Oncogene and tumor suppressor gene mutations in hepatocellular tumors. − Rakyat Biologi

Mutations activating ß-catenin are found in 20 to 40% of hepatocellular carcinomas (Table 1), showing that ß-catenin is the most frequently activated oncogene in HCC by mutation ^{2, 10, 11}. The WNT/ß-catenin pathway plays a key role in liver physiological phenomena, such as lineage specification, differentiation, stem cell renewal, epithelial-mesenchymal transition, zonation, proliferation, cell adhesion and liver regeneration ^12-19. We showed that ß-catenin mutations are associated with chromosome stability and this genetic alteration occurs more frequently in patients without HBV infection ^{20, 21}. In a recent study, Audard and collaborators found that ß-catenin activated HCC exhibit specific features associating high differentiation with a homogeneous microtrabeculo-acinar pattern, low-grade cellular atypia, and cholestasis ²². In addition, ß-catenin activated HCC are frequently developed in non-cirrhotic liver in absence of usual HCC risk factor ^{22, 23}. Depending of the series, ß-catenin activating mutations were found to be associated with either good ^{24, 25} or bad prognosis ²³ and its relation with prognosis remains debated.

TP53 is the tumor suppressor the most frequently mutated in HCC (Table 2). The mutational spectrum of TP53 gene in HCC from Qidong and Mozambique where aflatoxin B1 (AFB1) exposure level is high, revealed G->T transversion at codon 249 in more than 50% of the tumors ^{26, 27}. This mutation at codon 249 of TP53, leading to the amino acid substitution R249S, is exceptionally found in HCC from geographical regions without AFB1 exposure. Usually, in a determined geographic area, the frequency of the R249S mutation paralleled the estimated level of AFB1 exposure, supporting the hypothesis that the carcinogen has a causative role in hepatocarcinogenesis. In western countries, where there is no exposure to AFB1, TP53 mutations are found in approximately 20% of the HCC, without specific hotspot of mutations ²⁰. Finally, no TP53 mutations were found in benign hepatocellular tumors ^{28, 29}.

During the last 20 years, several studies have searched to identify other genes mutated in hepatocellular tumors (Table 1 and 2). Apart from CTNNB1 and TP53, all the other identified genes were found rarely mutated, i.e. in less than 10 % of the HCC cases. Although most of HCC are developed in a context chronic hepatitis and cirrhosis, a small proportion result from a malignant transformation of a benign adenoma. Accordingly, IL6ST and HNF1A that are frequently mutated in adenoma (Table 3), are rarely altered in HCC (Table 1 and 2) or in other malignant tumors ^30-32. In contrast, in adenoma CTNNB1 activation was shown to be associated with a higher risk of malignant transformation ^{5, 33-35}. Accordingly, this gene is found rarely mutated in HCA and more frequently activated in HCC, suggesting that ß-catenin activation is a common genetic determinant associated with both benign and malignant tumorigenesis in the liver.