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Desmoid fibromatosis in a child with DICER1-related tumor predisposition
Paul Scott Thorner1, Anne-Laure Chong2,3, Sung Mi Jung4
1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Insights
DICER1 tumor predisposition, a rare inherited disorder, can manifest as desmoid fibromatosis in children. This case highlights a DICER1 variant and CTNNB1 mutation, suggesting a synergistic pathway in tumor development.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- DICER1-related tumor predisposition is an inherited disorder typically presenting with mesenchymal tumors in children.
- Desmoid fibromatosis involves β-catenin dysregulation, often due to APC or CTNNB1 mutations, activating the WNT pathway.
Purpose of the Study:
- To report a unique case of chest wall desmoid fibromatosis in a child with a germline DICER1 hotspot variant.
- To investigate the potential synergistic mechanism between DICER1 variants and CTNNB1 mutations in desmoid fibromatosis development.
Main Methods:
- Case report of a pediatric patient with desmoid fibromatosis.
- Genetic analysis including germline DICER1 variant and somatic CTNNB1 mutation detection.
- Immunohistochemistry for β-catenin nuclear accumulation.
Main Results:
- The patient had a germline DICER1 hotspot variant and a somatic CTNNB1 hotspot mutation (c.134C>T, p.S45F) in the desmoid fibromatosis.
- Immunohistochemistry revealed β-catenin nuclear accumulation in the tumor.
- This suggests a mechanism similar to DICER1-related fetal lung tumors involving WNT pathway activation.
Conclusions:
- Desmoid fibromatosis can be a rare manifestation of DICER1-related tumor predisposition.
- A synergistic effect between germline DICER1 variants and somatic CTNNB1 mutations may drive WNT pathway activation in desmoid fibromatosis.
- This finding expands the spectrum of tumors associated with DICER1-related disorders.
Abstract:
DICER1-related tumor predisposition is an inherited disorder, generally pediatric in onset, featuring a characteristic array of mainly mesenchymal tumors. We report a chest wall desmoid fibromatosis, occurring in a child who uniquely carries a germline "hotspot" DICER1 variant that likely leads to impaired miRNA biogenesis in all cells. This lesion contained a hotspot CTNNB1 c.134C > T, (p.S45F) exon 3 somatic mutation and immunohistochemistry showed nuclear accumulation of β-catenin. Desmoid fibromatosis is known to be associated with dysregulation of β-catenin, resulting from altered APC or CTNNB1, leading to increased WNT pathway signaling. In fetal lung tumors linked to DICER1 hotspot variants, APC and/or CTNNB1 somatic mutations are found in most cases, suggesting a synergistic effect with DICER1 hotspot mutation to increase WNT pathway signaling. We postulate a similar mechanism is involved in this case and that desmoid fibromatosis is a rare mesenchymal lesion that could be part of DICER1-related tumor predisposition.
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