Specific Mutations in the β-Catenin Gene (CTNNB1) Correlate with Local Recurrence in Sporadic Desmoid Tumors

Abstract

Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. ␤-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding ␤-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%) , 45F (33%) , and 45P (8% , excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23% , P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear ␤-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. (Am J Pathol

Prognostic factors in desmoid tumours: an example of translational oncology

“…Five-year event-free survival was signifi cantly poorer in 45F-mutated than in 45A-mutated tumours. In this study, abdominal location and young age were also negative prognostic factors [3].…”

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast

“…Sequencing of known mutation hotspots of CTNNB1 on exon 3 6,[9][10][11]19 was performed in 21 metaplastic carcinomas (8 cases with b-catenin nuclear expression and 13 cases without nuclear expression), one breast fibromatosis and two sporadic desmoid tumours. As a positive control, DNA samples of the HCT116 colon cancer cell line, which is known to harbour CTNNB1 mutation in exon 3, 29 were included in each experiment.…”

“…11,19 b-catenin nuclear accumulation, however, does not equate with CTNNB1 mutation. Indeed, in desmoid tumours, either sporadic or associated with familial adenomatous polyposis syndrome, APC mutations may be the mechanism leading to b-catenin nuclear expression.…”