Specific Mutations in the B-Catenin Gene (CTNNB1) Correlate with Local Recurrence in Sporadic Desmoid Tumors
AJF Lazar, D Tuvin, S Hajibashi, S Habeeb, S Bolshakov, E Mayordomo-Aranda, CL Warneke, D Lopez-Terrada, RE Pollock, D Lev. MD Anderson Cancer Center, Houston; Texas Children's Hospital and Baylor College of Medicine, Houston
Background: Desmoid fibromatosis is a rare, non-metastatic neoplasm often showing relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. Beta-catenin deregulation is common in sporadic desmoids, with a high incidence of CTNNB1 (beta-catenin gene) mutations.
Design: We evaluated CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcomes. Desmoid specimens (195 tumors from 160 patients; 1985-2005) and dermal scars serving as controls were assembled into a clinical data-linked tissue microarray; CTNNB1 genotyping was performed for a 138 sporadic desmoid subset. Immunohistochemistry for beta-catenin and cyclinD1 was performed. Data was analyzed using Kaplan-Meier and other standard methods.
Results: CTNNB1 mutations were observed in 117/138 (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 due to rarity). Five-year recurrence free survival was significantly poorer in 45F-mutated desmoids (23%; p<0.0001) versus either 41A (57%) or non-mutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens; intensity inversely correlated with incidence of desmoid recurrence (p<0.01). Cyclin D1 expression was observed in 34% of primary desmoids; cases with increased nuclear cyclin D1 had higher levels of nuclear b-catenin and lower recurrence (p<0.01).
Conclusions: CTNNB1 mutations are common in desmoid tumors and may have prognostic and potentially diagnostic applications. Patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence, and therefore may especially benefit from adjuvant therapeutic approaches. The surprising result of 45F being associated with lower levels of beta-catenin nuclear accumulation and lower cyclinD1 expression may yield additional novel insights into the mechanism and function of this critical pathway.
Category: Bone & Soft Tissue
Monday, March 9, 2009 1:00 PM
Poster Session II # 20, Monday Afternoon