Dataset Information

Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.

ABSTRACT: Tumor heterogeneity is a major obstacle to the success of cancer treatment. An accurate understanding and recognition of tumor heterogeneity is critical in the clinical management of cancer patients. Here, we utilized single-cell RNA sequencing (scRNA-seq) to uncover the intra- and intertumoral heterogeneity of liver metastases from a patient with metastatic uveal melanoma. The two metastases analyzed were largely infiltrated by noncancerous cells with significant variability in the proportion of different cell types. Analysis of copy-number variations (CNVs) showed gain of 8q and loss of 6q in both tumors, but loss of Chromosome 3 was only detected in one of the tumors. Single-nucleotide polymorphism (SNP) array revealed a uniparental isodisomy 3 in the tumor with two copies of Chromosome 3, indicating a regain of Chromosome 3 during the development of the metastatic disease. In addition, both tumors harbored subclones with additional CNVs. Pathway enrichment analysis of differentially expressed genes revealed that cancer cells in the metastasis with isodisomy 3 showed up-regulation in epithelial-mesenchymal transition and myogenesis related genes. In contrast, up-regulation in interferon signaling was observed in the metastasis with monosomy 3 and increased T-cell infiltrate. This study highlights the complexity and heterogeneity of different metastases within an individual case of uveal melanoma.

SUBMITTER: Lin W

PROVIDER: S-EPMC8559622 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.

Lin Weitao W Beasley Aaron B AB Ardakani Nima Mesbah NM Denisenko Elena E Calapre Leslie L Jones Matthew M Wood Benjamin A BA Warburton Lydia L Forrest Alistair R R ARR Gray Elin S ES

Cold Spring Harbor molecular case studies 20211019 5

Tumor heterogeneity is a major obstacle to the success of cancer treatment. An accurate understanding and recognition of tumor heterogeneity is critical in the clinical management of cancer patients. Here, we utilized single-cell RNA sequencing (scRNA-seq) to uncover the intra- and intertumoral heterogeneity of liver metastases from a patient with metastatic uveal melanoma. The two metastases analyzed were largely infiltrated by noncancerous cells with significant variability in the proportion o ...[more]

PMID: 34470851

Similar Datasets

Project description:The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.

Project description:This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns.

Project description:BackgroundUveal melanoma is the most common malignant tumor of the eye in adults. About half of the patients develop distant metastases, most commonly liver metastases (>90%). These are associated with poorer overall survival compared to patients with extrahepatic metastases.Patients and methodsIn this retrospective study, patients diagnosed with metastatic uveal melanoma between January 2005 and December 2021 and treated at the Center for Dermato-oncology at the University of Tübingen, were included. The total cohort was divided into two groups. Group 1, in which the first diagnosis of metastasis was between 2005 and 2015 and group 2 with first metastasis between 2016 and 2021. Melanoma-specific survival (MSS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, test for differences was performed by the log-rank test.ResultsA total of 167 patients were included in the study. Since more than 90% of patients had developed liver metastases as their first site of metastasis, we focused our analysis on patients with liver metastases. Median MSS was 28 months (95% confidence interval (CI) (22.8-33.2 months)) in patients receiving first-line liver-directed therapy (n = 89) compared to 10 months (95% CI (8.4-11.6 months)) for patients with first-line systemic therapy (n = 45). The best MSS was found in patients of group 2 and liver-directed therapy as first-line treatment. Since survival with first-line liver-directed therapy was significantly better in group 2, subsequent systemic therapies must also be considered, especially immune checkpoint inhibitors.ConclusionThis analysis revealed that MSS has improved significantly in recent years. In our analysis, first-line liver-directed therapy was associated with improved survival compared to first-line systemic therapy. Further studies are urgently needed, for example, to investigate the combination of immune checkpoint inhibition or tebentafusp with liver-specific procedures from the outset.

Dataset Information

Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.

Publications

Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets