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Desmoid-type fibromatosis (DTF, aggressive fibromatosis) is a non-metastasizing mesenchymal neoplasm of deep soft tissue with a tendency towards local recurrence. Genetic alterations affecting canonical Wnt/β-catenin signaling are reported in the majority of DTF. While most sporadic DTF harbor somatic mutations in  CTNNB1 , germline mutations in adenomatous polyposis coli ( APC)  are known to occur in hereditary DTF types (FAP, Gardner-Syndrome). Additional single nucleotide variants (SNVs) in  AKT1  (E17K) and  BRAF  (V600E) were reported in pediatric DTF with potential clinical implications. We performed targeted next-generation sequencing (NGS) in a large cohort of 204 formalin-fixed DTF samples, comprising 22 pediatric cases (patients age ≤18 years). The mutational status was correlated with clinicopathological characteristics. Overall, deleterious  CTNNB1  mutations were detected in 89% of DTF, most frequently affecting the serine/threonine phosphorylation sites T41 and S45 of β-catenin. While the T41A  CTNNB1  mutation was significantly more often identified in the mesenterial localization, DTF originating from extra-intestinal sites more frequently harbored the S45P  CTNNB1  alteration. Beyond common mutations in  CTNNB1 , additional SNVs were demonstrated in 7% of the DTF cohort and in 18% of the pediatric DTF subgroup. The mutational spectrum included deleterious mutations in  AKT1  (G311S/D and T312I),  ALK  (R806H and G924S),  AR  (A159T),  EGFR  (P848L),  ERBB2  (H174Y),  IDH2  (H354Y),  KIT  (V559D),  RET  (T1038A),  SDHA  (R325M), and  SDHD  (R115W), as characterized by  in silico  prediction tools. In conclusion, our study indicates that DTF may harbor a broader mutational spectrum beyond  CTNNB1  mutations, comprising targetable alterations including the herewith first reported imatinib-sensitive  KIT  V559D mutation in DTF.

Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis – A systematic analysis of 204 cases