Identification of somatic APC mutations in recurrent desmoid tumors in a patient with familial adenomatous polyposis to determine actual recurrence of the original tumor or de novo occurrence.
We performed IHC of β-catenin and mutation analysis of CTNNB1 and APC in 18 paediatric desmoid tumours, diagnosed between 1990 and 2009 in the Erasmus MC, Rotterdam.
A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor.
Aggressive fibromatosis (AF) is a rare fibroblastic proliferative disease with a locally aggressive behavior and no distant metastasis, characterized by driver mutations in CTNNB1 or the APC gene.
To investigate whether this hypothesis could be extended to other Wnt-dependent tumor types, we searched for WT1 mutations and studied WT1 expression in beta-catenin mutant desmoid tumors.
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.
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.
Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test).
Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear β-catenin localization and dysregulated canonical Wnt signaling.
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.
FAP results from germline adenomatous polyposis coli (APC) gene mutations and desmoids arise following biallelic APC mutation, with one change usually occurring distal to the second beta-catenin binding/degradation repeat of the gene (3' to codon 1399).
Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (beta-catenin) mutations, were further investigated for beta-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor alpha (PDGFRA)/PDGF receptor beta (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach.
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.