Cooperation between distinct cancer drivers dictates inter-tumor heterogeneity in hepatocellular carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA624109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11518800_1.fastq.gz | Fastqsanger.gz | |||
| SRR11518800_2.fastq.gz | Fastqsanger.gz | |||
| SRR11518801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11518801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11518802_1.fastq.gz | Fastqsanger.gz |
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Project description:We generate multiple models of liver cancer to study heterogeneity at different levels
2020-12-16 | GSE148379 | GEO
Project description:Introduction: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in HCC and study their intra- and inter-tumor distribution in more advanced lesions. Methods: 151 samples representing the multi-step process of hepatocarcinogenesis were analyzed by targeted-sequencing and SNP array. Genes altered in early lesions [31 dysplastic nodules (DNs) and 38 small HCCs (sHCC)] were defined as trunk. The distribution of candidate trunk genes was explored in: a) different regions of large tumors [43 regions of 21 tumors, (2-3 regions/tumor)]; and b) different nodules of the same patient [39 multinodular tumors from 17 patients]. Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events in early stages. 89% of mutations in these genes were shared between different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs. 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC.
2019-07-05 | GSE102451 | GEO
Project description:Introduction: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in HCC and study their intra- and inter-tumor distribution in more advanced lesions. Methods: 151 samples representing the multi-step process of hepatocarcinogenesis were analyzed by targeted-sequencing and SNP array. Genes altered in early lesions [31 dysplastic nodules (DNs) and 38 small HCCs (sHCC)] were defined as trunk. The distribution of candidate trunk genes was explored in: a) different regions of large tumors [43 regions of 21 tumors, (2-3 regions/tumor)]; and b) different nodules of the same patient [39 multinodular tumors from 17 patients]. Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events in early stages. 89% of mutations in these genes were shared between different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs. 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC.
2019-07-05 | GSE102383 | GEO
Project description:The inter-patient variability of tumor proteomes has been investigated on a large scale but many tumors display also intra-tumoral heterogeneity (ITH) regarding morphological and genetic features. To what extent the local proteome of tumors intrinsically differs remains largely unknown. Here, we used hepatocellular carcinoma (HCC) as a model system, to quantify both inter- and intra-tumor heterogeneity across human patient specimens with spatial resolution. We first defined proteomic features that robustly distinguish neoplastic from the directly adjacent non-neoplastic tissue by integrating proteomic data from human patient samples and genetically defined mouse models with available gene expression data. We then demonstrated the existence of intra-tumoral variations in protein abundance that re-occur across different patient samples, and affect clinically relevant proteins, even in the absence of obvious morphological differences or genetic alterations. Our work demonstrates the suitability and the benefits of using mass spectrometry based proteomics to analyze diagnostic tumor specimens with spatial resolution
2018-01-24 | PXD007052 | Pride
Project description:Introduction: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in HCC and study their intra- and inter-tumor distribution in more advanced lesions. Methods: 151 samples representing the multi-step process of hepatocarcinogenesis were analyzed by targeted-sequencing and SNP array. Genes altered in early lesions [31 dysplastic nodules (DNs) and 38 small HCCs (sHCC)] were defined as trunk. The distribution of candidate trunk genes was explored in: a) different regions of large tumors [43 regions of 21 tumors, (2-3 regions/tumor)]; and b) different nodules of the same patient [39 multinodular tumors from 17 patients]. Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events in early stages. 89% of mutations in these genes were shared between different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs. 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC.
2019-07-05 | GSE98619 | GEO
Project description:Introduction: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in HCC and study their intra- and inter-tumor distribution in more advanced lesions. Methods: 151 samples representing the multi-step process of hepatocarcinogenesis were analyzed by targeted-sequencing and SNP array. Genes altered in early lesions [31 dysplastic nodules (DNs) and 38 small HCCs (sHCC)] were defined as trunk. The distribution of candidate trunk genes was explored in: a) different regions of large tumors [43 regions of 21 tumors, (2-3 regions/tumor)]; and b) different nodules of the same patient [39 multinodular tumors from 17 patients]. Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events in early stages. 89% of mutations in these genes were shared between different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs. 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC.
2019-07-05 | GSE98618 | GEO
Project description:Introduction: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in HCC and study their intra- and inter-tumor distribution in more advanced lesions. Methods: 151 samples representing the multi-step process of hepatocarcinogenesis were analyzed by targeted-sequencing and SNP array. Genes altered in early lesions [31 dysplastic nodules (DNs) and 38 small HCCs (sHCC)] were defined as trunk. The distribution of candidate trunk genes was explored in: a) different regions of large tumors [43 regions of 21 tumors, (2-3 regions/tumor)]; and b) different nodules of the same patient [39 multinodular tumors from 17 patients]. Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events in early stages. 89% of mutations in these genes were shared between different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs. 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC.
2019-07-05 | GSE98617 | GEO
Project description:Trunk events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma
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Project description:Background and aimsThe pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.MethodsBy performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.ResultsCooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.ConclusionsThis novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
| S-EPMC7726023 | biostudies-literature
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