scholarly journals Molecular Drivers of Tumor Progression in Microsatellite Stable APC Mutation-Negative Colorectal Cancers

2021 ◽  
Author(s):  
Adam Grant ◽  
Rosa M. Xicola ◽  
Vivian Nguyen ◽  
James Lim ◽  
Curtis Thorne ◽  
...  
Keyword(s):  
Immune Cell ◽  
Suppressor Gene ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Colorectal Cancers ◽  
Rna Expression ◽  
Activating Mutation ◽  
Cancer Genome Atlas ◽  
Increased Sensitivity ◽  
Apc Mutation

ABSTRACTBackgroundThe tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut–) CRCs.MethodsWe analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut– and APC mutation-positive (APCmut+) microsatellite stable CRCs.ResultsTranscriptionally, APCmut– CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut– CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3.ConclusionsAPCmut– CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

scholarly journals Molecular drivers of tumor progression in microsatellite stable APC mutation-negative colorectal cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam Grant ◽  
Rosa M. Xicola ◽  
Vivian Nguyen ◽  
James Lim ◽  
Curtis Thorne ◽  
...  
Keyword(s):  
Immune Cell ◽  
Suppressor Gene ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Colorectal Cancers ◽  
Rna Expression ◽  
Activating Mutation ◽  
Cancer Genome Atlas ◽  
Increased Sensitivity ◽  
Apc Mutation

AbstractThe tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut–) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut– and APC mutation-positive (APCmut+) microsatellite stable CRCs. Transcriptionally, APCmut– CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut– CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APCmut– CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

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.

Identification of T-cell-inflamed gastric adenocarcinoma in The Cancer Genome Atlas (TCGA).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 16-16 ◽  
Author(s):  
Steven Brad Maron ◽  
Jason John Luke ◽  
Raymond Hovey ◽  
Riyue Bao ◽  
Thomas Gajewski ◽  
...  
Keyword(s):  
T Cell ◽  
Objective Response ◽  
Copy Number Variations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Chi Square ◽  
Primary Tumors ◽  
Cancer Genome Atlas ◽  
Genome Atlas

16 Background: Gastroesophageal adenocarcinoma (GEC) is a significant global health problem. KEYNOTE-012 demonstrated a 22% objective response rate in patients with PD-L1 expressing GEC that received pembrolizumab. A subset of patients (pts) tumors express a T cell “inflamed” (TCI) phenotype, which can be measured using an IFN-γ-based immune signature and may prove more predictive of clinical benefit. Using a 160 gene RNA-Seq immune expression profile, we sought to characterize the molecular environments of TCI versus non-TCI GEC patients in The Cancer Genome Atlas (TCGA). Methods: 395 GEC pts with primary tumors in TCGA were clustered into TCI, non-TCI, and intermediate subtypes using both unsupervised hierarchical and K-means clustering (k = 3). Molecular characteristics were categorized using data acquired via CbioPortal and the UCSC Xena repository. Only non-silent somatic mutations and copy number variations (CNVs) reaching GISTIC2 -2 or +2 thresholds were considered. Statistical comparisons were performed using chi-square, ANOVA, and t-test. Results: The TCI subtype contained patients from all TCGA-defined subtypes - EBV-associated (56%), MSI-high (16%), chromosomal unstable (6%), and genomically stable (27%). No significant differences were seen between TCI and non-TCI for tumor site or stage. Mutations in PTEN, PIK3CA, CDH1, and RHOA were more frequent in TCI patients. ERBB2, CCNE1, and KRAS CNVs were infrequent in TCI patients as were PDE4D deletions ( p< 0.05 ). TCI tumors had higher expression of both co-inhibitory (PD-1, PD-L1/L2, CD28/80, BTLA, LAG3) and co-stimulatory (CD137/40/27, OX40, GITR, ICOS) checkpoint molecules ( p< 10-7). Total mutation burden was no different between TCI and non-TCI pts when excluding MSI-high pts nor when assessing MSI-high alone. Conclusions: The IFN immune phenotype encompassed GEC patients from all TCGA subsets. Correlation of clinical outcome with checkpoint blockade is necessary to confirm these molecular associations and the independent predictive utility of this immune-profile stratification.

scholarly journals Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable β-catenin Overexpression and a β-catenin Mutation

2017 ◽  
Vol 78 (04) ◽  
pp. 346-352 ◽  
Author(s):  
Megan Yanik ◽  
Megan Scott ◽  
Carol Bradford ◽  
Jonathan McHugh ◽  
Scott McLean ◽  
...  
Keyword(s):  
Treatment Options ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Molecular Alterations ◽  
Online Databases ◽  
Activating Mutation ◽  
Cancer Mutations ◽  
Cancer Genome Atlas ◽  
Sinonasal Teratocarcinosarcoma ◽  
Index Tumor

Objective Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options. Methods We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for β-catenin on paraffin-embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed. Results We identified an activating p.S45F mutation in β-catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/β-catenin pathway. We confirmed β-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known β-catenin mutations. Conclusion We identified a potential driver mutation in β-catenin in a sinonasal teratocarcinosarcoma, resulting in β-catenin overexpression. These findings suggest a role for the Wnt/β-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti-β-catenin targeted therapy.

scholarly journals A Six-lncRNA Signature for Immunophenotype Prediction of Glioblastoma Multiforme

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Gao ◽  
Xinzhuang Wang ◽  
Dayong Han ◽  
Enzhou Lu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Immune Cell ◽  
Area Under The Curve ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Non Coding Rna ◽  
Cancer Genome Atlas ◽  
The Central Nervous System

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system. As biomedicine advances, the researcher has found the development of GBM is closely related to immunity. In this study, we evaluated the GBM tumor immunoreactivity and defined the Immune-High (IH) and Immune-Low (IL) immunophenotypes using transcriptome data from 144 tumors profiled by The Cancer Genome Atlas (TCGA) project based on the single-sample gene set enrichment analysis (ssGSEA) of five immune expression signatures (IFN-γ response, macrophages, lymphocyte infiltration, TGF-β response, and wound healing). Next, we identified six immunophenotype-related long non-coding RNA biomarkers (im-lncRNAs, USP30-AS1, HCP5, PSMB8-AS1, AL133264.2, LINC01684, and LINC01506) by employing a machine learning computational framework combining minimum redundancy maximum relevance algorithm (mRMR) and random forest model. Moreover, the expression level of identified im-lncRNAs was converted into an im-lncScore using the normalized principal component analysis. The im-lncScore showed a promising performance for distinguishing the GBM immunophenotypes with an area under the curve (AUC) of 0.928. Furthermore, the im-lncRNAs were also closely associated with the levels of tumor immune cell infiltration in GBM. In summary, the im-lncRNA signature had important clinical implications for tumor immunophenotyping and guiding immunotherapy in glioblastoma patients in future.

scholarly journals Identification of prognostic hypoxia-related genes signature on the tumor microenvironment in esophageal cancer

2021 ◽  
Vol 18 (6) ◽  
pp. 7743-7758
Author(s):  
Linlin Tan ◽  
◽  
Dingzhuo Cheng ◽  
Jianbo Wen ◽  
Kefeng Huang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
High Risk ◽  
Immune Cells ◽  
Immune Cell ◽  
Risk Group ◽  
Roc Curves ◽  
Risk Groups ◽  
High Risk Group ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas

<abstract> <sec><title>Background</title><p>Hypoxia is a crucial factor in the development of esophageal cancer. The relationship between hypoxia and immune status in the esophageal cancer microenvironment is becoming increasingly important in clinical practice. This study aims to clarify and investigate the possible connection between immunotherapy and hypoxia in esophageal cancer.</p> </sec> <sec><title>Methods</title><p>The Cancer Genome Atlas databases are used to find two types of esophageal cancer cases. Cox regressions analyses are used to screen genes for hypoxia-related traits. After that, the genetic signature is validated by survival analysis and the construction of ROC curves. GSEA is used to compare differences in enrichment in the two groups and is followed by the CIBERSORT tool to investigate a potentially relevant correlation between immune cells and gene signatures.</p> </sec> <sec><title>Results</title><p>We found that the esophageal adenocarcinoma hypoxia model contains 3 genes (PGK1, PGM1, SLC2A3), and the esophageal squamous cell carcinoma hypoxia model contains 2 genes (EGFR, ATF3). The findings demonstrated that the survival rate of patients in the high-risk group is lower than in the lower-risk group. Furthermore, we find that three kinds of immune cells (memory activated CD4+ T cells, activated mast cells, and M2 macrophages) have a marked infiltration in the tissues of patients in the high-risk group. Moreover, we find that PD-L1 and CD244 are highly expressed in high-risk groups.</p> </sec> <sec><title>Conclusions</title><p>Our data demonstrate that oxygen deprivation is correlated with prognosis and the incidence of immune cell infiltration in patients with both types of esophageal cancer, which provides an immunological perspective for the development of personalized therapy.</p> </sec> </abstract>

scholarly journals A Novel Ferroptosis-Related lncRNAs Signature Predicts Clinical Prognosis and is Associated with Immune Landscape in Pancreatic Cancer

2021 ◽  
Author(s):  
Haiqin Ping ◽  
Xingqing Jia ◽  
Hengning Ke
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Pearson Correlation ◽  
The Cancer Genome Atlas ◽  
Lasso Regression ◽  
Clinical Prognosis ◽  
Pathway Enrichment ◽  
Cancer Genome Atlas ◽  
Pearson Correlation Analysis ◽  
Selection Operator

Abstract Pancreatic cancer is one of the most lethal malignancies and currently therapies are severely lacking. In this study, we aimed to establish a novel ferroptosis-related lncRNAs signature to predict the prognosis of patients with pancreatic cancer and evaluate the predictive abilities of candidate lncRNAs. According to The Cancer Genome Atlas (TCGA) database, a total of 182 patients with pancreatic cancer were included in our study. Ferroptosis-related lncRNAs were screened by Pearson correlation analysis with 60 reported ferroptosis-related genes. Through univariate, least absolute shrinkage and selection operator (LASSO) regression and multivariate regression analyses, a novel signature based on five ferroptosis-related lncRNAs(ZNF236-DT, CASC8, PAN3-AS1, SH3PXD2A-AS1, LINP1) was constructed. Risk-related differentially expressed genes (DEGs) were subjected to enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.The results revealed that that immune cell infiltration, immune-related functions and checkpoints were factors to affect prognoisis of pancreatic cancer. In summary, we identified the prognostic ferroptosis-related lncRNAs in pancreatic cancer and these lncRNAs may serve as therapeutic targets for pancreatic cancer.

scholarly journals Multi-omics analysis to identify driving factors in colorectal cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1633-1650
Author(s):  
Xi Xu ◽  
Chaoju Gong ◽  
Yunfeng Wang ◽  
Yanyan Hu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Omics Analysis ◽  
Competing Endogenous Rna Network ◽  
Cancer Genome Atlas

Aim: We aim to identify driving genes of colorectal cancer (CRC) through multi-omics analysis. Materials & methods: We downloaded multi-omics data of CRC from The Cancer Genome Atlas dataset. Integrative analysis of single-nucleotide variants, copy number variations, DNA methylation and differentially expressed genes identified candidate genes that carry CRC risk. Kernal genes were extracted from the weighted gene co-expression network analysis. A competing endogenous RNA network composed of CRC-related genes was constructed. Biological roles of genes were further investigated in vitro. Results: We identified LRRC26 and REP15 as novel prognosis-related driving genes for CRC. LRRC26 hindered tumorigenesis of CRC in vitro. Conclusion: Our study identified novel driving genes and may provide new insights into the molecular mechanisms of CRC.

scholarly journals Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

2019 ◽  
Vol 104 (9) ◽  
pp. 3826-3834 ◽  
Author(s):  
Shahida K Flores ◽  
Ziming Cheng ◽  
Angela M Jasper ◽  
Keiko Natori ◽  
Takahiro Okamoto ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
The Cancer Genome Atlas ◽  
Exon 2 ◽  
Von Hippel Lindau ◽  
Familial Pheochromocytoma ◽  
Cancer Genome Atlas ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Spliced Variant

Abstract Context von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. Objective We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. Design We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. Results We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. Conclusion A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.

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