The established role of the Wnt/β-catenin pathway in DTF forms an attractive therapeutic target, however, drugs targeting this pathway are still in an experimental stage and not yet available in the clinic.
Primary sporadic DTFs harboring a CTNNB1S45F mutation have a higher risk of recurrence after surgery compared to T41A, S45P, and WT DTF, but this association seems to be mediated by tumor size.
We performed LEF1 and β-catenin immunohistochemistry in DTF (n=26), superficial fibromatosis (n=19), sclerosing mesenteritis (n=12), gastrointestinal stromal tumor (n=17), and cutaneous scar (n=14) using tissue microarray and whole sections.
β-Catenin, the genetic key player of desmoid tumors shows nuclear accumulation due to mutations that prevent its degradation leading to activation of Wnt signaling and myofibroblastic cell proliferation.
We explored the influence of both mutations and WT on structure stability and affinity of β-catenin for α-catenin and the pattern of gene expression that may influence DF behavior.
Nuclear expression of non-phospho β-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho β-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.
CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.
Papillary thyroid carcinoma with nodular fasciitis-like stroma and β-catenin mutations should be renamed papillary thyroid carcinoma with desmoid-type fibromatosis.
All 15 desmoid tumors were positive for β-catenin (surrogate marker of Wnt/β-catenin pathway dysregulation) which was negative in control normal skin and scar samples.
Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear β-catenin localization and dysregulated canonical Wnt signaling.
Isolated and cultured desmoid tumor cells harboring any one of the CTNNB1 mutation status had unique characteristics, and could be useful to investigate desmoid tumors with different mutation status of CTNNB1.
However, the spectrum of β-catenin-driven (β-catenin-altered) neoplasia of mesenchymal origin has been steadily widening to include, in addition to desmoid tumors, a variety of benign and intermediate-biology neoplasms of soft tissue (intranodal palisaded myofibroblastoma), head and neck (juvenile nasopharyngeal angiofibroma and sinonasal hemangiopericytoma/glomangiopericytoma), and ovarian (microcystic stromal tumor) origin.
For the current study, the CTNNB1 mutation status was analyzed in DF samples from the prospective German Interdisciplinary Sarcoma Group (GISG) phase 2 study evaluating imatinib to induce progression arrest in DF Response Evaluation Criteria In Solid Tumors (RECIST) progressive patients.
In addition to the CTNNB1 mutation (64%), pediatric AF showed AKT1 (31%), BRAF (19%), and TP53 (9%) mutations, whereas only the CTNNB1 mutation was found in adult AF.