Zhen-Hao Liu1, Bao-Feng Lian2, Qiong-Zhu Dong3, Han Sun2, Jin-Wang Wei3, Yuan-Yuan Sheng3, Wei Li2, Yi-Xue Li2, Lu Xie4, Lei Liu5, Lun-Xiu Qin6. 1. Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China. 2. Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China. 3. Department of General Surgery, Zhongshan Hospital, Fudan University, Cancer Research Center, Institutes of Biomedical Science, Fudan University, Shanghai 200032, China. 4. Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China. Electronic address: luxiex2017@outlook.com. 5. Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China. Electronic address: liulei_fdu@163.com. 6. Department of General Surgery, Zhongshan Hospital, Fudan University, Cancer Research Center, Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China. Electronic address: qinlx@fudan.edu.cn.
Abstract
BACKGROUND: Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. CONCLUSION: CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management.
BACKGROUND:Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. CONCLUSION:CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management.