Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

Xue, Ruidong; Chen, Lu; Zhang, Chong; Fujita, Masashi; Li, Ruoyan; Yan, Shumei; Ong, Choon Kiat; Liao, Xiwen; Gao, Qiang; Sasagawa, Shota; Li, Yanmeng; Wang, Jincheng; Guo, Hua; Huang, Qiuxia; Zhong, Qian; Tan, Jian; Qi, Lisha; Gong, Wenchen; Hong, Zhixian; Li, Meng; Zhao, Jingmin; Peng, Tao; Lu, Yinying; Lim, Kiat Hon; Boot, Arnoud; Ono, Atushi; Chayama, Kazuaki; Zhang, Zemin; Rozen, Steve; Teh, Bin Tean; Wang, Xin Wei; Nakagawa, Hidewaki; Zeng, Mu‐Sheng; Bai, Fan; Zhang, Ning

doi:10.1016/j.ccell.2019.04.007

Cited by 210 publications

(256 citation statements)

References 68 publications

(77 reference statements)

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“…(19) Interestingly, among the US HCCs, (20) Asian patients had higher detection rates of the AA signature (24 [15%] of 160 HCCs) than non-Asian patients ( Table 1). In addition, we noticed that 11 (11%) of 103 ICCs from China (21) and 29 (24%) of 121 cHCC-ICCs from the Asian region (mainland China, Singapore, and Japan) (22) contained the AA signature (Table 1).…”

Section: Aa Exposure Is Closely Associated With Liver Cancers From Chmentioning

confidence: 96%

“…Zhai et al (15) Singapore 9 4 (44) 2 (22) 1 (11) Ahn et al (16) Korea 231 16 (7) 12 (5) 8 (3) Worldwide HCC total 1,957 186 (10) 144 (7) 95 (5) ICC Zou et al (21) China (mainland) 103 11 (11) 8 (8) 3 (3) cHCC-ICC Xue et al (22) Asia ‡ 121 29 (24) 20 (17) 17 (14) *Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure > 0 (P < 0.05). † Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure no less than 20% (P < 0.05).…”

Section: Tumor Protein P53 and Janus Kinase 1 Mutations Are Enriched mentioning

confidence: 99%

“…In Taiwan, approximately one third of the people consume Chinese herbal remedies containing AA, which could be associated with the highest incidence of upper urinary tract cancers in the world. (6) The genome-wide mutational signature of characteristic A>T transversions (Catalogue of Somatic Mutations in Cancer [COSMIC] signature 22), specifically reflecting AA-implicated mutagenesis, is frequently found in Taiwanese upper urinary tract cancers. (6,7) Recently, AA was implicated in human liver cancer due to the AA mutational signature with characteristic A>T transversions.…”

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confidence: 99%

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The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

Luo

Zhao

et al. 2019

Hepatology

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Background and Aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure–induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA‐mediated genomic alterations that could be implicated in human cancers with AA‐associated mutational signature. Approach and Results We subjected mice, including phosphatase and tensin homolog (Pten)‐deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4. Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose‐dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4‐treated or Pten‐deficient mice. AAI led to DNA damage and AAI‐DNA adduct that could initiate liver cancers through characteristic adenine‐to‐thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA‐associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI‐DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA‐implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA‐affected human tumors. Conclusions This study provides evidence for AA‐induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA‐associated human cancers, especially liver cancers.

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Section: Aa Exposure Is Closely Associated With Liver Cancers From Chmentioning

confidence: 96%

Section: Tumor Protein P53 and Janus Kinase 1 Mutations Are Enriched mentioning

confidence: 99%

mentioning

confidence: 99%

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The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

Luo

Zhao

et al. 2019

Hepatology

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“…Therefore, new therapies targeting various oncogenic signaling pathways are being developed and some are at various phases of clinical testing [3]. Concurrently, the availability of mouse genetic models and high-quality transcriptomic data from pathology specimens through The Cancer Genome Atlas (TCGA) consortium are fueling efforts to gain a deeper understanding of the molecular heterogeneity in the pathogenesis of HCC in order to identify new therapeutic targets and tailor precision treatment strategies [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

Khan

Ghosh

Variya

et al. 2020

Preprint

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Suppressor of cytokine signaling (SOCS) proteins SOCS1 and SOCS3 are considered tumor suppressors in liver hepatocellular carcinoma (LIHC). To gain insight into the underlying molecular mechanisms, the expression of SOCS1/ SOCS3 was evaluated in The Cancer Genome Atlas LIHC dataset along with key oncogenic signaling pathway genes. SOCS1 expression was not significantly reduced in HCC yet higher expression predicted favorable prognosis, whereas SOCS3 lacked predictive potential despite lower expression. Only a small proportion of the cell cycle, receptor tyrosine kinase, growth factor and RAS-RAF-MEK-MAPK signaling genes negatively correlated with SOCS1 or SOCS3, of which even fewer showed elevated expression in HCC and predicted survival. However, many PI3K-AKT-MTOR pathway genes showed mutual exclusivity with SOCS1/SOCS3 and displayed independent predictive ability. Among genes that negatively correlated with SOCS1/SOCS3, CDK2, MLST8, AURKA, MAP3K4 and RPTOR showed corresponding modulations in the livers of mice lacking Socs1 or Socs3 during liver regeneration and in experimental HCC, and in Hepa1-6 murine HCC cells overexpressing SOCS1/SOCS3. However, Cox proportional hazards model identified CXCL8, DAB2 and PIK3R1 as highly predictive in combination with SOCS1 or SOCS3. These data suggest that developing prognostic biomarkers and precision treatment strategies based on SOCS1/SOCS3 expression need careful testing in different patient cohorts.Prognostic significance of SOCS1 and SOCS3 in HCC Khan et al.,3 genes that regulate hepatocyte proliferation and survival. Our findings show that the expression of SOCS1 and SOCS3 negatively correlates with several genes in a similar fashion, but also show distinct regulation of a number of genes in several oncogenic signaling pathways. The latter could explain, at least partly, the inability of SOCS3 to compensate for the loss of SOCS1 and vice versa in animal models of HCC. We identify SOCS1 but not SOCS3 as an independent prognostic factor, whereas both display improved predictive potential when combined with certain key genes of the oncogenic signaling pathways. Besides, our findings reveal important differences between published works on putative HCC biomarkers and the TCGA data, highlighting the need for further studies on prognostic biomarkers for precision HCC therapy.

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“…3 Genomic studies of cholangiocarcinoma have implicated a variety of known cancer drivers such as TP53, KRAS, ERBB2 and others that play a role in the oncogenic process. [4][5][6][7] There are a number of environmental and genetic risk factors for developing cholangiocarcinoma. Environmental factors, such as chemical exposure or parasitic infections, as well as comorbid conditions, such as primary biliary cholangitis, lead to an elevated risk of CCA.…”

Section: Introductionmentioning

confidence: 99%

Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7

Greer

Ögmundsdóttir

Chen

et al. 2019

Preprint

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Cholangiocarcinoma is an aggressive cancer originating from the bile duct. Although cholangiocarcinoma does occur in families, to date no specific causative gene has been identified. We identified ATG7 as a cancer susceptibility gene using a joint genetic analysis of an extended pedigree with familial cholangiocarcinoma in combination with a population genetic association study. Affected family members had a germline mutation (c.2000C>T [p.Arg659*]) in the autophagy related gene, ATG7, and all of the affected individuals had cholangiocarcinoma tumors harboring somatic genomic deletions of ATG7. From a population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G [p.Asp522Glu]) associated with increased risk of cholangiocarcinoma. The autophagy substrate p62 demonstrated a higher accumulation in tumors of p.Asp522Glu carriers compared with noncarriers indicating defective autophagy. To determine whether the germline ATG7 mutation had functional consequences, we developed an ATG7-deficient cholangiocyte cell line, derived from human bile duct, to test for autophagy-mediated lipidation activity. The germline mutation from the familial cholangiocarcinoma demonstrated a lack of lipidation activity compared to the wildtype ATG7. Moreover, in zebrafish embryos depleted of atg7, a reproducible necrotic headphenotype was rescued by injection of wildtype ATG7 but not mutant ATG7. Our findings point to ATG7 as a causative genetic risk factor for cholangiocarcinoma and implicate autophagy as a novel cancer driver mechanism.

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Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

Cited by 210 publications

References 68 publications

The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

Prognostic significance ofSOCS1andSOCS3tumor suppressors in hepatocellular carcinoma and its correlation to key oncogenic signaling pathways

Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7

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