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1.
Oncoimmunology ; 12(1): 2261278, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38126027

RESUMEN

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP , Neoplasias de la Úvea , Adulto , Humanos , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/terapia , Neoplasias de la Úvea/metabolismo , Mutación , Inmunoterapia
2.
Cancer Med ; 12(13): 14062-14071, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37211960

RESUMEN

BACKGROUND: Uveal melanoma metastasizes to the liver. We aimed to explore the metabolic activity of liver metastases (LM) as a biomarker for survival. METHODS: We analyzed newly diagnosed patients with metastatic UM (MUM) with LM detected by liver-directed imaging and had undergone a PET/CT at diagnosis. FINDINGS: 51 patients were identified between 2004 and 2019. Median age was 62 years, 41% male and 22% ECOG ≥1. LDH, ALP, and GGT were elevated in 49%, 37%, and 57% of patients. Median LM SUVmax was 8.5 (3-42.2). Same size lesions presented a wide range of metabolic activity. Median OS was 17.3 m (95% CI:10.6-23.9). Patients with SUVmax ≥8.5 had an OS of 9.4 m (95% CI:6.4-12.3), whereas patients with SUVmax <8.5 had an OS of 38.4 m (95% CI:21.4-55.5; p < 0.0001, HR = 2.9). We observed similar results when studying M1a disease separately. Multivariate analysis showed SUVmax as an independent prognostic factor for the whole population and those with M1a disease. INTERPRETATION: Increased metabolic activity of LM seems to be an independent predictor of survival. MUM is a heterogeneous disease and metabolic activity probably reflects a different intrinsic behavior.


Asunto(s)
Neoplasias Hepáticas , Melanoma , Neoplasias de la Úvea , Humanos , Masculino , Persona de Mediana Edad , Femenino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Melanoma/patología , Neoplasias de la Úvea/patología , Pronóstico , Fluorodesoxiglucosa F18 , Estudios Retrospectivos
3.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800878

RESUMEN

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an "immune-cold" tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.


Asunto(s)
Linfocitos Infiltrantes de Tumor/patología , Melanoma/patología , Neovascularización Patológica/fisiopatología , Neoplasias de la Úvea/patología , Anciano , Animales , Presentación de Antígeno , Análisis por Conglomerados , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Subgrupos Linfocitarios/patología , Macrófagos/patología , Masculino , Melanoma/irrigación sanguínea , Melanoma/genética , Melanoma/inmunología , Redes y Vías Metabólicas , Persona de Mediana Edad , Neovascularización Patológica/genética , Pronóstico , Transducción de Señal , Células del Estroma/patología , Microambiente Tumoral , Neoplasias de la Úvea/irrigación sanguínea , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/inmunología
4.
J Natl Cancer Inst ; 110(5): 486-492, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29244173

RESUMEN

Background: It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided. Results: We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (Ptrend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis. Conclusions: The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.


Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Aprobación de Drogas/estadística & datos numéricos , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , United States Food and Drug Administration , Ensayos Clínicos como Asunto/normas , Humanos , Oncología Médica/estadística & datos numéricos , Neoplasias/clasificación , Neoplasias/patología , Calidad de Vida , Medición de Riesgo , Estados Unidos/epidemiología
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