scholarly journals Multi-Platform Omics Analysis for Identification of Molecular Characteristics and Therapeutic Targets of Uveal Melanoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Joon Kim ◽  
Seo Jin Park ◽  
Kyung Joo Maeng ◽  
Sung Chul Lee ◽  
Christopher Seungkyu Lee
Keyword(s):  
Uveal Melanoma ◽  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Synthetic Lethal ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Sirna Library

AbstractCurrently, there is no effective treatment for metastatic uveal melanoma (UVM). Here, we aimed to identify the mechanism involving intrinsic chemoresistance of metastatic UVM and the relevant therapeutic targets for UVM. We analyzed cohorts of 80 and 67 patients with primary UVM and skin cutaneous melanoma (SKCM), respectively, using The Cancer Genome Atlas dataset. Mutational burdens identified by whole exome sequencing were significantly lower in UVM than in SKCM patients. COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair. Transcriptome analysis revealed that the MYC signature was more enriched in UVM patients, as compared to SKCM patients. Fifty-nine (73.8%) of 80 UVM patients showed gains in MYC copy number, and a high MYC copy number was associated with aggressive clinicopathological features of tumors and poor survival. Kinome-wide siRNA library screening identified several therapeutic targets, reported as synthetic lethal targets for MYC-addicted cancers. Notably, UVM cell lines showed high susceptibility to a WEE1 inhibitor (MK-1775; adavosertib) at a clinically tolerable dose. Overall, our study identified high MYC activity in UVM, and suggested G2/M checkpoint inhibitors as effective therapeutic targets for UVM.

scholarly journals Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy

2022 ◽  
Author(s):  
Fan Kou ◽  
Lei Wu ◽  
Ye Zhu ◽  
Baihui Li ◽  
Ziqi Huang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Whole Exome ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

AbstractSomatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.

Association between PD-L1 variants and PD-L1 expression: A pan-cancer analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13661-e13661
Author(s):  
Xiang Wang ◽  
Ding Zhang ◽  
Guoqiang Wang ◽  
Anqi Duan ◽  
Xiang Ruan ◽  
...  
Keyword(s):  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Copy Number Gain ◽  
The Cancer Genome Atlas ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Positive Rate ◽  
Cancer Genome Atlas ◽  
Copy Number Amplification

e13661 Background: Programmed cell death-1 (PD-L1) expression has become a predictive biomarker of response to immune checkpoint inhibitors (ICIs) in several types of solid tumors. Patients with high expression of PD-L1 can benefit more from immunotherapy. However, whether PD-L1 variants would influence the PD-L1 expression has not been fully studied. Methods: Patients with both mutation and immunohistochemistry results for PD-L1 expression from our dataset was analyzed. Patients with both mutation and RNA expression data were obtained from The Cancer Genome Atlas (TCGA) and also analyzed. Results: In our dataset, 10002 patients were included in the analysis. 101 (1%) patients harbored PD-L1 variants, including 24 with single nucleotide variant (SNV), 1 with fusion, 3 with copy-number reduction, 59 with copy-number gain, and 16 germline SNV. The PD-L1 positive rate was 42% in patients with SNV, 100% in fusion, 0% in copy-number reduction, 78% in copy-number gain, 19% in germline SNV and 39% in patients without PD-L1 variants. 32 studies of 10071 patients from TCGA were included for analysis. 244 (2.22%) patients harboring PD-L1 variants, including 2 with frame shift mutations, 3 with nonsense mutations, 38 with missense mutations, 2 with splices, 3 with fusions, 83 with copy-number reduction and 118 with copy-number amplification. The PD-L1 expression in patients with PD-L1 variants was significantly higher than patients without PD-L1 variants (P < 0.001). Further analysis among PD-L1 variants groups showed that PD-L1 fusion and amplification were associated with higher PD-L1 expression. Conclusions: Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.

The Microenvironment Combining with Immune Infiltration of Uveal Melanoma

2021 ◽  
Author(s):  
Daowei Zhang ◽  
Jiawen Wu ◽  
Jihong Wu ◽  
Shenghai Zhang
Keyword(s):  
Uveal Melanoma ◽  
Immune Cells ◽  
Therapeutic Targets ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Malignant Tumours ◽  
Cancer Genome Atlas ◽  
Key Genes ◽  
Low Expression

Abstract Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Although immunotherapy provided novel options in the disease's progression, it only benefits a minority of patients. The understanding of the UM microenvironment and the potential therapeutic targets in the microenvironment is still undefined. We aimed to propose a novel classification of UM microenvironment to identify ideal biomarkers for prognosis and potential targets for effective immunotherapy.Methods: In this study, we obtained the gene expression profile of 80 UM patients from the Cancer Genome Atlas (TCGA) and calculated immune/stromal scores based on the Estimation of stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm dividing patients into the high- and low-expression groups. Then, 1024 immune-related differently expressed genes (DEGs) were selected in total following the annotation and enrichment analysis and key genes were screened by PPI network. Consequently, we conducted CIBERSORT algorithm and TIMER database to analyses the correlation between key genes and immune cells as well as utilized GeneCards database to analyses the correlation between key genes and the disease. Additionally, GSVA was performed to enrich the nonparametric and unsupervised signaling pathways of key genes and the drug sensitivity of them were predicted.Results: Based on high- and low-expression groups, we found that there were 888 up-regulated DEGs and 126 down-regulated DEGs in total, which were mainly enriched in 4 pathways in GO and 3 pathways in KEGG. Combining with the 10 genes screened by PPI, KM-plot showed that B2M and HLA-B were significantly affected the survival of UM patients. Among 22 immune cells, B2M and HLA-B were mainly corelated with 11 of them. GSVA results revealed 42 pathways significantly enriched of B2M while 41 pathways enriched of HLA-B. Finally, we predicted the Paclitaxel as the hopefully treatment for HLA-B.Conclusions: Our study not only understands deeper of fundamental biological features of microenvironment but also with potential therapeutic targets of UM.

scholarly journals Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1061 ◽  
Author(s):  
Mathieu F. Bakhoum ◽  
Bita Esmaeli
Keyword(s):  
Uveal Melanoma ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Tissue Samples ◽  
Molecular Investigation ◽  
Cancer Genome Atlas ◽  
First Time ◽  
Primary Tissue ◽  
Genome Atlas

The Cancer Genome Atlas (TCGA) uveal melanoma project was a comprehensive multi-platform deep molecular investigation of 80 uveal melanoma primary tissue samples supported by the National Cancer Institute. In addition to identification of important mutations for the first time, it identified four different clusters (subgroups) of patients paralleling prognosis. The findings of the TCGA marker paper are summarized in this review manuscript and other investigations that have stemmed from the findings of the TCGA project are reviewed.

scholarly journals Integrated mutational landscape analysis of uterine leiomyosarcomas

2021 ◽  
Vol 118 (15) ◽  
pp. e2025182118
Author(s):  
Jungmin Choi ◽  
Aranzazu Manzano ◽  
Weilai Dong ◽  
Stefania Bellone ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Copy Number ◽  
Muscle Layer ◽  
The Cancer Genome Atlas ◽  
Repair Deficiency ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Dna Repair Deficiency ◽  
Number Variation ◽  
Fresh Frozen ◽  
Cancer Genome Atlas

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

scholarly journals Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098153
Author(s):  
Qing Bi ◽  
Yang Liu ◽  
Tao Yuan ◽  
Huizhen Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Survival Data ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

scholarly journals Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Nathan D. Seligson ◽  
Richard D. Maradiaga ◽  
Colin M. Stets ◽  
Howard M. Katzenstein ◽  
Sherri Z. Millis ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Additional Data ◽  
Gene Expression Omnibus ◽  
Mtor Pathway ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Potential Therapeutic Target ◽  
Disease Stabilization ◽  
Cancer Genome Atlas ◽  
Ewing Family Of Tumors

AbstractSarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

scholarly journals Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kristina Totland Carm ◽  
Andreas M. Hoff ◽  
Anne Cathrine Bakken ◽  
Ulrika Axcrona ◽  
Karol Axcrona ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Classification ◽  
Primary Diagnosis ◽  
The Cancer Genome Atlas ◽  
Clinical Usefulness ◽  
Whole Exome ◽  
Primary Prostate Cancer ◽  
Cancer Genome Atlas ◽  
Prostate Cancers

Abstract Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier’s performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer.

scholarly journals Opposite Roles of BAP1 in Overall Survival of Uveal Melanoma and Cutaneous Melanoma

2020 ◽  
Vol 9 (2) ◽  
pp. 411 ◽  
Author(s):  
Feng Liu-Smith ◽  
Yunxia Lu
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Cutaneous Melanoma ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Small Subset ◽  
Mrna Levels ◽  
Cancer Genome Atlas

Background: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM). BAP1 loss is common in UM and is associated with a worse prognosis. BAP1 loss is rare in CM and the outcome is unclear. Methods: UM and CM data was retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS). Results: BAP1-low mRNA predicted a poor OS in UM (HR = 9.57, 95% CI: 2.82, 32.5) but a contrasting better OS in CM (HR = 0.73, 95% CI: 0.56, 0.95). These results remained unchanged after adjusting for sex, age, and stage in UM and CM, or after adjusting for ulceration or Breslow depth in CM. Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients. Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors. Conclusions: Low BAP1 mRNA was significantly associated with a better OS in CM patients, in sharp contrast to UM. High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients. Function of BAP1 was largely different in CM and UM despite of a small subset of shared co-expressed genes.

scholarly journals Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial–mesenchymal transition

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Chaoju Gong ◽  
Jie Shen ◽  
Zejun Fang ◽  
Lei Qiao ◽  
Ruifang Feng ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Transcriptional Level ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Epithelial Marker ◽  
Cancer Genome Atlas

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell–cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial–mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.

Sign in / Sign up

Export Citation Format

Share Document