Table 3 Studies on AAV infection and HCC development in humans

[44]

France

HCC samples and corresponding non-tumor tissues = 193

Liver tissue

Clonal integration of AAV type 2 was found in 11 of 193 HCCs. Integrations occurred in the known cancer driver genes CCNA2, (four cases), TERT (one case), CCNE1 (three cases), TNFSF10 (two cases) and KMT2B (one case), leading to overexpression of the target genes. Tumors with AAV integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV in these patients.

AAV is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

[101]

South Korea

HCC patients = 289 (159 hepatitis-B-related cases; 16 hepatitis-C-related cases; 114 viral serology-negative cases)

HCC tissue

AAV type 2 DNA was detected in 0.7% (2/289) of the patients. AAV-related HCC showed no signs of liver cirrhosis.

AAV-associated HCC was very rare in Korean patients with HCC. This study is the first to report the clinical characteristics of Korean patients with AAV-associated HCC. These findings suggest epidemiologic differences in viral hepatocarcinogenesis between Korean and European patients.

[90]

Japan

HCC patients = 243 (73 prior HBV without HCV infection; 81 chronic HBV; 56 prior HBV with HCV infection; 33 non-B non-C cases as negative controls)

Liver tissue

AAV type 2 was found to integrate into 3 genes in two prior HBV and 1 non-B non-C patients. CCNE1 and CCNA2 were targeted by AAV2 only in prior HBV, while SLC6A5 was integrated in a non-B non-C patient.

Despite the seroclearance of hepatitis B surface antigen, HBV or AAV integration in prior HBV was not rare; therefore, such patients are at risk of developing HCC.

[89]

France

Patients with liver tumor = 1461 (936 HCC; 225 hepatocellular adenomas; 97 focal nodular hyperplasia; 87 hepatoblastoma or transitional tumors; 46 cholangiocarcinoma; 36 fibrolamellar carcinoma; 34 other tumors)

Liver tissue

AAV types 2 and hybrid 2/13 DNA was detected in 21% of the patients, including 8% of the tumor tissues. Episomal viral forms were found in 4% of the non-tumor tissues, frequently associated with viral RNA expression and HHV-6. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localization of the integration site.

Clonal AAV insertions were positive selected during HCC development on noncirrhotic liver challenging the notion of AAV as a nonpathogenic virus.