An integrated analysis of hepatocellular carcinoma reveals recurring genetic alterations.
Major finding: An integrated analysis of HCC reveals recurring genetic alterations.
Clinical relevance: IRF2 is inactivated exclusively in HBV-related tumors and impairs p53 function.
Impact: HCC risk factors such as hepatitis infection and alcohol intake may be associated with distinct mutations.
Hepatocellular carcinoma (HCC) is largely attributable to specific risk factors such as hepatitis B or C infection, high alcohol intake, and nonalcoholic fatty liver disease. Guichard and colleagues performed whole-exome sequencing on 24 HCCs and copy-number analysis and validation of recurrently mutated genes in an additional 125 HCCs related to various risk factors. The WNT/β-catenin pathway was most frequently affected, with activating mutations in β-catenin in 32.8% of tumors (though rarely in HBV-related tumors) and inactivating mutations in AXIN1 or APC in 15.2% and 1.6% of tumors, respectively. The p53 pathway was the second most commonly affected, with inactivating mutations in TP53 in 20.8% of tumors and homozygous deletions or mutations in CDKN2A in 8% of tumors. Additionally, inactivating mutations of interferon regulatory factor 2 (IRF2) were identified in 4.8% of HCCs. Functional analyses revealed that IRF2 silencing led to significant increases in HCC cell proliferation and tumor xenograft growth that were associated with decreased p53 protein levels and target gene expression. IRF2 mutations were exclusively found in tumors associated with HBV infection, suggesting that IRF2 may act as a tumor suppressor in HBV-associated HCC. SWI/SNF complex subunits comprised the third most frequently mutated group of genes, with ARID1A and ARID2 mutated in 16.8% and 5.6% of tumors, respectively, and unique mutations in PBRM1, SMARCA2, SMARCA4, and SMARCB1 identified by exome sequencing. ARID1A mutations were significantly associated with alcohol-related HCCs and often co-occurred with β-catenin mutations. These findings suggest that alterations in specific genes or pathways may be associated with each other or with particular risk factors in HCC, providing insight into the etiology of one of the leading causes of cancer-related deaths.