DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
15
01
2021
received:
11
09
2020
accepted:
08
02
2021
pubmed:
14
3
2021
medline:
6
1
2022
entrez:
13
3
2021
Statut:
ppublish
Résumé
DNA methylation patterns are highly rearranged in HCCs. However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis [MethICA]) leveraging independent component analysis to disentangle the diverse processes contributing to DNA methylation changes in tumors. Applied to a collection of 738 HCCs, MethICA unraveled 13 stable methylation components preferentially active in specific chromatin states, sequence contexts, and replication timings. These included signatures of general processes associated with sex and age but also signatures related to specific driver events and molecular subgroups. Catenin beta 1 mutations were major modulators of methylation patterns in HCC, characterized by a targeted hypomethylation of transcription factor 7-bound enhancers in the vicinity of Wnt target genes as well as a widespread hypomethylation of late-replicated partially methylated domains. By contrast, demethylation of early replicated highly methylated domains was a signature of replication stress, leading to an extensive hypomethylator phenotype in cyclin-activated HCC. Inactivating mutations of the chromatin remodeler AT-rich interactive domain-containing protein 1A were associated with epigenetic silencing of differentiation-promoting transcriptional networks, also detectable in cirrhotic liver. Finally, a hypermethylation signature targeting polycomb-repressed chromatin domains was identified in the G1 molecular subgroup with progenitor features. This study elucidates the diversity of processes remodeling HCC methylomes and reveals the epigenetic and transcriptional impact of driver alterations.
Sections du résumé
BACKGROUND AND AIMS
DNA methylation patterns are highly rearranged in HCCs. However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis [MethICA]) leveraging independent component analysis to disentangle the diverse processes contributing to DNA methylation changes in tumors.
APPROACH AND RESULTS
Applied to a collection of 738 HCCs, MethICA unraveled 13 stable methylation components preferentially active in specific chromatin states, sequence contexts, and replication timings. These included signatures of general processes associated with sex and age but also signatures related to specific driver events and molecular subgroups. Catenin beta 1 mutations were major modulators of methylation patterns in HCC, characterized by a targeted hypomethylation of transcription factor 7-bound enhancers in the vicinity of Wnt target genes as well as a widespread hypomethylation of late-replicated partially methylated domains. By contrast, demethylation of early replicated highly methylated domains was a signature of replication stress, leading to an extensive hypomethylator phenotype in cyclin-activated HCC. Inactivating mutations of the chromatin remodeler AT-rich interactive domain-containing protein 1A were associated with epigenetic silencing of differentiation-promoting transcriptional networks, also detectable in cirrhotic liver. Finally, a hypermethylation signature targeting polycomb-repressed chromatin domains was identified in the G1 molecular subgroup with progenitor features.
CONCLUSIONS
This study elucidates the diversity of processes remodeling HCC methylomes and reveals the epigenetic and transcriptional impact of driver alterations.
Identifiants
pubmed: 33713365
doi: 10.1002/hep.31796
pii: 01515467-202108000-00020
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
816-834Subventions
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Informations de copyright
© 2021 American Association for the Study of Liver Diseases.
Références
Llovet JM, Zucman‐Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16018. https://doi.org/10.1038/nrdp.2016.18 .
doi: 10.1038/nrdp.2016.18
Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007;45:42‐52.
Hoshida Y, Nijman SMB, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69:7385‐7392.
Cancer Genome Atlas Research Network . Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017;169:1327‐1341.e23.
Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505‐511.
Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, et al. Whole‐genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet 2016;48:500‐509.
Zhang C, Li Z, Cheng Y, Jia F, Li R, Wu M, et al. CpG island methylator phenotype association with elevated serum alpha‐fetoprotein level in hepatocellular carcinoma. Clin Cancer Res 2007;13:944‐952.
Stefanska B, Huang J, Bhattacharyya B, Suderman M, Hallett M, Han ZG, et al. Definition of the landscape of promoter DNA hypomethylation in liver cancer. Cancer Res 2011;71:5891‐5903.
Neumann O, Kesselmeier M, Geffers R, Pellegrino R, Radlwimmer B, Hoffmann K, et al. Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors. Hepatology 2012;56:1817‐1827.
Shen J, Wang S, Zhang YJ, Kappil M, Wu HC, Kibriya MG, et al. Genome‐wide DNA methylation profiles in hepatocellular carcinoma. Hepatology 2012;55:1799‐1808.
Mah WC, Thurnherr T, Chow PKH, Chung AYF, Ooi LLPJ, Toh HC, et al. Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. PLoS One 2014;9:e104158. https://doi.org/10.1371/journal.pone.0104158 .
doi: 10.1371/journal.pone.0104158
Cheng J, Wei D, Ji Y, Chen L, Yang L, Li G, et al. Integrative analysis of DNA methylation and gene expression reveals hepatocellular carcinoma‐specific diagnostic biomarkers. Genome Med 2018;10:42. https://doi.org/10.1186/s13073‐018‐0548‐z .
doi: 10.1186/s13073-018-0548-z
Kisiel JB, Dukek BA, Kanipakam RVSR, Ghoz HM, Yab TC, Berger CK, et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology 2019;69:1180‐1192.
Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Méndez‐González J, et al. DNA methylation‐based prognosis and epidrivers in hepatocellular carcinoma. Hepatology 2015;61:1945‐1956.
Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell‐of‐origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 2018;173:291‐304.e6.
Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, et al. Human aging‐associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 2010;20:434‐439.
Zhou W, Dinh HQ, Ramjan Z, Weisenberger DJ, Nicolet CM, Shen H, et al. DNA methylation loss in late‐replicating domains is linked to mitotic cell division. Nat Genet 2018;50:591‐602.
Vandiver AR, Irizarry RA, Hansen KD, Garza LA, Runarsson A, Li X, et al. Age and sun exposure‐related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol 2015;16:80. https://doi.org/10.1186/s13059‐015‐0644‐y .
doi: 10.1186/s13059-015-0644-y
Letouzé E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013;23:739‐752.
Yao L, Shen H, Laird PW, Farnham PJ, Berman BP. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. Genome Biol 2015;16:105. https://doi.org/10.1186/s13059‐015‐0668‐3 .
doi: 10.1186/s13059-015-0668-3
Chakravarthy A, Furness A, Joshi K, Ghorani E, Ford K, Ward MJ, et al. Pan‐cancer deconvolution of tumour composition using DNA methylation. Nat Commun 2018;9:3220. https://doi.org/10.1038/s41467‐018‐05570‐1 .
doi: 10.1038/s41467-018-05570-1
Zinovyev A, Kairov U, Karpenyuk T, Ramanculov E. Blind source separation methods for deconvolution of complex signals in cancer biology. Biochem Biophys Res Commun 2013;430:1182‐1187.
Alexandrov LB, Nik‐Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415‐421.
Teschendorff AE, Journée M, Absil PA, Sepulchre R, Caldas C. Elucidating the altered transcriptional programs in breast cancer using independent component analysis. PLoS Comput Biol 2007;3:e161. https://doi.org/10.1371/journal.pcbi.0030161 .
doi: 10.1371/journal.pcbi.0030161
Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat Commun 2018;9:5235. https://doi.org/10.1038/s41467‐018‐07552‐9 .
doi: 10.1038/s41467-018-07552-9
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy‐number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012;44:694‐698.
Letouzé E, Shinde J, Renault V, Couchy G, Blanc JF, Tubacher E, et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun 2017;8:1315. https://doi.org/10.1038/s41467‐017‐01358‐x .
doi: 10.1038/s41467-017-01358-x
Hirsch TZ, Negulescu A, Gupta B, Caruso S, Noblet B, Couchy G, et al. BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar‐like features and activated PKA. J Hepatol 2020;72:924‐936.
Nault JC, Martin Y, Caruso S, Hirsch TZ, Bayard Q, Calderaro J, et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology 2020;71:164‐182.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biol 2014;15:550. https://doi.org/10.1186/s13059‐014‐0550‐8 .
doi: 10.1186/s13059-014-0550-8
Hyvärinen A. Fast and robust fixed‐point algorithms for independent component analysis. IEEE Trans Neural Netw 1999;10:626‐634.
Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi‐Moussavi A, et al.; Roadmap Epigenomics Consortium . Integrative analysis of 111 reference human epigenomes. Nature 2015;518:317‐330.
Salhab A, Nordström K, Gasparoni G, Kattler K, Ebert P, Ramirez F, et al. A comprehensive analysis of 195 DNA methylomes reveals shared and cell‐specific features of partially methylated domains. Genome Biol 2018;19:150. https://doi.org/10.1186/s13059‐018‐1510‐5 .
doi: 10.1186/s13059-018-1510-5
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti‐Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009;462:315‐322.
Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, et al. DNA‐binding factors shape the mouse methylome at distal regulatory regions. Nature 2011;480:490‐495.
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycomb‐mediated methylation on Lys27 of histone H3 pre‐marks genes for de novo methylation in cancer. Nat Genet 2007;39:232‐236.
Easwaran H, Johnstone SE, Van Neste L, Ohm J, Mosbruger T, Wang Q, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res 2012;22:837‐849.
Teschendorff AE, Menon U, Gentry‐Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, et al. Age‐dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 2010;20:440‐446.
Berman BP, Weisenberger DJ, Aman JF, Hinoue T, Ramjan Z, Liu Y, et al. Regions of focal DNA hypermethylation and long‐range hypomethylation in colorectal cancer coincide with nuclear lamina‐associated domains. Nat Genet 2011;44:40‐46.
Rebouissou S, Franconi A, Calderaro J, Letouzé E, Imbeaud S, Pilati C, et al. Genotype‐phenotype correlation of CTNNB1 mutations reveals different ß‐catenin activity associated with liver tumor progression. Hepatology 2016;64:2047‐2061.
Sun X, Chuang JC, Kanchwala M, Wu L, Celen C, Li L, et al. Suppression of the SWI/SNF component Arid1a promotes mammalian regeneration. Cell Stem Cell 2016;18:456‐466.
Piper M, Barry G, Hawkins J, Mason S, Lindwall C, Little E, et al. NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1. J Neurosci 2010;30:9127‐9139.
Hiraike Y, Waki H, Yu J, Nakamura M, Miyake K, Nagano G, et al. NFIA co‐localizes with PPARγ and transcriptionally controls the brown fat gene program. Nat Cell Biol 2017;19:1081‐1092.
Singh PNP, Yadav US, Azad K, Goswami P, Kinare V, Bandyopadhyay A. NFIA and GATA3 are crucial regulators of embryonic articular cartilage differentiation. Development 2018;145:dev156554. https://doi.org/10.1242/dev.156554 .
doi: 10.1242/dev.156554
Chen KS, Bridges CR, Lynton Z, Lim JWC, Stringer BW, Rajagopal R, et al. Transcription factors NFIA and NFIB induce cellular differentiation in high‐grade astrocytoma. J Neurooncol 2020;146:41‐53.
Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouzé E, Blanc JF, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol 2017;67:727‐738.
Moeini A, Torrecilla S, Tovar V, Montironi C, Andreu‐Oller C, Peix J, et al. An immune gene expression signature associated with development of human hepatocellular carcinoma identifies mice that respond to chemopreventive agents. Gastroenterology 2019;157:1383‐1397.e11.
Zhu M, Lu T, Jia Y, Luo X, Gopal P, Li L, et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 2019;177:608‐621.e12.
Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics 2009;1:239‐259.
Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC, et al. Genome‐wide hypomethylation in hepatocellular carcinogenesis. Cancer Res 2001;61:4238‐4243.