Novel pathogenic alterations in pediatric and adult desmoid-type fibromatosis \u2013 A systematic analysis of 204 cases

Marcel Trautmann,Jessica Becker,Jan Rehkämper,Sebastian Huss,Wolfgang Hartmann,Inga Grünewald,Eva Wardelmann,Heidrun Gevensleben

doi:10.1038/s41598-020-60237-6

Abstract

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.

Highlights

Desmoid-type fibromatosis (DTF, aggressive fibromatosis) is a non-metastasizing mesenchymal neoplasm of deep soft tissue with a tendency towards local recurrence
While in patients with familial adenomatous polyposis (FAP) β-catenin is not degraded through inactivating mutations in adenomatous polyposis coli (APC), most sporadic DTF harbor alterations in CTNNB1; both leading to a nuclear accumulation of β-catenin and an oncogenic activation of the Wnt/β-catenin signal transduction pathway[3,4,5,6]
Meazza et al analyzed a small cohort of DTF employing next-generation sequencing (NGS) for mutational analysis and reported potential clinical implications for pediatric DTF harboring gain-of-function mutations in AKT1 and BRAF19. These findings suggest a more complex mutational spectrum of DTF than expected so far, which may potentially be associated with therapeutic implications

Summary

Introduction

Desmoid-type fibromatosis (DTF, aggressive fibromatosis) is a non-metastasizing mesenchymal neoplasm of deep soft tissue with a tendency towards local recurrence. While in patients with familial adenomatous polyposis (FAP) β-catenin is not degraded through inactivating mutations in APC, most sporadic DTF harbor alterations in CTNNB1; both leading to a nuclear accumulation of β-catenin and an oncogenic activation of the Wnt/β-catenin signal transduction pathway[3,4,5,6]. Penel et al reported no significant difference with regard to the outcome between surgical vs non-surgical treatment approaches[14]. These results still have to be evaluated in prospective trials

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