Published online before print October 2, 2008

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(American Journal of Pathology. 2008;173:1518-1527.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080475

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

Alexander J.F. Lazar^*, Daniel Tuvin^*, Shohrae Hajibashi^*, Sultan Habeeb^¶, Svetlana Bolshakov^*, Empar Mayordomo-Aranda^¶, Carla L. Warneke^||, Dolores Lopez-Terrada^¶, Raphael E. Pollock^* and Dina Lev^*

From the Sarcoma Research Center,^* and Departments of Pathology, Surgical Oncology, Cancer Biology, and Division of Quantitative Sciences,|| The University of Texas MD Anderson Cancer Center, Houston; and the Department of Pathology,^¶ Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas

Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. β-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding β-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 β-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.