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Gene Signature Associated with Upregulation of the Wnt/?-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization.

ABSTRACT: PURPOSE:To identify gene mutations in tumors undergoing transarterial embolization and explore the relationship between gene mutations and tumor response to embolization. MATERIALS AND METHODS:This was a retrospective review that included 17 patients with primary or metastatic liver tumors treated with embolization and had specimens analyzed for a 341-gene panel next-generation sequence assay. Pathologic conditions included hepatocellular, carcinoid, pancreatic neuroendocrine, melanoma, medullary thyroid, and liver acinar-cell carcinoma. Disease, procedure data, and tumor response data were collected. Dimensionality reduction was performed by using principal component analysis. A linear support vector machine was used to learn a prediction rule and identify the genes most predictive of objective tumor response (partial or complete) per modified Response Evaluation Criteria In Solid Tumors. Cross-validation was used to test the prediction on the holdout set. Permutation testing was used to determine statistical significance of prediction accuracy. Recursive feature elimination was used to identify the most predictive genes. RESULTS:At 4 months after embolization, 9 tumors showed a response and 8 did not. Using the top two principal components, prediction accuracy of the gene mutation signature was 70% (±11%), which was statistically significant (P < .05). The most predictive genes were CTNNB1, MEN1, and NCOR1: three genes associated with the Wnt/?-catenin and hypoxia signaling pathways. CONCLUSIONS:This study identifies gene mutations in tumors treated with transarterial embolization. A gene-mutation signature obtained from the mutation data suggests that upregulation of the Wnt/?-catenin signaling pathway may be associated with sensitivity to embolization.

SUBMITTER: Ziv E

PROVIDER: S-EPMC5325772 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Gene Signature Associated with Upregulation of the Wnt/β-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization.

Ziv Etay E Yarmohammadi Hooman H Boas F Edward FE Petre Elena Nadia EN Brown Karen T KT Solomon Stephen B SB Solit David D Reidy Diane D Erinjeri Joseph P JP

Journal of vascular and interventional radiology : JVIR 20170124 3

<h4>Purpose</h4>To identify gene mutations in tumors undergoing transarterial embolization and explore the relationship between gene mutations and tumor response to embolization.<h4>Materials and methods</h4>This was a retrospective review that included 17 patients with primary or metastatic liver tumors treated with embolization and had specimens analyzed for a 341-gene panel next-generation sequence assay. Pathologic conditions included hepatocellular, carcinoid, pancreatic neuroendocrine, mel ...[more]

PMID: 28126478

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Project description:Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.

Dataset Information

Gene Signature Associated with Upregulation of the Wnt/?-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization.

Publications

Gene Signature Associated with Upregulation of the Wnt/β-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization.

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