National Institute of Biological Sciences, Beijing, Beijing, China.
Eastern Hepatobiliary Surgery Hospital, Yangpu, Shanghai, China.
PLoS One. 2014 May 5;9(5):e95307. doi: 10.1371/journal.pone.0095307. eCollection 2014.
Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. HCC is a particularly serious threat to the Chinese population. Although many molecular alterations are known to be involved in the tumorigenesis of hepatocytes, no systemic survey has examined the somatic mutations in HCC samples from Chinese patients. Our goal was to elucidate somatic mutations in Chinese HCC patients and investigate the possible molecular mechanisms involved in tumorigenesis.
A total of 110 hepatitis B virus (HBV)-positive HCC samples and 46 HBV-negative HCC samples were genotyped for hot-spot mutations in the CSF1R, CTNNB1, KRAS, BRAF, NRAS, ERBB2, MET, PIK3CA, JAK1, and SMO genes. The transcriptomes of the CTNNB1 mutation-positive HCC samples from the HBV-positive patients (CB+ HCC) were compared to adjacent non-cancerous livers, and significantly altered genes were functionally validated in vitro.
CTNNB1 mutations accounted for the majority of the mutations detected in our study. A slightly higher mutation rate was found in the HBV-positive patients than in their negative counterparts. A distinct pattern of CTNNB1 mutation was detected in these two populations, and drastic changes at the transcriptomic level were detected in the CB+ tumors compared to adjacent non-cancerous livers. Potential tumor suppressors (FoxA3 and Onecut1) and oncogenes (MAFG and SSX1) were functionally validated.
Our work is the first systemic characterization of oncogenic mutations in HCC samples from Chinese patients. Targeting the Wnt-β-catenin pathway may represent a valid treatment option for Chinese HCC patients. Our work also suggests that targeting ONECUT1, FOXA3, SSX1, and MAFG may be a valid treatment option for CTNNB1 mutation positive HCC patients.
肝细胞癌（HCC）是全球第六大常见实体瘤，也是癌症相关死亡的第三大主要原因。HCC 对中国人群构成了特别严重的威胁。尽管已知许多分子改变参与了肝细胞的肿瘤发生，但尚未有系统的研究检查过来自中国患者的 HCC 样本中的体细胞突变。我们的目标是阐明中国 HCC 患者的体细胞突变，并研究肿瘤发生中涉及的可能分子机制。
对 110 例乙型肝炎病毒（HBV）阳性 HCC 样本和 46 例 HBV 阴性 HCC 样本进行基因分型，以检测 CSF1R、CTNNB1、KRAS、BRAF、NRAS、ERBB2、MET、PIK3CA、JAK1 和 SMO 基因中的热点突变。将 HBV 阳性患者（CB+ HCC）的 CTNNB1 突变阳性 HCC 样本的转录组与相邻的非癌肝脏进行比较，并在体外对显著改变的基因进行功能验证。
CTNNB1 突变在本研究中检测到的突变中占大多数。HBV 阳性患者的突变率略高于阴性患者。在这两个群体中检测到 CTNNB1 突变的独特模式，并且与相邻的非癌肝脏相比，CB+肿瘤在转录组水平上发生了剧烈变化。潜在的肿瘤抑制因子（FoxA3 和 Onecut1）和癌基因（MAFG 和 SSX1）进行了功能验证。
我们的工作是首次对中国患者 HCC 样本中的致癌突变进行系统表征。靶向 Wnt-β-catenin 通路可能代表中国 HCC 患者的有效治疗选择。我们的工作还表明，针对 CTNNB1 突变阳性 HCC 患者，靶向 ONECUT1、FOXA3、SSX1 和 MAFG 可能是一种有效的治疗选择。
