EGAGenomicsHaitao Zhaohttps://ega-archive.org/dacs/EGAC00001000627EGAEGA DAC EGAC00001000627EGAzhaoht@pumch.cn<h4>Background & aims</h4>The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy.<h4>Methods</h4>A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).<h4>Results</h4>The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.<h4>Conclusions</h4>Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis.Miao Ruoyu R, Luo Haitao H, Zhou Huandi H, Li Guangbing G, Bu Dechao D, Yang Xiaobo X, Zhao Xue X, Zhang Haohai H, Liu Song S, Zhong Ying Y, Zou Zhen Z, Zhao Yan Y, Yu Kuntao K, He Lian L, Sang Xinting X, Zhong Shouxian S, Huang Jiefu J, Wu Yan Y, Miksad Rebecca A RA, Robson Simon C SC, Jiang Chengyu C, Zhao Yi Y, Zhao Haitao HCarcinomas, Carcinoma, Liver, Adult Liver Cancers, Hepatocellular carcinoma, Liver Cancer, Hepatoma, adult primary hepatocellular carcinoma, Liver Cancers, study., Cell Carcinoma, Liver Cell, Cancers, adult hepatoma, Adult, Hepatomas, Liver Cell Carcinoma, Hepatocellular Carcinoma, Cell Carcinomas, HCC, Liver Cell Carcinomas, Hepatocellular, Adult Liver Cancer, Adult Liver, Hepatocellular Carcinomas, ICT, CancerBiomarker, Biological Markers, Viral Marker, Serum Marker, Viral, Surrogate Endpoints, Clinical, Surrogate Endpoint, End Points, determination, Clinical Markers, Laboratory, hepatitis B virus related hepatocellular carcinoma, Surrogate, Clinical Marker, Biological Marker, Serum Markers, Endpoints, Biochemical, End Point, chemical analysis., Endpoint, Biochemical Markers, Immunologic, Serum, Laboratory Marker, Biologic Marker, Surrogate Marker, Immune Marker, Surrogate End Points, hepatitis B virus-related hepatocellular carcinoma, Surrogate Markers, Laboratory Markers, Immunologic Markers, Immune, Markers, Biochemical Marker, Marker, Biological, Surrogate End Point, Viral Markers, assay, Immunologic Marker, Biologic, Biologic Markers, Immune Markersdp53, Materials, Surrogate Endpoints, Laboratory, 0438/31, acetylglucosaminyltransferase-like protein, dDYRK2, growth and development, adult hepatoma, Profiles, tissue specimen, Liver Cell Carcinoma, CDK5/p23, Medical Specialties, Mutations, ftz-f2, Biological, Method, bbl, [Tau protein] kinase activity, myd, Decision-Making, like-acetylglucosaminyltransferase, 3540, Genomes, tau-protein kinase II activity, BCC7, 0702/07, 0037/17, beta-Tub6D, Tissue, dmp53, adult primary hepatocellular carcinoma, HLD5, Mbp-1, T, 1422/04, procedures, Signatures, Hepatocellular Carcinoma, 1260/10, Expression Signature, Dp53, medicine, Provirus, Medicine, cdk5/p20, Homo sapiens disease, CG17117, CXXC finger protein 9, l(3)02667, p50/tubulin, single organism signaling, CG10873, Liver, Viral, anatomical protrusion, Procedure, ttk/FTZ-F2, Arabidopsis dual specificity kinase 1 activity, APC1, Medical Speciality, Clinical Decision Making, Marker, Expression Signatures, mKIAA0609, simple tissue, bfy, tau protein kinase activity, ADK1, Expression Profile, HTH, Hth, Carcinomas, fg, End Points, Hepatoma, CG3401, beta3Tub, beta3TUB, Immunologic, whole genome, Methodological, Laboratory Marker, GSK, DTB3, MDC1D, enr, Material, FTZ-F2, bhy, Hepatocellular., other neoplasm, CG31325, HYCC1, beta[[3]]-Tub, DmelCG17117, TTK69, Clinical Marker, number, Prognostic Factors, 143391_i_at, beta3 TU, Ttk69, tramtrak, LFS1, LARGE1, Mps1p, l(3)05745, jecur, Aim, 1184/16, AIM, 5311, Medical Specialities, Adult Liver Cancer, disease or disorder, 1418/06, anon-EST:Liang-2.13, integration, Medical, Technique, DNMT1, Clinical, Liver Cancer, DNMT1_HUMAN, MDDGB6, Profile, TPK, Viral integrations, STK31, ESK, Study, API6, drugs, Medical Decision Making, beta[[3]]-tubulin, Insurance, Testis-specific gene 24 protein, esk, Biologic, TPK I, Cancer, 1325/15, DNA (cytosine-5)-methyltransferase 1, Dmbeta3, whole blood, Serum Markers, prac, disorders, beta3t, Factor, MCMT, Immune Marker, CG11558, AL022661, Surrogate End Point, p53/tubulin, Gene Expression Signatures, condition, background, integrations, ftzf2/ttk, Biologic Markers, CXXC9, CG33336, ATP:tau-protein O-phosphotransferase activity, 5125, Hepatocellular carcinoma, CT-2, TTK, Ttk, Surrogate, Endpoints, postnatal growth, D-p53, Dm-P53, Cancers, beta3, CXXC-type zinc finger protein 9, dtl, Tub, Integration, l(3)j7B8, like-glycosyltransferase, MPH1, signalling process, Gene Expression Profiles, betatub60D, ttkp69, Virus Integrations, CLEC2C, Immune Markers, Biological Markers, Viral Marker, single-organism developmental process, HSN1E, 0250/25, postnatal development, Biochemical, Mbp1, Gene Expression Profile, Endpoint, Viral integration, Serum, Hepatomas, betaTub3, Tp53, Speciality, Laboratory Markers, Techniques, DMP53, diseases, Specialities, Virus, diseases and disorders, Dmp53, 1323/07, DRCTNNB1A, human disease, 1209/10, Insurance Medicine, Prognoses, twk, Medical Decision-Making, iecur, Esk1, DmP53, tau-protein kinase I activity, Adult, B3t, DmelCG3401, Immune, Markers, Methodological Studies, 1209/05, Provirus Integration, Viral Markers, Transcriptomes, TPK II, Medicines, tau-tubulin kinase activity, protein threonine/tyrosine kinase activity, Carcinoma, Specialties, brain protein kinase PK40erk activity, Surrogate Endpoint, gyltl1b-b, Expression Profiles, Liver Cell, Biochemical Markers, Biologic Marker, results, 3t, Gene Expression, dual-specificity kinase activity, clone 2.9, HCC, MDDGA6, Diseases, Specialty, Genetic Materials, Adult Liver, KIAA0609, Genetic Material, acetylglucosaminyltransferase-like 1A, Tub60D, Transcriptome Profiles, ADCADN, beta-tub, anon-EST:Liang-2.9, Mitotic checkpoint regulator, Factors, gyltl1b, UNQ203/PRO229, TTK88, Prognostic, DNA (cytosine-5-)-methyltransferase 1, mdc1d, DmelCG33336, l(3)j2A1, Methodological Study, LARGE_HUMAN, Ttk88, Insurance Medicines, disease, hth1, hth2, Patient, Biochemical Marker, spine, 1372/08, P53, p44, Cistron, Hepatocellular Carcinomas, betaTub, Prognostic Factor, other disease, MPS1, Mps1, Procedures, p50, Clinical Markers, Transcriptome Profile, osn, oss, p53, Cell Carcinoma, Gene, presence, froggy, Gyltl1a, Surrogate End Points, protrusion, protein tau kinase activity, Cell Carcinomas, Surrogate Markers, 1396/14, Liver Cell Carcinomas, Studies, CG1856, ATP:protein phosphotransferase (Ser/Thr- and Tyr-phosphorylating) activity, glycogen synthase kinase-3beta activity, Biomarker, tau kinase activity, Genetic, clone 2.13, D.m.BETA-60D, Biological Marker, 1119/04, CT96, Integrations, Liver Cancers, LARGE, non-neoplastic, BPFD#36, Immunologic Markers, Trp53, PYT, Clients, ovs, Cyclosome subunit 1, betaTub60C, CLK1, disorder, beta3-tubulin, ttk69, TRP53, Immunologic Marker, DNA MTase HsaI, beta-Tub60D, Transcriptome, Dm-HTH, Medical Specialty, DmelCG1856, BETA 60D, DNMT, beta3-Tub, End Point, medical condition, Tree, Provirus Integrations, Cistrons, Client, Xp53, development, count in organism, DNA methyltransferase HsaI, dual-specificity protein kinase, MPS1L1, Gene Expression Signature, techniques, beta[[3]] tubulin, Serum Marker, distinct, Adult Liver Cancers, E(yan)100D, beta60C, l(3)86Ca, 1281/04, patient, Surrogate Marker, introduction, Livers, 1049/07, Meis1, cardinality, Hepatocellular, TTKA, Signature, growth, m.HsaI, methodology, glycosyltransferase-like protein LARGE1falsePUMCH-ICT Hepatocellular Carcinoma Study Data Access CommitteeData Access Committee EGAC00001000627EGAC00001000627960624859455EGAS00001002338EGAD00001003348