construct based on the pGL3 reporter vector, reproducing the exact AAV2 inserted sequence.”

The researchers compared gene mutations of the positive tumor samples with nontumor liver samples. They found clonal integration of AAV2 in 11 of the HCC samples. The AAV2 integrations occurred in multiple cancer driver genes including cyclin A2 (n = 4), TERT (n = 1), cyclin E1 (n = 3), tumor necrosis factor superfamily member 10 (n = 2) and lysine-specific methyltransferase 2B (n = 1). These integrations led to the overexpression of the target genes, according to the research.

“Tumors with viral integration mainly developed in noncirrhotic liver [nine of 11 HCC samples] and without known risk factors [six of 11 HCC samples], suggesting a pathogenic role for AAV2 in these patients,” the researchers wrote.

The researchers concluded: “AAV2 is often used as a vector in gene therapy,” the researchers said. “Although the insertion of its DNA into tumor promoting genes is rare, and probably a chance event, precautions must be taken regarding the use of this virus.”

Disclosure: IntegraGen performed all the next-generation sequencing. Zucman-Rossi reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.