Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis

Letouzé, Éric; Shinde, Jayendra; Renault, Victor; Couchy, Gabrielle; Blanc, Jean‐Frédéric; Tubacher, Emmanuel; Bayard, Quentin; Bacq, Delphine; Meyer, Vincent; Semhoun, Jérémy; Bioulac‐Sage, Paulette; Prévôt, Sophie; Azoulay, Daniel; Paradis, Valérie; Imbeaud, Sandrine; Deleuze, Jean‐François; Zucman‐Rossi, Jessica

doi:10.1038/s41467-017-01358-x

Cited by 250 publications

(303 citation statements)

References 51 publications

(76 reference statements)

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“…Like in resected HCC BCLC 0/A, most mutations in advanced HCC were related to mutational signatures 4 (polycyclic aromatic hydrocarbon exposure), 5 (clock-like, related to age), and 16 (liver hallmark, increased by alcohol consumption), ubiquitous in liver cancers. (17) Three samples from African migrants displayed a high mutation load related to signature 24 (aflatoxin B1 exposure; Fig. 5C,D; Supporting Fig.…”

Section: Genetic Landscape Of Advanced Hccmentioning

confidence: 95%

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

et al. 2019

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To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty‐one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole‐exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT‐rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced‐stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1‐G6 transcriptomic classification and the molecular prognostic 5‐gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5‐gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty‐two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.

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Section: Genetic Landscape Of Advanced Hccmentioning

confidence: 95%

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

et al. 2019

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“…By contrast, the signature was in <1% of HCCs from Japan (17,18) and France. (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: 99%

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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“…COSMIC signature 24 was found to be an aflatoxin B1‐associated signature, and was more frequent in African cases with significant enrichment of a somatic TP53 p. Arg249Ser mutation, which is a typical mutation of aflatoxin B1‐exposed HCC. Letouzé et al further analyzed WGS of European HCC cases and identified 10 mutational signatures (COSMIC signatures 1, 4, 5, 6, 12, 17, 16, 22, 23, and 24). Of note, they affirmed a significant association between COSMIC signature 16 and epidemiological backgrounds such as male gender, alcohol intake, and tobacco consumption.…”

Section: Mutational Signatures In the Hcc Genomementioning

confidence: 99%

“…Letouz e et al 23 8 Although the frequency of AA-associated HCC is low in Japan and Western countries, exposure to AA or their derivatives would play an important role in HCC globally, especially in East Asia, implying substantial opportunities for prevention and intensive screening of HCC in these endemic areas.…”

Section: Structural Rearran Gements An D Virus Integration In H Ccmentioning

confidence: 99%

Molecular genomic landscapes of hepatobiliary cancer

Shibata

Arai²,

Totoki³

2018

Cancer Science

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Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi‐ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53,TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53,ARID1A,KRAS,SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non‐core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi‐omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular‐genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

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Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis

Cited by 250 publications

References 51 publications

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

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

Molecular genomic landscapes of hepatobiliary cancer

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