(P 363) Β-CATENIN MUTATIONS AND TRANSCRIPTOMIC REPROGRAMMING IN DESMOID FIBROMATOSIS (DF)

Objective: Active surveillance (AS) is the first-line strategy for the vast majority of DF patients. One in four patients experiences spontaneous regression as first event and an additional 30% develop a tumor regression after an early progression. However, approximately 35% may require active treatment for meaningful clinical tumor progression. We previously reported that DF surgical specimens of patients who underwent surgery for DF have an inflammatory phenotype when harboring T41A-mutated β-catenin (PMID: 28627792). However, there is a limited knowledge of biology and immune contexture of DF and biomarkers to predict the clinical course during AS are lacking. In this study, we deeply investigated transcriptomic profile of patients with-CTNNB1 mutated DF exploiting a prospective clinical trial on AS in patients with a primary diagnosis of DF.

Methods: A prospective study was conducted at our Institution and enrolled 56 patients affected by primary sporadic DF. CTNNB1 mutation status of DF biopsies was determined by Sanger sequencing. CTNNB1-targeted DNA sequencing with NGS approaches was performed in case of WT DF at Sanger sequencing. FFPE biopsies at DF diagnosis had been prospectively collected and 39 biopsies from patients with CTNB1-mutated DF were suitable for RNA extraction and sequencing with RNA-Seq technique. Functional analysis of deregulated genes was obtained by Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA).

Results: In this clinical study, we observed the following distribution of CTNNB1 mutations: S45F in 10 patients (31.3%), T41A in 22 (68.7%), S45P in 3 (7.6%), WT in 2 (5.1%), and “other” in 2 (5.1%). The computational analysis was then conducted to compare the more represented mutations (T41A vs S45F). Class comparison analysis at IPA identified 490 genes differentially expressed between S45F and T41A β-catenin-mutated DF biopsies (p < 0.05). T41A-mutated DF were positively enriched in gene sets related to inflammatory and immune system compared to S45F-mutated DF. Positive enrichment of ‘Epithelial Mesenchymal Transition’ (EMT) gene set was observed in S45F-mutated DF. At a median study follow-up of 18 months, 34% of patients experienced tumor progression, 25% tumor regression and 38% had stable disease as first event during AS according to RECIST criteria. A further class comparison analysis revealed 174 transcripts showing deregulated expression in DF from patients who experienced tumor progression (N=14) compared to DF from patients who had a tumor regression (N=9) during AS. A down-regulation of genes and molecular functions related to muscle activity and contractility and a negative enrichment of ‘Myogenesis’ gene set were observed in patients who experienced tumor progression.

Conclusion: In this preliminary analysis, we confirm that DF with T41A B-catenin gene mutation has an ‘inflammatory phenotype’, as previously reported. We found an up-regulation of EMT genes in DF with S45F B-catenin gene mutation. A difference between gene expression in DF from patients who experienced either tumor progression or regression according to RECIST was observed. Further analyses evaluating association between DF β-catenin driven molecular alterations and patient outcome are ongoing.