Identification of portal vein tumor thrombus with an independent clonal origin in hepatocellular carcinoma via multi-omics data analysis
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摘要
Objective: Multiple mechanisms underlying the development of portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) have been reported recently. However, the origins of PVTT remain unknown. Increasing multi-omics data on PVTTs in HCCs have made it possible to investigate whether PVTTs originate from the corresponding primary tumors(Ts).Methods: The clonal relationship between PVTTs and their corresponding primary Ts was investigated using datasets deposited in public databases. One DNA copy number variations dataset and three gene expression datasets were downloaded for the analyses.Clonality analysis was performed to investigate the clonal relationship between PVTTs and Ts from an individual patient.Differential gene expression analysis was applied to investigate the gene expression profiles of PVTTs and Ts.Results: One out of 19 PVTTs had no clonal relationship with its corresponding T, whereas the others did. The PVTTs with independent clonal origin showed different gene expression and enrichment in biological processes from the primary Ts. Based on the unique gene expression profiles, a gene signature including 24 genes was used to identify pairs of PVTTs and primary Ts without any clonal relationship. Validation in three datasets showed that these types of pairs of PVTTs and Ts can be identified by the 24-gene signature.Conclusions: Our findings show a direct evidence for PVTT origin and consolidate the heterogeneity of PVTTs observed in clinic.The results suggest that PVTT investigation at a molecular level is clinically necessary for diagnosis and treatment.
Objective: Multiple mechanisms underlying the development of portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) have been reported recently. However, the origins of PVTT remain unknown. Increasing multi-omics data on PVTTs in HCCs have made it possible to investigate whether PVTTs originate from the corresponding primary tumors(Ts).Methods: The clonal relationship between PVTTs and their corresponding primary Ts was investigated using datasets deposited in public databases. One DNA copy number variations dataset and three gene expression datasets were downloaded for the analyses.Clonality analysis was performed to investigate the clonal relationship between PVTTs and Ts from an individual patient.Differential gene expression analysis was applied to investigate the gene expression profiles of PVTTs and Ts.Results: One out of 19 PVTTs had no clonal relationship with its corresponding T, whereas the others did. The PVTTs with independent clonal origin showed different gene expression and enrichment in biological processes from the primary Ts. Based on the unique gene expression profiles, a gene signature including 24 genes was used to identify pairs of PVTTs and primary Ts without any clonal relationship. Validation in three datasets showed that these types of pairs of PVTTs and Ts can be identified by the 24-gene signature.Conclusions: Our findings show a direct evidence for PVTT origin and consolidate the heterogeneity of PVTTs observed in clinic.The results suggest that PVTT investigation at a molecular level is clinically necessary for diagnosis and treatment.
Objective: Multiple mechanisms underlying the development of portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) have been reported recently. However, the origins of PVTT remain unknown. Increasing multi-omics data on PVTTs in HCCs have made it possible to investigate whether PVTTs originate from the corresponding primary tumors(Ts).Methods: The clonal relationship between PVTTs and their corresponding primary Ts was investigated using datasets deposited in public databases. One DNA copy number variations dataset and three gene expression datasets were downloaded for the analyses.Clonality analysis was performed to investigate the clonal relationship between PVTTs and Ts from an individual patient.Differential gene expression analysis was applied to investigate the gene expression profiles of PVTTs and Ts.Results: One out of 19 PVTTs had no clonal relationship with its corresponding T, whereas the others did. The PVTTs with independent clonal origin showed different gene expression and enrichment in biological processes from the primary Ts. Based on the unique gene expression profiles, a gene signature including 24 genes was used to identify pairs of PVTTs and primary Ts without any clonal relationship. Validation in three datasets showed that these types of pairs of PVTTs and Ts can be identified by the 24-gene signature.Conclusions: Our findings show a direct evidence for PVTT origin and consolidate the heterogeneity of PVTTs observed in clinic.The results suggest that PVTT investigation at a molecular level is clinically necessary for diagnosis and treatment.
引文
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13.Saito M,Seo Y,Yano Y,Uehara K,Hara S,Momose K,et al.Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules:a case report.Ann Hepatol.2013;12:969-73.
14.Zhang H,Ye JY,Weng XL,Liu FT,He L,Zhou DZ,et al.Comparative transcriptome analysis reveals that the extracellular matrix receptor interaction contributes to the venous metastases of hepatocellular carcinoma.Cancer Genet.2015;208:482-91.
15.Nemes S,Danielsson A,Parris TZ,Jonasson JM,Bülow E,Karlsson P,et al.A diagnostic algorithm to identify paired tumors with clonal origin.Genes Chromosomes Cancer.2013;52:1007-16.
16.Haffner MC,Mosbruger T,Esopi DM,Fedor H,Heaphy CM,Walker DA,et al.Tracking the clonal origin of lethal prostate cancer.J Clin Invest.2013;123:4918-22.
17.Tripathi S,Pohl MO,Zhou YY,Rodriguez-Frandsen A,Wang GJ,Stein DA,et al.Meta-and orthogonal integration of influenza"OMICs"data defines a role for UBR4 in virus budding.Cell Host Microbe.2015;18:723-35.
18.Reich M,Liefeld T,Gould J,Lerner J,Tamayo P,Mesirov JP.Genepattern 2.0.Nat Genet.2006;38:500-1.
19.Ceulemans A,Verhulst S,Van Haele M,Govaere O,Ventura JJ,Van Grunsven LA,et al.Rna-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.Cell Death Dis.2017;8:e3164.
20.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;69:7385-92.
21.Sia D,Jiao Y,Martinez-Quetglas I,Kuchuk O,Villacorta-Martin C,Castro De Moura M,et al.Identification of an immune-specific class of hepatocellular carcinoma,based on molecular features.Gastroenterology.2017;153:812-26.
22.Song FF,Li XC,Song FJ,Zhao YR,Li HX,Zheng H,et al.Comparative genomic analysis reveals bilateral breast cancers are genetically independent.Oncotarget.2015;6:31820-9.
23.Venkatraman ES,Olshen AB.A faster circular binary segmentation algorithm for the analysis of array CGH data.Bioinformatics.2007;23:657-63.
24.Sia D,Villanueva A,Friedman SL,Llovet JM.Liver cancer cell of origin,molecular class,and effects on patient prognosis.Gastroenterology.2017;152:745-61.
25.Turner KM,Deshpande V,Beyter D,Koga T,Rusert J,Lee C,et al.Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.Nature.2017;543:122-5.
26.Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation.Cell.2011;144:646-74.
27.Wang M,Xi D,Ning Q.Virus-induced hepatocellular carcinoma with special emphasis on HBV.Hepatol Int.2017;11:171-80.
28.Tomczak K,Czerwińska P,Wiznerowicz M.The cancer genome atlas(TCGA):an immeasurable source of knowledge.Contemp Oncol.2015;19:A68-77.
29.The Cancer Genome Atlas Research Network.Comprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell.2017;169:1327-1341.e23.
30.Hoadley KA,Yau C,Wolf DM,Cherniack AD,Tamborero D,Ng S,et al.Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.Cell.2014;158:929-44.
2.Kokudo T,Hasegawa K,Matsuyama Y,Takayama T,Izumi N,Kadoya M,et al.Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion.JHepatol.2016;65:938-43.
3.Sakamoto K,Nagano H.Surgical treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus.Hepatol Res.2017;47:957-62.
4.Bruix J,Sherman M.Management of hepatocellular carcinoma:an update.Hepatology.2011;53:1020-2.
5.Cheng SQ,Chen MS,Cai JQ,National Research Cooperative Group for Diagnosis,Treatment of Hepatocellular Carcinoma with Tumor Thrombus.Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus:2016 edition.Oncotarget.2017;8:8867-76.
6.Tang YF,Liu SP,Li N,Guo WX,Shi J,Yu HM,et al.14-3-3ζpromotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α.Oncotarget.2016;7:15854-67.
7.Ye LY,Chen W,Bai XL,Xu XY,Zhang Q,Xia XF,et al.Hypoxiainduced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis.Cancer Res.2016;76:818-30.
8.Zhang J,Pan YF,Ding ZW,Yang GZ,Tan YX,Yang C,et al.Rmp promotes venous metastases of hepatocellular carcinoma through promoting il-6 transcription.Oncogene.2015;34:1575-83.
9.Guo WX,Liu SP,Cheng YQ,Lu L,Shi J,Xu GX,et al.ICAM-1-related noncoding rna in cancer stem cells maintains ICAM-1expression in hepatocellular carcinoma.Clin Cancer Res.2015;22:2041-50.
10.Ye QH,Qin LX,Forgues M,He P,Kim JW,Peng AC,et al.Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.Nat Med.2003;9:416-23.
11.Yang Y,Chen L,Gu J,Zhang HS,Yuan JP,Lian QY,et al.Recurrently deregulated lnc RNAs in hepatocellular carcinoma.Nat Commun.2017;8:14421.
12.Guo WX,Xue J,Shi J,Li N,Shao Y,Yu XY,et al.Proteomics analysis of distinct portal vein tumor thrombi in hepatocellular carcinoma patients.J Proteome Res.2010;9:4170-5.
13.Saito M,Seo Y,Yano Y,Uehara K,Hara S,Momose K,et al.Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules:a case report.Ann Hepatol.2013;12:969-73.
14.Zhang H,Ye JY,Weng XL,Liu FT,He L,Zhou DZ,et al.Comparative transcriptome analysis reveals that the extracellular matrix receptor interaction contributes to the venous metastases of hepatocellular carcinoma.Cancer Genet.2015;208:482-91.
15.Nemes S,Danielsson A,Parris TZ,Jonasson JM,Bülow E,Karlsson P,et al.A diagnostic algorithm to identify paired tumors with clonal origin.Genes Chromosomes Cancer.2013;52:1007-16.
16.Haffner MC,Mosbruger T,Esopi DM,Fedor H,Heaphy CM,Walker DA,et al.Tracking the clonal origin of lethal prostate cancer.J Clin Invest.2013;123:4918-22.
17.Tripathi S,Pohl MO,Zhou YY,Rodriguez-Frandsen A,Wang GJ,Stein DA,et al.Meta-and orthogonal integration of influenza"OMICs"data defines a role for UBR4 in virus budding.Cell Host Microbe.2015;18:723-35.
18.Reich M,Liefeld T,Gould J,Lerner J,Tamayo P,Mesirov JP.Genepattern 2.0.Nat Genet.2006;38:500-1.
19.Ceulemans A,Verhulst S,Van Haele M,Govaere O,Ventura JJ,Van Grunsven LA,et al.Rna-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.Cell Death Dis.2017;8:e3164.
20.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;69:7385-92.
21.Sia D,Jiao Y,Martinez-Quetglas I,Kuchuk O,Villacorta-Martin C,Castro De Moura M,et al.Identification of an immune-specific class of hepatocellular carcinoma,based on molecular features.Gastroenterology.2017;153:812-26.
22.Song FF,Li XC,Song FJ,Zhao YR,Li HX,Zheng H,et al.Comparative genomic analysis reveals bilateral breast cancers are genetically independent.Oncotarget.2015;6:31820-9.
23.Venkatraman ES,Olshen AB.A faster circular binary segmentation algorithm for the analysis of array CGH data.Bioinformatics.2007;23:657-63.
24.Sia D,Villanueva A,Friedman SL,Llovet JM.Liver cancer cell of origin,molecular class,and effects on patient prognosis.Gastroenterology.2017;152:745-61.
25.Turner KM,Deshpande V,Beyter D,Koga T,Rusert J,Lee C,et al.Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.Nature.2017;543:122-5.
26.Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation.Cell.2011;144:646-74.
27.Wang M,Xi D,Ning Q.Virus-induced hepatocellular carcinoma with special emphasis on HBV.Hepatol Int.2017;11:171-80.
28.Tomczak K,Czerwińska P,Wiznerowicz M.The cancer genome atlas(TCGA):an immeasurable source of knowledge.Contemp Oncol.2015;19:A68-77.
29.The Cancer Genome Atlas Research Network.Comprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell.2017;169:1327-1341.e23.
30.Hoadley KA,Yau C,Wolf DM,Cherniack AD,Tamborero D,Ng S,et al.Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.Cell.2014;158:929-44.
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