In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1086-1086
Abstract:
Background: Desmoids tumors (DTs) are rare mesenchymal infiltrative lesions that exhibit a high risk of local recurrence despite surgery with negative margins. Most sporadic DTs harbor CTNNB1 (β-catenin) mutations involving specific phosphorylation sites and consequently leading to protein stabilization. CTNNB1 mutation spectra in DT typically involve only the 3 different point mutations T41A, S45F and S45P, suggesting that the type of mutation may specifically affect β-catenin signaling and its transcriptional activity. We hypothesized that CTNNB1 mutation type can influence β-catenin pattern of gene expression. Methods: We selected 33 formalin-fixed primary surgically treated DTs specimens balanced in regards to CTNNB1 gene status: 14 with T41A, 10 with S45F and 9 with no mutation (WT). In order to identify the deregulated molecular profiles among the groups, a gene expression microarray analysis was performed using the Whole-Genome DASL assay and BeadArray Chips (Illumina). We explored network modeling through Gene Set Enrichment Analysis (GSEA) that reveals the regulatory relationships among genes providing a systematic understanding of molecular mechanisms underlying biological processes of CTNNB1 mutational status. Functional pathway analysis was performed imposing a significant level of FDR & lt;25% and interrogating gene sets belonging to Gene Ontology (GO; n = 905), and Transcription Factor database (TF; n = 577). Our GSEA-based analysis was summarized with the visualization of enrichment maps through Cytoscape. Results: Fourteen TF gene sets, including MEF2 and RSRFC4 TFs that bind growth factor-inducible and muscle-specific promoters, were significantly enriched in WT compared to mutated DTs. Similarly GO gene sets showed a significant enrichment for terms related to “contractile fiber” and “myofibril” in which MYL6B, MYL3, MYL5, desmin, myomesin1, titin and supervillin were the most significantly modulated genes. By comparing T41A and S45F mutants we found: STAT3 and SRF TF gene sets significantly enriched in T41A and PAX3 in S45F cases. T41A compared to S45F cases showed 46 GO enriched gene sets belonging to “inflammatory response”, “defense response”, “humoral immune response” (i. e. chemokines, IL6 and IL8). Conclusion: This preliminary analysis identified molecules, functional pathways and β-catenin targets differently expressed according to CTNNB1 mutation status. These data need to be further validated. Citation Format: Chiara Colombo, Loris De Cecco, Antonino Belfiore, Silvana Canevari, Marco Fiore, Silvia Stacchiotti, Elena Palassini, Alessandro Gronchi, Silvana Pilotti, Federica Perrone. CTNNB1-mutated desmoid tumors have different gene expression patterns compared to wild-type ones. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1086. doi:10.1158/1538-7445.AM2015-1086
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-1086
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
