scholarly journals The Potential Role of Selected miRNA in Uveal Melanoma Primary Tumors as Early Biomarkers of Disease Progression

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 271 ◽  
Author(s):  
Joanna Patrycja Wróblewska ◽  
Michał Stefan Lach ◽  
Adam Ustaszewski ◽  
Katarzyna Kulcenty ◽  
Matthew Ibbs ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Oncogenic Pathways ◽  
Micro Rnas ◽  
Mirna Expression Data ◽  
Metastatic Risk

Uveal melanoma (UM) is the most common primary tumor of the eye diagnosed in adults, associated with a high risk of metastasis and thereby, poor prognosis. Among known risk factors for the development of metastatic disease is the loss of BAP1 expression and chromosome 3 monosomy in the primary tumor. However, the expression levels of specific micro RNAs (miRNA) in tumor tissue may also serve as a valuable marker for determining the risk of metastatic disease in patients with primary uveal melanoma. In our study, we analyzed the miRNA expression data of cases selected from The Cancer Genome Atlas study on uveal melanoma, and determined a panel of 15 miRNAs differentially expressed between patients with primary and metastatic disease. Next, 6 miRNAs were validated on a group of 46 tumor samples from primary and metastatic patients. We have shown, that expression of hsa-miR-592, hsa-miR-346, and hsa-miR-1247 was significantly increased, while hsa-miR-506 and hsa-miR-513c were decreased in the tumors of patients with metastatic disease. Hsa-miR-196b expression did not differ between the two subgroups, however, we showed significant correlation with BAP1 expression. Moreover, hsa-miR-592 also showed correlation with monosomy 3 tumors. Gene ontology analysis revealed involvement of those miRNAs with cellular processes mediating the metastatic process. Our results showed that miRNAs play an important role in the deregulation of several oncogenic pathways in UM and can, thereby, promote metastatic spread to distant organs. Moreover, differentially expressed miRNAs may be used as an interesting biomarker for the assessment of metastatic risk in uveal melanoma patients.

scholarly journals Prediction and analysis of skin cancer progression using genomics profiles of patients

2018 ◽  
Author(s):  
Sherry Bhalla ◽  
Harpreet Kaur ◽  
Anjali Dhall ◽  
Gajendra P. S. Raghava
Keyword(s):  
Cancer Progression ◽  
Primary Tumor ◽  
Prediction Models ◽  
Simple Expression ◽  
The Cancer Genome Atlas ◽  
Machine Learning Techniques ◽  
Validation Dataset ◽  
Metastatic Tumors ◽  
Primary Tumors ◽  
Genomic Features

AbstractMetastatic state of the Skin Cutaneous Melanoma (SKCM) has led to high mortality rate worldwide. Previously, various studies have revealed the association of the metastatic melanoma with the diminished survival rate in comparison to primary tumors. Thus, prediction of melanoma at primary tumor state is crucial to employ optimal therapeutic strategy for prolonged survival of patients. The RNA, miRNA and methylation data of The Cancer Genome Atlas (TCGA) cohort of SKCM is comprehensively analysed to recognize key genomic features that can categorize various states of metastatic tumors from primary tumors with high precision. Subsequently, various prediction models were developed using filtered genomic features implementing various machine learning techniques to classify these primary tumors from metastatic tumors. The SVC model (with class weight and RBF kernel) developed using 17 mRNA features achieved maximum MCC 0.73 with sensitivity, specificity and accuracy 89.19%, 90.48% and 89.47% respectively on independent validation dataset. Our study reveals that gene expression based features performs better than features obtained from miRNA profiling and epigenomic profiling. Our analysis shows that the expression of genesC7, MMP3, KRT14, KRT17, MASP1, and miRNA hsa-mir-205 and hsa-mir-203a are among the key genomic features that may substantially contribute to the oncogenesis of melanoma even on the basis of simple expression threshold. The major prediction models and analysis modules to predict metastatic and primary tumor samples of SKCM are available from a webserver, CancerSPP (http://webs.iiitd.edu.in/raghava/cancerspp/).

scholarly journals Biglycan (BGN) is differentially expressed in metastatic breast cancer, both in metastases to the brain and to the lymph nodes.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Differentially Expressed ◽  
Down Regulation ◽  
Primary Tumors ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that biglycan, encoded by BGN, was among the genes whose expression was most different in the brain metastases of with patients with metastatic breast cancer as compared to primary tumors of the breast. Interestingly, biglycan was also among the genes most differentially expressed transcriptome-wide when comparing primary tumors of the breast to normal breast tissue. We observed significant down-regulation of biglycan in metastasis to the brain. Molecular functions and down-regulation of BGN may be important for metastasis of primary tumor-derived cancer cells the brain in humans with metastatic breast cancer, and suggests a role for changes in biglycan expression during a spectrum of transformation from benign tissue of the breast, primary tumor and finally to metastasis of the brain.

scholarly journals Tumor Microenvironment Analysis Identified Subtypes Associated With the Prognosis and the Tumor Response to Immunotherapy in Bladder Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongxian Zhang ◽  
Jiwen Song ◽  
Junqiang Dong ◽  
Zhuo Liu ◽  
Lixuan Lin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Genetic Characteristics ◽  
Signature Genes ◽  
Micro Rnas

Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned.Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA.Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively.Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.

scholarly journals Aberrant MicroRNA Expression and Its Implications for Uveal Melanoma Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 815 ◽  
Author(s):  
Kyra N. Smit ◽  
Jiang Chang ◽  
Kasper Derks ◽  
Jolanda Vaarwater ◽  
Tom Brands ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Target Genes ◽  
Microrna Expression ◽  
Differentially Expressed ◽  
Melanoma Metastasis ◽  
Genetic Changes ◽  
Expression Of Genes ◽  
Aggressive Cancer ◽  
Metastatic Risk ◽  
Egf Signaling

Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown. This study aimed to elucidate the potential role of microRNAs in the metastasis of UM. Using a next-generation sequencing approach in 26 UM samples we identified thirteen differentially expressed microRNAs between high-risk UM and low/intermediate-risk UM, including the known oncomirs microRNA-17-5p, microRNA-21-5p, and miR-151a-3p. Integration of the differentially expressed microRNAs with expression data of predicted target genes revealed 106 genes likely to be affected by aberrant microRNA expression. These genes were involved in pathways such as cell cycle regulation, EGF signaling and EIF2 signaling. Our findings demonstrate that aberrant microRNA expression in UM may affect the expression of genes in a variety of cancer-related pathways. This implies that some microRNAs can be responsible for UM metastasis and are promising potential targets for future treatment.

scholarly journals How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2043
Author(s):  
Mariarosaria Marseglia ◽  
Adriana Amaro ◽  
Nicola Solari ◽  
Rosaria Gangemi ◽  
Elena Croce ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Suppressor Gene ◽  
Driver Mutations ◽  
Intrinsic Resistance ◽  
Primary Tumors ◽  
Therapeutic Choice ◽  
Map Kinase Pathway ◽  
Metastatic Risk ◽  
Blocking Antibodies

Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP–TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.

scholarly journals In Vivo Lymphatic Circulating Tumor Cells and Progression of Metastatic Disease

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2866
Author(s):  
Mikyung Han ◽  
Julia Alex Watts ◽  
Azemat Jamshidi-Parsian ◽  
Urooba Nadeem ◽  
Mustafa Sarimollaoglu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
High Sensitivity ◽  
Disease Stage ◽  
Primary Tumors ◽  
Integrative Assessment

The dissemination of circulating tumor cells (CTCs) by lymph fluid is one of the key events in the development of tumor metastasis. However, little progress has been made in studying lymphatic CTCs (L-CTCs). Here, we demonstrate the detection of L-CTCs in preclinical mouse models of melanoma and breast cancer using in vivo high-sensitivity photoacoustic and fluorescent flow cytometry. We discovered that L-CTCs are be detected in pre-metastatic disease stage. The smallest primary tumor that shed L-CTCs was measured as 0.094mm×0.094mm, its volume was calculated as 0.0004 mm3; and its productivity was estimated as 1 L-CTC per 30 minutes. As the disease progressed, primary tumors continued releasing L-CTCs with certain individual dynamics. The integrated assessment of lymph and blood underlined the parallel dissemination of CTCs at all disease stages. However, the analysis of links between L-CTC counts, blood CTC (B-CTC) counts, primary tumor size and metastasis did not reveal statistically significant correlations, likely due to L-CTC heterogeneity. Altogether, our results showed the feasibility of our diagnostic platform using photoacoustic flow cytometry for preclinical L-CTC research with translational potential. Our findings also demonstrated new insights into lymphatic system involvement in CTC dissemination. They help to lay the scientific foundation for the consideration of L-CTCs as prognostic markers of metastasis and to emphasize the integrative assessment of lymph and blood.

scholarly journals Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations

2011 ◽  
Vol 29 (31) ◽  
pp. 4137-4142 ◽  
Author(s):  
Kathryn S. King ◽  
Tamara Prodanov ◽  
Vitaly Kantorovich ◽  
Tito Fojo ◽  
Jacqueline K. Hewitt ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Tumor Development ◽  
Gene Mutations ◽  
National Institutes Of Health ◽  
High Rate ◽  
Adrenal Tumors ◽  
Primary Tumors ◽  
Tumor In Childhood

Purpose To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. Patients and Methods From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Results Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. Conclusion The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

scholarly journals Emerging paradigms in metastasis research

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Ashik Ahmed Abdul Pari ◽  
Mahak Singhal ◽  
Hellmut G. Augustin
Keyword(s):  
Metastatic Disease ◽  
Primary Tumor ◽  
Holistic Approach ◽  
Primary Tumors ◽  
Metastatic Colonization ◽  
Discovery Research ◽  
Metastasis Research ◽  
Recent Developments ◽  
Rate Limiting ◽  
Therapeutic Avenue

Historically, therapy of metastatic disease has essentially been limited to using strategies that were identified and established to shrink primary tumors. The limited efficacy of such treatments on overall patient survival stems from diverging intrinsic and extrinsic characteristics of a primary tumor and metastases originating therefrom. To develop better therapeutic strategies to treat metastatic disease, there is an urgent need to shift the paradigm in preclinical metastasis research by conceptualizing metastatic dissemination, colonization, and growth as spatiotemporally dynamic processes and identifying rate-limiting vulnerabilities of the metastatic cascade. Clinically, while metastatic colonization remains the most attractive therapeutic avenue, comprehensive understanding of earlier steps may unravel novel metastasis-restricting therapies for presurgical neoadjuvant application. Moving beyond a primary tumor-centric view, this review adopts a holistic approach to understanding the spatial and temporal progression of metastasis. After reviewing recent developments in metastasis research, we highlight some of the grand challenges and propose a framework to expedite mechanism-based discovery research feeding the translational pipeline.

scholarly journals The immunoglobulin light chain kappa locus is differentially expressed in the primary tumors of patients with breast cancer and this is an intrinsic transcriptional feature of the primary tumor.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Light Chain ◽  
Primary Tumor ◽  
Tumor Infiltrating Lymphocytes ◽  
Differentially Expressed ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Light Chain ◽  
Genetic Event ◽  
Primary Tumors

We recently described differential expression and down-regulation of the immunoglobulin light chain kappa constant locus (IGKC) in brain metastases of patients with breast cancer (1). Immunoglobulin gene expression is generally thought of as restricted to cells of lymphocytic lineage (2). Expression of IGKC has previously been reported in primary tumors of the breast in patients with breast cancer, but ascribed to the presence of tumor-infiltrating lymphocytes (3-5). We analyzed tumor gene expression at the transcriptome level using independent microarray datasets (6, 7) here to determine in an unbiased fashion whether IGKC expression was differential in the primary tumors of patients with breast cancer and whether this could be ascribed to the presence of lymphocytes in tumor tissues studied. We provide evidence here that IGKC is differentially expressed in the primary tumors of patients with breast cancer and that this is a genetic event intrinsic to the primary tumor, not the result of the presence of lymphocytes.

scholarly journals The Treatment and Outcome of Patients With Soft Tissue Sarcomas and Synchronous Metastases

Sarcoma ◽  
2002 ◽  
Vol 6 (2) ◽  
pp. 69-73 ◽  
Author(s):  
John M. Kane ◽  
J. William Finley ◽  
Deborah Driscoll ◽  
William G. Kraybill ◽  
John F. Gibbs
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Strong Association ◽  
Soft Tissue Sarcomas ◽  
Poor Overall Survival ◽  
Primary Tumors ◽  
Synchronous Metastases ◽  
Metastatic Sites

Introduction: There is a strong association between poor overall survival and a short disease-free interval for patients with soft tissue sarcomas (STS) and metastatic disease. Patients with STS and synchronous metastases should have a very dismal prognosis.The role of surgery in this subgroup of patients with STS has not been defined.Patients and Methods: A single-institution retrospective review was performed of 48 patients with STS and synchronous metastases in regard to patient demographics, presentation, tumor characteristics, metastatic sites, treatment, follow-up, and survival over a 27-year period.Results: Most primary tumors were ≥10 cm (58%), high-grade histology (77%), and located on the extremity (60%).The most frequent site of metastatic disease was the lung (63%); 27% of patients had metastases to ≥2 organ sites. Surgery to the primary tumor was performed in 94% of patients (n = 45) and 68% had additional radiation therapy (n = 32). Thirty- five percent of patients underwent at least one metastastectomy (n = 17). Chemotherapy was administered to 90% of patients (n = 43); 31% received ≥3 different regimens (n = 15) and 25% were given intra-arterial or intracavitary therapy (n = 12). Median overall survival was 15 months with a 21% 2-year survival. Local control of the primary tumor was achieved in 54% (n = 26), and metastastectomy was performed in 35% (n = 17). No analyzed factors were associated with an improvement in overall survivalConclusions: Despite multiple poor prognostic factors, the survival of patients with STS and metastases is comparable to those who develop delayed metastatic disease. However, unlike patients who present with metachronous disease, there was no improved survival observed for patients treated with metastastectomy. Consequently, treatment for patients with STS and synchronous metastases should be approached with caution. Surgical management of STS with synchronous metastases must be considered palliative and should be reserved for patients requiring palliation of symptoms. Patients must also be well informed of the noncurative nature of the procedure.

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