Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression.
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ABSTRACT:
SUBMITTER: Stalhammar G
PROVIDER: S-EPMC7962103 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.
| S-EPMC5671412 | biostudies-literature
Project description:PurposeReduced nuclear expression of BRCA1 associated protein 1 (BAP-1) is associated with a high risk for metastasis in uveal melanoma. Manual assessment of the expression level may face issues with interobserver reproducibility. This could be improved with digital image analysis (DIA).MethodsThirty enucleated eyes with uveal melanoma from the Emory Eye Center (Atlanta, GA; years 2009-2017) were included and stained with BAP-1. Retrospective data on patient and tumor characteristics were retrieved. Patients were randomized to a training or validation cohort. Their tumor sections were digitally scanned and scored for percentage of BAP-1-positive cells with the QuPath Bioimage analysis software.ResultsInterobserver concordance was 75% (Cohen's κ 0.52) with manual BAP-1 scoring and 88% to 94% with DIA (Cohen's κ 0.75-0.88). Positive and negative predictive values for metastasis were 90% and 100% with DIA, 80% and 86% with manual scoring, and 78% and 88% with gene expression class 2. In binary logistic regression, manual and DIA of BAP-1 and gene expression class 2 were associated with metastasis, but none retained significance in multiple regression. Metastasis-free survival was significantly shorter with low BAP-1 expression as defined by DIA (log-rank P = 0.02), but not with manual scoring (log-rank P = 0.36) or with gene expression class 2 (log-rank P = 0.17).ConclusionsDIA of BAP-1 is a competitive alternative to manual assessment as well as gene expression profiling in prognostication of enucleated specimens with uveal melanoma.Translational relevanceThe emerging scope for automatization of qualified diagnostic tasks is applied to uveal melanoma.
| S-EPMC6504204 | biostudies-literature
Project description:Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan-Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.
| S-EPMC7141227 | biostudies-literature
Project description:PurposePeriodic acid-Schiff (PAS) positive patterns of vasculogenic mimicry (VM) have been associated with poor prognosis in uveal melanoma (UM). We examined these patterns with digital image analysis and transmission electron microscopy, and correlated them with BAP-1 expression, gene expression class, macrophage infiltration, and metastatic disease in full tumor cross-sections and intratumor regions.MethodsThirty-two enucleated eyes with UM were stained immunohistochemically (BAP-1, laminin, CD31, and CD68) and with PAS without hematoxylin counterstain. Retrospective data on gene expression class and patient survival were retrieved. Tumor sections were digitally scanned and analyzed with the QuPath Bioimage analysis software, and imaged with transmission electron microscopy.ResultsThe mean area proportion covered by CD31, laminin, and PAS positive patterns in tumor cross-sections was 0.9% (SD 0.6), 3.0% (SD 1.9), and 8.4% (SD 5.9), respectively. PAS density was statistically significantly greater in tumors with gene expression class 2 (p=0.02). The cumulative 5-year metastasis-free survival decreased for each quartile of increased PAS density (1.0, 0.75, 0.40, and 0.17, p=0.004). Forty percent of the tumors had heterogeneous BAP-1 expression. Intratumor regions with low BAP-1 expression were more likely to harbor VM (p<0.0001), and had statistically significantly greater PAS density (p<0.0001) and number of CD68 positive cells (p=0.01).ConclusionsPAS positive patterns in UM are composed of a mixture of blood vessels and extracellular matrix (ECM), including VM. Increased density of PAS positive patterns correlated with gene expression class and metastasis, and colocated to tumor regions with macrophage infiltration and low BAP-1 expression.
| S-EPMC6776441 | biostudies-literature
Project description:PurposeThe mechanism underlying cancer heterogeneity and plasticity remains elusive, in spite of the fact that multiple hypotheses have been put forward. We intended to clarify this heterogeneity in uveal melanoma (UM) by looking for evidence of cancer stem cell involvement and a potential role of ZEB1 in cancer cell plasticity.MethodsSpheroids derived from human UM cells as well as xenograft tumors in nude mice were dissected for signs of heterogeneity and plasticity. Two human UM cell lines were studied: the epithelioid type C918 cell line and the spindle type OCM1 cell line. We knocked down ZEB1 in both cell lines to investigate its involvement in the regulation of stem-like cell formation and vascularization by qRT-PCR, immunohistochemistry, flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays.ResultsWe found that a small side population (SP) in OCM1 showed stem cell-like properties such as heterogeneity, remote dissemination and nuclear dye exclusion after spheroid formation in vitro. ZEB1 regulated UM stem cell generation indirectly by promoting cell proliferation to form large size tumors in vivo and spheroid in vitro, and directly by binding to stemness genes such as TERT and ABCB1. In addition, we found that ZEB1 participates in vasculogenic mimicry system formation through the regulation of CD34 and VE-cadherin expression.ConclusionsFrom our data we conclude that cancer stem cells may contribute to UM heterogeneity and plasticity and that ZEB1 may play a regulatory role in it.
| S-EPMC9050762 | biostudies-literature
Project description:Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanized antibodies in use for several cancers, had been reported. 48 human UMs were analyzed by expression profiling. Evidence for signaling in tumors was obtained through the application of a UM-specific EGF signature. The EGFR specific kinase inhibitor, Gefitinib, and the humanized monoclonal antibody, Cetuximab, were tested for their effect on EGFR signaling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and TNF-alpha release was analyzed for Cetuximab. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. Gene expression profiles of 19 unique samples from uveal melanoma patients were measured.
| S-ECPF-GEOD-51880 | biostudies-other
Project description:BackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA).MethodsClonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan-Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level.ResultsTumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E-07) and cytotoxic pathway score (p = 2.9E-08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e-5) and spleen tyrosine kinase (SYK) (p = 0.0011).ConclusionsHighly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.
| S-EPMC7747763 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p=0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.
| S-SCDT-10_1038-S44321-024-00082-6 | biostudies-other
Project description:A high percentage of uveal melanoma patients develop metastatic tumors that predominately occur in the liver. To identify genes associated with metastasis in this pathology, we studied 63 molecular profiles derived from gene expression microarrays performed from enuceated primary tumors. Metastasis free survival analysis was performed to obtain clinical and genomic variables associated to metastasis occurrence. We also compared within the 57 tumors with at least 36 months follow-up, 28 uveal melanoma from patients who developed liver metastases (meta1 group) with 29 tumors arising from patients without metastases (or later metastases, i.e. after 36 months) (meta0 group). The transcriptome of 63 uveal melanoma from enucleation of untreated patients were analyzed using Affymetrix U133plus2 Arrays.
| S-ECPF-GEOD-22138 | biostudies-other
Project description:G protein alpha q and 11 are mutated in 90% of uveal melanoma and they activate the MAPK pathway. Using expression microarray analysis, we identified a unique MEK dependent transcriptional signature with genes that are involved in proliferation and tumor cell invasion. Uveal melanoma cells were profiled on Illumina Human HT-12 arrays per manufacturer's instructions
| S-ECPF-GEOD-33655 | biostudies-other