Dataset Information

Underexpression of Specific Interferon Genes Is Associated with Poor Prognosis of Melanoma.

ABSTRACT: Because the prognosis of melanoma is challenging and inaccurate when using current clinical approaches, clinicians are seeking more accurate molecular markers to improve risk models. Accordingly, we performed a survival analysis on 404 samples from The Cancer Genome Atlas (TCGA) cohort of skin cutaneous melanoma. Using our recently developed gene network model, we identified biological signatures that confidently predict the prognosis of melanoma (p-value < 10-5). Our model predicted 38 cases as low-risk and 54 cases as high-risk. The probability of surviving at least 5 years was 64% for low-risk and 14% for high-risk cases. In particular, we found that the overexpression of specific genes in the mitotic cell cycle pathway and the underexpression of specific genes in the interferon pathway are both associated with poor prognosis. We show that our predictive model assesses the risk more accurately than the traditional Clark staging method. Therefore, our model can help clinicians design treatment strategies more effectively. Furthermore, our findings shed light on the biology of melanoma and its prognosis. This is the first in vivo study that demonstrates the association between the interferon pathway and the prognosis of melanoma.

SUBMITTER: Zainulabadeen A

PROVIDER: S-EPMC5256985 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Underexpression of Specific Interferon Genes Is Associated with Poor Prognosis of Melanoma.

Zainulabadeen Aamir A Yao Philip P Zare Habil H

PloS one 20170123 1

Because the prognosis of melanoma is challenging and inaccurate when using current clinical approaches, clinicians are seeking more accurate molecular markers to improve risk models. Accordingly, we performed a survival analysis on 404 samples from The Cancer Genome Atlas (TCGA) cohort of skin cutaneous melanoma. Using our recently developed gene network model, we identified biological signatures that confidently predict the prognosis of melanoma (p-value < 10-5). Our model predicted 38 cases as ...[more]

PMID: 28114321

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Project description:Background B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether LINC00173 is a biomarker in ALL and to explore its expression level in other human cancer types. Methods A nested case–control study including Mexican children with BCP-ALL was conducted. LINC00173 expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively. LINC00173 expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA). Results A lower expression of LINC00173 in BCP-ALL cases compared to normal subjects was observed (p < 0.05). ALL patients who carry the TCF3/PBX1 fusion gene displayed lower expression of LINC00173 in contrast to other BCP-ALL molecular subtypes (p < 0.04). LINC00173 underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213–3.120) and die (HR = 2.073, 95% CI = 1.211–3.547). Patients with TCF3/PBX1 and underexpression of LINC00173 had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04–29.71; OS: HR = 11.19, 95% CI = 26–32). TCGA data analysis revealed that underexpression of LINC00173 is also associated with poor clinical outcomes in six new reported tumor types. Conclusion Our findings suggest that LINC00173 is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of LINC00173 and TCF3/PBX1 and the risk to relapse and die in BCP-ALL, which is worse in TCF3/PBX1-positive cases displaying underexpression of LINC00173. Experimental studies are needed to provide insight into the LINC00173 and TCF3/PBX relationship.

Project description:BackgroundUveal melanoma (UM) is a rare eye tumor. There are two classes of UM, which can be discriminated by the chromosome 3 status or global mRNA expression profile. Metastatic progression is predominantly originated from class II tumors or from tumors showing loss of an entire chromosome 3 (monosomy 3). We performed detailed EFS (embryonal Fyn-associated substrate) methylation analyses in UM, cultured uveal melanocytes and normal tissues, to explore the role of the differentially methylated EFS promoter region CpG island in tumor classification and metastatic progression.MethodsEFS methylation was determined by direct sequencing of PCR products from bisulfite-treated DNA or by sequence analysis of individual cloned PCR products. The results were associated with clinical features of tumors and tumor-related death of patients.ResultsAnalysis of 16 UM showed full methylation of the EFS CpG island in 8 (50%), no methylation in 5 (31%) and partial methylation in 3 (19%) tumors. Kaplan-Meier analysis revealed a higher risk of metastatic progression for tumors with EFS methylation (p = 0.02). This correlation was confirmed in an independent set of 24 randomly chosen tumors. Notably, only UM with EFS methylation gave rise to metastases. Real-time quantitative RT-PCR expression analysis revealed a significant inverse correlation of EFS mRNA expression with EFS methylation in UM. We further found that EFS methylation is tissue-specific with full methylation in peripheral blood cells, and no methylation in sperm, cultured primary fibroblasts and fetal muscle, kidney and brain. Adult brain samples, cultured melanocytes from the uveal tract, fetal liver and 3 of 4 buccal swab samples showed partial methylation. EFS methylation always affects both alleles in normal and tumor samples.ConclusionsBiallelic EFS methylation is likely to be the result of a site-directed methylation mechanism. Based on partial methylation as observed in cultured melanocytes we hypothesize that there might be methylated and unmethylated precursor cells located in the uveal tract. The EFS methylation of a UM may depend on which type of precursor cell the tumor originated from.

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Underexpression of Specific Interferon Genes Is Associated with Poor Prognosis of Melanoma.

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Underexpression of Specific Interferon Genes Is Associated with Poor Prognosis of Melanoma.

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