Abstract
The evolutionary history of hepatobiliary cancers is embedded in their genomes. By analysing their catalogue of somatic mutations and the DNA sequence context in which they occur, it is possible to infer the mechanisms underpinning tumorigenesis. These mutational signatures reflect the exogenous and endogenous origins of genetic damage as well as the capacity of hepatobiliary cells to repair and replicate DNA. Genomic analysis of thousands of patients with hepatobiliary cancers has highlighted the diversity of mutagenic processes active in these malignancies, highlighting a prominent source of the inter-cancer-type, inter-patient, intertumour and intratumoural heterogeneity that is observed clinically. However, a substantial proportion of mutational signatures detected in hepatocellular carcinoma and biliary tract cancer remain of unknown cause, emphasizing the important contribution of processes yet to be identified. Exploiting mutational signatures to retrospectively understand hepatobiliary carcinogenesis could advance preventative management of these aggressive tumours as well as potentially predict treatment response and guide the development of therapies targeting tumour evolution.
Key points
-
In hepatobiliary cancer genomes, mutational signatures arise from diverse exogenous and endogenous insults as well as from cell-intrinsic repair mechanisms; a substantial proportion remains of unknown origin.
-
Mutational signatures are variably active and clonal during disease initiation and exhibit aetiological associations in invasive tumours.
-
Specific signatures exhibit high intertumour and intratumoural heterogeneity in hepatobiliary cancers, suggesting that distinct mutational processes might have key roles in subclonal diversification and disease relapse.
-
Identifying exogenous exposures responsible for mutational signatures can guide the development of preventative health measures to avoid these genotoxicants.
-
Mutational signatures might have important implications for response to diverse treatments (such as chemotherapy, targeted therapy and immunotherapy) given their molecular and pathobiological correlates in patients with hepatobiliary cancers.
-
Advances in circulating tumour DNA technology might provide opportunities to longitudinally track operative mutational processes during treatment as well as to develop therapeutic strategies targeting the mediators of such processes.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).
Banales, J. M. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17, 557–588 (2020).
Bertuccio, P. et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J. Hepatol. 71, 104–114 (2019).
Le, M. D., Henson, D., Young, H. & Albores-Saavedra, J. Is gallbladder cancer decreasing in view of increasing laparoscopic cholecystectomy? Ann. Hepatol. 10, 306–314 (2011).
Miranda-Filho, A. et al. Gallbladder and extrahepatic bile duct cancers in the Americas: incidence and mortality patterns and trends. Int. J. Cancer 147, 978–989 (2020).
McNamara, M. G. et al. Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer. J. Hepatol. 73, 1109–1117 (2020).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
Beaufrere, A., Calderaro, J. & Paradis, V. Combined hepatocellular-cholangiocarcinoma: an update. J. Hepatol. 74, 1212–1224 (2021).
Cheung, A. C., Walker, D. I., Juran, B. D., Miller, G. W. & Lazaridis, K. N. Studying the exposome to understand the environmental determinants of complex liver diseases. Hepatology 71, 352–362 (2020).
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020). The updated catalogue of mutational signatures (49 SBSs, 11 DBSs, 4 clustered-base substitutions, 17 small insertion-and-deletions) derived from 19,184 tumour exomes and 4,645 tumour whole genomes.
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). The original catalogue of 21 mutational signatures derived from 6,535 tumour exomes and 507 tumour whole genomes.
EFSA Panel on Contaminants in the Food Chain (CONTAM) et al. Risk assessment of aflatoxins in food. EFSA J. 18, e06040 (2020).
McCullough, A. K. & Lloyd, R. S. Mechanisms underlying aflatoxin-associated mutagenesis — implications in carcinogenesis. DNA Repair. 77, 76–86 (2019).
Liu, Z. M. et al. Hepatitis B virus infection contributes to oxidative stress in a population exposed to aflatoxin B1 and high-risk for hepatocellular carcinoma. Cancer Lett. 263, 212–222 (2008).
Chu, Y. J. et al. Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers. Int. J. Cancer 141, 711–720 (2017).
Koshiol, J. et al. Association of aflatoxin and gallbladder cancer. Gastroenterology 153, 488–494.e1 (2017). A molecular epidemiology study that implicated aflatoxin exposure as a risk factor for gallbladder cancer, independent of the R249S mutation in TP53 previously linked with aflatoxin-associated HCC.
Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341.e23 (2017).
Nepal, C. et al. Integrative molecular characterization of gallbladder cancer reveals microenvironment-associated subtypes. J. Hepatol. 74, 1132–1144 (2021).
Gouas, D., Shi, H. & Hainaut, P. The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy. Cancer Lett. 286, 29–37 (2009).
Grosse, Y. et al. A review of human carcinogens — part A: pharmaceuticals. Lancet Oncol. 10, 13–14 (2009).
Nault, J. C. & Letouze, E. Mutational processes in hepatocellular carcinoma: the story of aristolochic acid. Semin. Liver Dis. 39, 334–340 (2019).
Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836.e16 (2019).
Ng, A. W. T. et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci. Transl. Med. 9, eaan6446 (2017). A clinicogenomic study that implicated the aristolochic acid mutational signature with HCC worldwide, in particular in Asia.
Chan, J. Y. E. A. Whole exome sequencing identifies clinically relevant mutational signatures in resected hepatocellular carcinoma. Liver Cancer Int. 1, 25–35 (2020).
Lu, Z. N. et al. The mutational features of aristolochic acid-induced mouse and human liver cancers. Hepatology 71, 929–942 (2020).
Nepal, C. et al. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology 68, 949–963 (2018).
Ganne-Carrie, N. & Nahon, P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J. Hepatol. 70, 284–293 (2019).
McGee, E. E. et al. Smoking, alcohol, and biliary tract cancer risk: a pooling project of 26 prospective studies. J. Natl Cancer Inst. 111, 1263–1278 (2019).
Secretan, B. et al. A review of human carcinogens–Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 10, 1033–1034 (2009).
Letouze, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017). A clinicogenomic study that described the mutational profiles of HCC linked to distinct aetiologies, including alcohol, tobacco and aflatoxin.
Petrick, J. L. et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project. Br. J. Cancer 118, 1005–1012 (2018).
Li, W. et al. Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene. Proc. Natl Acad. Sci. USA 114, 6752–6757 (2017).
Alexandrov, L. B. et al. Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618–622 (2016).
Nik-Zainal, S. et al. The genome as a record of environmental exposure. Mutagenesis 30, 763–770 (2015).
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e18 (2018).
Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).
Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2016).
Dong, L. Q. et al. Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma. J. Hepatol. 69, 89–98 (2018). A genomics analysis describing inter-tumoural heterogeneity and evolutionary patterns of mutations and signatures across 69 distinct tumour foci from 6 patients with intrahepatic cholangiocarcinoma.
Venkatesan, S. et al. Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution. Ann. Oncol. 29, 563–572 (2018).
Jusakul, A. et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 7, 1116–1135 (2017).
Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).
Nepal, C. et al. Integrative molecular characterization of gallbladder cancer presents microenvironment-associated subtypes. J. Hepatol. 74, 1132–1144 (2020).
Yachida, S. et al. Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma. Cancer Cell 29, 229–240 (2016).
Li, M. et al. Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut 68, 1024–1033 (2019).
Marusawa, H., Takai, A. & Chiba, T. Role of activation-induced cytidine deaminase in inflammation-associated cancer development. Adv. Immunol. 111, 109–141 (2011).
Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).
Sia, D. et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144, 829–840 (2013).
Endo, Y. et al. Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling. Oncogene 26, 5587–5595 (2007).
Komori, J. et al. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 47, 888–896 (2008).
Kou, T. et al. Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int. J. Cancer 120, 469–476 (2007).
Chan-On, W. et al. Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region diversification. Int. J. Oncol. 35, 287–295 (2009).
Thomas, D. C. et al. Fidelity of mammalian DNA replication and replicative DNA polymerases. Biochemistry 30, 11751–11759 (1991).
Peng, X. et al. Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers. Cell Rep. 23, 255–269.e4 (2018).
Ma, J., Setton, J., Lee, N. Y., Riaz, N. & Powell, S. N. The therapeutic significance of mutational signatures from DNA repair deficiency in cancer. Nat. Commun. 9, 3292 (2018).
Volkova, N. V. et al. Mutational signatures are jointly shaped by DNA damage and repair. Nat. Commun. 11, 2169 (2020).
Akdemir, K. C. et al. Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure. Nat. Genet. 52, 1178–1188 (2020).
Clements, O., Eliahoo, J., Kim, J. U., Taylor-Robinson, S. D. & Khan, S. A. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J. Hepatol. 72, 95–103 (2020).
Svicher, V. et al. Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B. Gut 70, 2337–2348 (2020).
Peneau, C. et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut 71, 616–626 (2022).
Zapatka, M. et al. The landscape of viral associations in human cancers. Nat. Genet. 52, 320–330 (2020).
Hamdane, N. et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 156, 2313–2329.e7 (2019).
Mak, L. Y. et al. Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance. J. Hepatol. 73, 952–964 (2020).
Vartanian, J. P. et al. Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathog. 6, e1000928 (2010).
Wardell, C. P. et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J. Hepatol. 68, 959–969 (2018).
Znaor, A. et al. The public health challenge of liver cancer in Mongolia. Lancet Gastroenterol. Hepatol. 3, 660–662 (2018).
Candia, J. et al. The genomic landscape of Mongolian hepatocellular carcinoma. Nat. Commun. 11, 4383 (2020).
Pinyol, R. et al. Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J. Hepatol. 75, 865–878 (2021).
Muller, M., Bird, T. G. & Nault, J. C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J. Hepatol. 72, 990–1002 (2020).
Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019). A clinicogenomic analysis of microdissected hepatocytes from normal and cirrhotic livers, identifying clonal and non-clonal mutations, signatures, and larger genomic alterations that appear to have implications for HCC initiation.
Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621.e12 (2019).
Lee, M. et al. Genomic structures of dysplastic nodule and concurrent hepatocellular carcinoma. Hum. Pathol. 81, 37–46 (2018).
Vilarinho, S. et al. Exome analysis of the evolutionary path of hepatocellular adenoma-carcinoma transition, vascular invasion and brain dissemination. J. Hepatol. 67, 186–191 (2017).
Nault, J. C. et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology 152, 880–894.e6 (2017).
Temko, D., Tomlinson, I. P. M., Severini, S., Schuster-Bockler, B. & Graham, T. A. The effects of mutational processes and selection on driver mutations across cancer types. Nat. Commun. 9, 1857 (2018).
Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304.e6 (2018).
Tomkova, M., Tomek, J., Kriaucionis, S. & Schuster-Bockler, B. Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol. 19, 129 (2018).
Supek, F. & Lehner, B. Clustered mutation signatures reveal that Error-Prone DNA repair targets mutations to active genes. Cell 170, 534–547.e23 (2017).
Guest, R. V. et al. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res. 74, 1005–1010 (2014).
Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012).
Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).
Nault, J. C. et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology 71, 164–182 (2020).
Andersen, J. B. et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142, 1021–1031.e15 (2012).
Moeini, A. et al. Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity. J. Hepatol. 66, 952–961 (2017).
Montal, R. et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J. Hepatol. 73, 315–327 (2020).
Gingras, M. C. et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Rep. 14, 907–919 (2016).
Gao, Q. et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell 179, 561–577.e22 (2019).
Rubanova, Y. et al. Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig. Nat. Commun. 11, 731 (2020).
Craig, A. J., von Felden, J., Garcia-Lezana, T., Sarcognato, S. & Villanueva, A. Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 17, 139–152 (2020).
Gao, Q. et al. Cell culture system for analysis of genetic heterogeneity within hepatocellular carcinomas and response to pharmacologic agents. Gastroenterology 152, 232–242.e4 (2017).
Nakashima, O. & Kojiro, M. Recurrence of hepatocellular carcinoma: multicentric occurrence or intrahepatic metastasis? A viewpoint in terms of pathology. J. Hepatobil. Pancreat. Surg. 8, 404–409 (2001).
Portolani, N. et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann. Surg. 243, 229–235 (2006).
Xue, R. et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology 150, 998–1008 (2016).
Furuta, M. et al. Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J. Hepatol. 66, 363–373 (2017).
Robinson, D. R. et al. Integrative clinical genomics of metastatic cancer. Nature 548, 297–303 (2017).
Ouyang, L. et al. Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas. BMC Med. Genomics 7, 2 (2014).
Reiter, J. G. et al. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19, 639–650 (2019).
Priestley, P. et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature 575, 210–216 (2019).
Pleasance, E. et al. Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes. Nat. Cancer 1, 452–468 (2020).
Job, S. et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology 72, 965–981 (2020).
Bhandari, V., Li, C. H., Bristow, R. G., Boutros, P. C. & PCAWG Consortium. Divergent mutational processes distinguish hypoxic and normoxic tumours. Nat. Commun. 11, 737 (2020).
Kaplan, A. R. & Glazer, P. M. Impact of hypoxia on DNA repair and genome integrity. Mutagenesis 35, 61–68 (2020).
Caruso, S. et al. Analysis of liver cancer cell lines identifies agents with likely efficacy against hepatocellular carcinoma and markers of response. Gastroenterology 157, 760–776 (2019).
Castven, D. et al. Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification. Int. J. Cancer 144, 2782–2794 (2019).
Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC Mutagenesis. Cell 176, 1282–1294.e20 (2019).
Schauer, S. N. et al. L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Res. 28, 639–653 (2018).
Law, E. K. et al. APOBEC3A catalyzes mutation and drives carcinogenesis in vivo. J. Exp. Med. 217, e20200261 (2020).
Ma, W. et al. APOBEC3B promotes hepatocarcinogenesis and metastasis through novel deaminase-independent activity. Mol. Carcinog. 58, 643–653 (2019).
Wang, D. et al. APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression. Gut 68, 1846–1857 (2019).
Kim, S. K. et al. A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations. Int. J. Cancer 134, 1067–1076 (2014).
Eso, Y. et al. MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. Cancer Res. 76, 4383–4393 (2016).
Hikita, H. et al. Activation of the mitochondrial apoptotic pathway produces reactive oxygen species and oxidative damage in hepatocytes that contribute to liver tumorigenesis. Cancer Prev. Res. 8, 693–701 (2015).
Busuttil, R. A. et al. Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. Cancer Res. 65, 11271–11275 (2005).
Nguyen, J. et al. Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis. Oncotarget 9, 29495–29507 (2018).
Coia, H. et al. Prevention of lipid peroxidation-derived cyclic DNA adduct and mutation in high-fat diet-induced hepatocarcinogenesis by theaphenon E. Cancer Prev. Res. 11, 665–676 (2018).
Shen, J. et al. Oncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma. Oncogene 35, 6271–6280 (2016).
Zou, X. et al. A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage. Nat. Cancer 2, 643–657 (2021).
Drost, J. et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science 358, 234–238 (2017).
Dow, M. et al. Integrative genomic analysis of mouse and human hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 115, E9879–E9888 (2018).
Omichessan, H., Severi, G. & Perduca, V. Computational tools to detect signatures of mutational processes in DNA from tumours: a review and empirical comparison of performance. PLoS One 14, e0221235 (2019).
Ginsburg, O., Ashton-Prolla, P., Cantor, A., Mariosa, D. & Brennan, P. The role of genomics in global cancer prevention. Nat. Rev. Clin. Oncol. 18, 116–128 (2021).
Groopman, J. D., Kensler, T. W. & Wild, C. P. Protective interventions to prevent aflatoxin-induced carcinogenesis in developing countries. Annu. Rev. Public Health 29, 187–203 (2008).
National Cancer Institute. Aristolochic Acids https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/aristolochic-acids.
Asrani, S. K., Mellinger, J., Arab, J. P. & Shah, V. H. Reducing the global burden of alcohol-associated liver disease: a blueprint for action. Hepatology 73, 2039–2050 (2020).
Maronpot, R. R. Biological basis of differential susceptibility to hepatocarcinogenesis among mouse strains. J. Toxicol. Pathol. 22, 11–33 (2009).
Riva, L. et al. The mutational signature profile of known and suspected human carcinogens in mice. Nat. Genet. 52, 1189–1197 (2020). An in vivo mutagenesis screen of 20 known or suspected genotoxicants leading to liver tumour formation, linking the mutational signature associated with the water pollutant, 1,2,3-trichloropropane, with two known signatures in patients with HCC.
Valle, J. W., Kelley, R. K., Nervi, B., Oh, D. Y. & Zhu, A. X. Biliary tract cancer. Lancet 397, 428–444 (2021).
Vogel, A. et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv238–iv255 (2018).
Valle, J. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273–1281 (2010).
Shroff, R. T. et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 5, 824–830 (2019).
Lamarca, A. et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 22, 690–701 (2021).
Heeke, A. L. et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis. Oncol. https://doi.org/10.1200/PO.17.00286 (2018).
Gordan, J. D. et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J. Clin. Oncol. 38, 4317–4345 (2020).
Abou-Alfa, G. K. et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21, 796–807 (2020).
Zhu, A. X. et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 7, 1669–1677 (2021).
Bekaii-Saab, T. S. et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 16, 2385–2399 (2020).
Ricci, A. D. et al. PARP inhibitors in biliary tract cancer: a new kid on the block? Medicines 7, 54 (2020).
Sangro, B., Sarobe, P., Hervas-Stubbs, S. & Melero, I. Advances in immunotherapy for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18, 525–543 (2021).
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).
Zhang, W. et al. Genetic features of aflatoxin-associated hepatocellular carcinoma. Gastroenterology 153, 249–262.e2 (2017).
Szikriszt, B. et al. A comprehensive survey of the mutagenic impact of common cancer cytotoxics. Genome Biol. 17, 99 (2016).
Pich, O. et al. The mutational footprints of cancer therapies. Nat. Genet. 51, 1732–1740 (2019).
Venkatesan, S., Swanton, C., Taylor, B. S. & Costello, J. F. Treatment-induced mutagenesis and selective pressures sculpt cancer evolution. Cold Spring Harb. Perspect. Med. 7, a026617 (2017).
Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254.e39 (2021).
Hiam-Galvez, K. J., Allen, B. M. & Spitzer, M. H. Systemic immunity in cancer. Nat. Rev. Cancer 21, 345–359 (2021).
Driscoll, C. B. et al. APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. Nat. Commun. 11, 790 (2020).
Hyung, J. et al. Clinical benefit of maintenance therapy for advanced biliary tract cancer patients showing no progression after first-line gemcitabine plus cisplatin. Cancer Res. Treat. 51, 901–909 (2019).
Granadillo Rodriguez, M., Flath, B. & Chelico, L. The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: a long road ahead. Open. Biol. 10, 200188 (2020).
Barzak, F. M. et al. Selective inhibition of APOBEC3 enzymes by single-stranded DNAs containing 2′-deoxyzebularine. Org. Biomol. Chem. 17, 9435–9441 (2019).
Cipponi, A. et al. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer. Science 368, 1127–1131 (2020).
Das, T. K., Esernio, J. & Cagan, R. L. Restraining network response to targeted cancer therapies improves efficacy and reduces cellular resistance. Cancer Res. 78, 4344–4359 (2018).
Ma, L. et al. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Hepatol. 75, 1397–1408 (2021).
Mody, K. et al. Circulating tumor DNA profiling of advanced biliary tract cancers. JCO Precis. Oncol. 3, 1–9 (2019).
Abou-Alfa, G. K. et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 21, 671–684 (2020).
Duan, M. et al. Diverse modes of clonal evolution in HBV-related hepatocellular carcinoma revealed by single-cell genome sequencing. Cell Res. 28, 359–373 (2018).
von Felden, J. et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene 40, 140–151 (2021).
Mouliere, F. et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci. Transl. Med. 10, eaat4921 (2018).
Vandekerkhove, G. et al. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer. Nat. Commun. 12, 184 (2021).
Jalili, P. et al. Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots. Nat. Commun. 11, 2971 (2020).
Li, C. H. et al. Sex differences in oncogenic mutational processes. Nat. Commun. 11, 4330 (2020).
Carrot-Zhang, J. et al. Comprehensive analysis of genetic ancestry and its molecular correlates in cancer. Cancer Cell 37, 639–654.e6 (2020).
Afsari, B. et al. Supervised mutational signatures for obesity and other tissue-specific etiological factors in cancer. eLife 10, e61082 (2021).
Degasperi, A. et al. A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies. Nat. Cancer 1, 249–263 (2020).
Yi, S. W., Choi, J. S., Yi, J. J., Lee, Y. H. & Han, K. J. Risk factors for hepatocellular carcinoma by age, sex, and liver disorder status: A prospective cohort study in Korea. Cancer 124, 2748–2757 (2018).
Shaib, Y. H., El-Serag, H. B., Davila, J. A., Morgan, R. & McGlynn, K. A. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128, 620–626 (2005).
Antwi, S. O., Mousa, O. Y. & Patel, T. Racial, ethnic, and age disparities in incidence and survival of intrahepatic cholangiocarcinoma in the United States; 1995-2014. Ann. Hepatol. 17, 274–285 (2018).
Jackson, S. S. et al. Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project. J. Hepatol. 73, 863–872 (2020).
Ramai, D. et al. Demographics, tumor characteristics, treatment, and clinical outcomes of patients with ampullary cancer: a Surveillance, Epidemiology, and End Results (SEER) cohort study. Minerva Gastroenterol. Dietol. 65, 85–90 (2019).
Maynard, H. et al. Germline alterations in patients with biliary tract cancers: a spectrum of significant and previously underappreciated findings. Cancer 126, 1995–2002 (2020).
Liu, Y. & Wu, F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Env. Health Perspect. 118, 818–824 (2010).
Rapisarda, V. et al. Hepatocellular carcinoma and the risk of occupational exposure. World J. Hepatol. 8, 573–590 (2016).
Khan, S. A., Toledano, M. B. & Taylor-Robinson, S. D. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB 10, 77–82 (2008).
Lee, M. H. et al. A metallomic approach to assess associations of serum metal levels with gallstones and gallbladder cancer. Hepatology 71, 917–928 (2020).
Polesel, J. et al. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann. Oncol. 20, 353–357 (2009).
Kanwal, F. et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 155, 1828–1837.e2 (2018).
Park, J. H. et al. Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: a South Korean nationwide cohort study. Eur. J. Cancer 150, 73–82 (2021).
Jackson, S. S. et al. Anthropometric risk factors for cancers of the biliary tract in the biliary tract cancers pooling project. Cancer Res. 79, 3973–3982 (2019).
He, X. D. et al. Association of metabolic syndromes and risk factors with ampullary tumors development: a case-control study in China. World J. Gastroenterol. 20, 9541–9548 (2014).
McGee, E. E. et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults. Int. J. Cancer 144, 707–717 (2019).
Choi, J. et al. Aspirin use and the risk of cholangiocarcinoma. Hepatology 64, 785–796 (2016).
Rawla, P., Sunkara, T., Thandra, K. C. & Barsouk, A. Epidemiology of gallbladder cancer. Clin. Exp. Hepatol. 5, 93–102 (2019).
Castro, F. A. et al. Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease. Clin. Gastroenterol. Hepatol. 12, 1038–1045.e7 (2014).
Muraki, T. et al. Pancreatobiliary maljunction-associated gallbladder cancer is as common in the west, shows distinct clinicopathologic characteristics and offers an invaluable model for anatomy-induced reflux-associated physio-chemical carcinogenesis. Ann. Surg. https://doi.org/10.1097/SLA.0000000000004482 (2020).
Ji, J., Sundquist, K. & Sundquist, J. A population-based study of hepatitis D virus as potential risk factor for hepatocellular carcinoma. J. Natl Cancer Inst. 104, 790–792 (2012).
Sun, J. et al. Trends in hepatocellular carcinoma incidence and risk among persons with HIV in the US and Canada, 1996-2015. JAMA Netw. Open 4, e2037512 (2021).
Murphy, G. et al. Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. Hepatology 60, 1963–1971 (2014).
Sripa, B. et al. Liver fluke induces cholangiocarcinoma. PLoS Med. 4, e201 (2007).
Koshiol, J. et al. Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer Med. 5, 3310–3235 (2016).
Acknowledgements
The laboratory of J.B.A. is supported by competitive funding from the Novo Nordisk Foundation, Danish Medical Research Council (FSS) and Danish Cancer Society. C.J.O. is supported by a postdoctoral fellowship from the Marie Sklodowska-Curie action (MSCA, EpiTarget), H2020.
Competing interests
The authors declare no competing interests.
Author information
Authors and Affiliations
Contributions
All authors contributed equally to this manuscript.
Corresponding author
Peer review
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks Tatsuhiro Shibata and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Zhuravleva, E., O’Rourke, C.J. & Andersen, J.B. Mutational signatures and processes in hepatobiliary cancers. Nat Rev Gastroenterol Hepatol 19, 367–382 (2022). https://doi.org/10.1038/s41575-022-00587-w
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-022-00587-w
This article is cited by
-
DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications
European Journal of Medical Research (2024)