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The Desmoid Tumor Research Foundation

February 2020

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

Author Information

Trautmann M(1)(2), Rehkamper J(1), Gevensleben H(3), Becker J(4), Wardelmann E(1), Hartmann W(1)(2), Grunewald I(1)(2), Huss S(1).

(1)Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, Germany. (2)Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, Germany. (3)Institute of Pathology, Bonn University Hospital, Bonn, Germany. (4)Institute of Human Genetics, University of Bonn, School of Medicine & Bonn University Hospital, Bonn, Germany.

Publication

Sci Rep

Summary

Genetic alterations affecting canonical Wnt/Beta-catenin signaling are reported in the majority of Desmoid-type fibromatosis (DTF, aggressive fibromatosis). 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). 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 beta-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.

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