Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma
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Abstract
Purpose: Chromosomal instability is a hallmark of cancer that results in broad and focal copy-number alterations (CNAs), two events associated with distinct molecular, immunologic, and clinical features. In hepatocellular carcinoma (HCC), the role of CNAs has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features. Experimental Design: We analyzed SNP array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational, and methylation profiles, tumor immune composition, and clinicopathologic data. Results: HCCs with low broad CNA burdens (defined as BS ≤ 4; 17%) presented high inflammation, active infiltrate signaling, high cytolytic activity, and enrichment of the “HCC immune class” and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS ≥ 11; 40%), displayed immune-excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen-presenting machinery (i.e., HLA), widespread hypomethylation, and decreased rates of observed/expected neoantigenic mutations. High FSs were independent of tumor immune features, but were related to proliferation, TP53 dysfunction, and progenitor cell traits. Conclusions: HCCs with high chromosomal instability exhibit features of immune exclusion, whereas tumors displaying low burdens of broad CNAs present an immune active profile. These CNA scores can be tested to predict response to immunotherapies.
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Inflamed tumours make up about 30% of hepatocellular carcinomas and show extensive immune infiltration, increased immune checkpoint expression, interferon signalling activation, and a low burden of large chromosomal alterations.
“Inflamed tumours constitute ~30% of HCCs and exhibit extensive immune cell infiltration and immune activity, detected as increased expression of immune checkpoints (such as PD-1 or its ligand PD-L1), activation of IFN signalling and a low burden of large chromosomal alterations70,71,78.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [70]
The Introduction (page unavailable) describes an HCC Immune Class comprising about one third of cases, with high immune infiltration and PD-1/PD-L1 expression. The Results (page unavailable) link low broad copy-number alteration burden to interferon signalling, immune infiltration, and higher checkpoint expression. But low-burden tumours account for 17% of HCCs, and the paper reports an association with the Immune Class—not that all inflamed tumours have low alteration burden. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHigh tumour mutational burden does not correlate with increased immune infiltration in hepatocellular carcinoma.
“Furthermore, a high TMB does not correlate with increased immune infiltration70,71.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [70]
The Results report that low-broad-CNA HCCs had fewer mutations but greater immune infiltration than high-broad-CNA HCCs, consistent with infiltration not increasing with mutation burden in those groups. The paper does not report a direct correlation analysis of high TMB and immune infiltration; it also notes that only 2% of the HCC samples had TMB above 10 mutations/Mb. The claim is therefore broader than the comparison studied. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn hepatocellular carcinoma, large-scale copy-number alterations cause loss of antigen-presentation genes, suggesting that these alterations shape the tumour microenvironment.
“Indeed, in HCC, the presence of large-scale copy-number alterations results in the loss of genes involved in antigen presentation, suggesting that copy-number alterations contribute shaping of the TME70.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [70]
The Results report that losses of antigen-presentation genes, including HLA-DQB1, were enriched in HCC tumors with high burdens of broad copy-number alterations. The Discussion proposes that these losses could affect the tumor immune environment, but says further studies are needed to establish causality. Thus, “results in” overstates the evidence. Page numbers were not available in our copy. (LLM, conf=0.88)
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References 57 · Cited by 58
- Authors
- Bassaganyas, L., Pinyol, R., Esteban-Fabró, R., Torrens, L., Torrecilla, S., Willoughby, C. E., Franch-Expósito, S., Vila-Casadesús, M., Salaverria, I., Montal, R., Mazzaferro, V., Camps, J., Sia, D., & Llovet, J. M.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- 2Gastrointestinal and Pancreatic Oncology Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
- 3Bioinformatics Unit, CIBERehd, Barcelona, Catalonia, Spain.
- 4Lymphoid Neoplasms Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
- 6Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy.
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Tisch Cancer Institute (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Llovet, Josep M.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-12-01
- Volume
- 26
- Issue
- 23
- Pages
- 6350-6361
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7710584
- OpenAlex
- W3081621032
- Cited by
- 58
- References
- 57
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 12 · 2022: 13 · 2021: 7 · 2020: 1
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- European Commission Horizon 2020 (667273-2)
- U.S. Department of Defense (CA150272P3)
- NCI (P30 CA196521)
- Spanish National Health Institute (SAF-2016-76390, PID2019-105378RB-I00)
- Fundación Científica de la Asociacion Española Contra el Cáncer (C9380/A26813)
- Generalitat de Catalunya (AGAUR, SGR-1358, 2017 SGR 1035)
- Beatriu de Pinos (AGAUR, 2016BP00161)
- MICINN (BES-2017-081286)
- Sara Borrell (CD19/00109)
- European Regional Development Fund (CPII18/00026, PI17/01304)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, copy number alterations, chromosomal instability, tumor immune microenvironment, immune exclusion, antigen presentation, HLA, DNA methylation, neoantigens, DNA repair, immunotherapy response prediction, dysplastic nodules
- MeSH terms
- Aged, Antigen-Presenting Cells, Antigens, Neoplasm, Female, Follow-Up Studies, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Mutation, Phenotype, Prognosis, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, DNA Methylation, Chromosomal Instability, DNA Copy Number Variations
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