Dataset Information

Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver genes. We identify two main types of tumor evolution, i.e., linear, and non-linear models where non-linear type could be further divided into classes, which we call shallow branching and deep branching. We find that linear evolving HCC is less aggressive than other types. GTF2IRD2B mutations are enriched in HCC with linear evolution, while TP53 mutations are the most frequent genetic alterations in HCC with non-linear models. Furthermore, we observe significant B cell enrichment in linear trees compared to non-linear trees suggesting the need for further research to uncover potential variations in immune cell types within genomically determined phylogeny types. These results hint at the possibility that tumor cells and their microenvironment may collectively influence the tumor evolution process.

SUBMITTER: Kacar Z

PROVIDER: S-EPMC11245610 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

Kacar Zeynep Z Slud Eric E Levy Doron D Candia Julián J Budhu Anuradha A Forgues Marshonna M Wu Xiaolin X Raziuddin Arati A Tran Bao B Shetty Jyoti J Pomyen Yotsawat Y Chaisaingmongkol Jittiporn J Rabibhadana Siritida S Pupacdi Benjarath B Bhudhisawasdi Vajarabhongsa V Lertprasertsuke Nirush N Auewarakul Chirayu C Sangrajrang Suleeporn S Mahidol Chulabhorn C Ruchirawat Mathuros M Wang Xin Wei XW

Communications biology 20240329 1

Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver g ...[more]

PMID: 38553628

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Project description:Tumor-infiltrating T-lymphocytes are defined as T-lymphocytes that infiltrated into tumor tissues; however, their composition, clinical significance, and underlying mechanism in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues are still not completely understood. Herein, we collected marker genes of T cell subpopulations from a previous study and estimated their relative infiltrating levels in HCC and adjacent non-tumor tissues. Specifically, the infiltrating levels of all the T cells were significantly reduced in HCC as compared with non-tumor tissues. Unsupervised clustering of the HCC samples by the T cell infiltrating levels revealed that the HCC samples could be clearly classified into two groups. The driver genes, including PTK2B, ATM, PIK3C2B, and KIT, and several CNAs were observed to be associated with reduced T cell infiltrating levels. Particularly, deletion of TP53 more frequently occurred in low T cell infiltration HCC samples and resulted in its downregulation and cell cycle progression, indicating that cell cycle progression was closely associated with reduced T cell infiltration. In contrast, for the samples with high infiltration T cells, its immune evasion might be regulated by the immune checkpoint regulators, such as PD-1/PD-L1 and CTLA4. Moreover, Olaparib, one of the PARP inhibitors, and immune checkpoint inhibitors might be therapeutic candidates for the samples from the two T cell infiltrating clusters. Clinically, the tumor-infiltrating levels of cytotoxic CD4 cell, Mucosal associated invariant T (MAIT) cell, and exhausted CD8+ T cell might be used as predictors for vascular invasion, recurrence, and overall survival. Collectively, we systematically evaluated the clinical significance and potential molecular mechanisms of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma, which might broaden our insights into the immunological features of HCC and provide potential immunotherapeutic targets.

Project description:CD73, a cell-surface N-linked glycoprotein that produces extracellular adenosine, is a novel target for cancer immunotherapy. Although anti-CD73 antibodies have entered clinical development, CD73 has both protumor and antitumor functions, depending on the target cell and tumor type. The aim of this study was to characterize CD73 regulation in human hepatocellular carcinoma (HCC). We examined CD73 expression, localization, and activity using molecular, biochemical, and cellular analyses on primary HCC surgical specimens, coupled with mechanistic studies in HCC cells. We analyzed CD73 glycan signatures and global alterations in transcripts encoding other N-linked glycoproteins by using mass spectrometry glycomics and RNA sequencing (RNAseq), respectively. CD73 was expressed on tumor hepatocytes where it exhibited abnormal N-linked glycosylation, independent of HCC etiology, tumor stage, or fibrosis presence. Aberrant glycosylation of tumor-associated CD73 resulted in a 3-fold decrease in 5'-nucleotidase activity (P < 0.0001). Biochemically, tumor-associated CD73 was deficient in hybrid and complex glycans specifically on residues N311 and N333 located in the C-terminal catalytic domain. Blocking N311/N333 glycosylation by site-directed mutagenesis produced CD73 with significantly decreased 5'-nucleotidase activity in vitro, similar to the primary tumors. Glycosylation-deficient CD73 partially colocalized with the Golgi structural protein GM130, which was strongly induced in HCC tumors. RNAseq analysis further revealed that N-linked glycoprotein-encoding genes represented the largest category of differentially expressed genes between HCC tumor and adjacent tissue. Conclusion: We provide the first detailed characterization of CD73 glycosylation in normal and tumor tissue, revealing a novel mechanism that leads to the functional suppression of CD73 in human HCC tumor cells. The present findings have translational implications for therapeutic candidate antibodies targeting cell-surface CD73 in solid tumors and small-molecule adenosine receptor agonists that are in clinical development for HCC.

Dataset Information

Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

Publications

Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma.

Similar Datasets

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