Expansion of the MEN1 tumor spectrum: convergent molecular evidence of MEN1 inactivation in a fibromyxosarcoma, VIPoma, and gastric neuroendocrine carcinoma
5 affiliations
- 1Endocrine Genetics Unit, Laboratory of Cellular and Molecular Endocrinology (LIM-25), Division of Endocrinology and Metabolism, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP)
- 2Pathology Laboratory, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP)
- 3Pathology Department, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP)
- 4Vall d’Hebron Institute of Oncology Barcelona
- 5Division of Endocrine Oncology, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP)
Abstract
Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor predisposition syndrome primarily characterized by parathyroid, pituitary, and pancreaticoduodenal neuroendocrine tumors. Although several non-endocrine neoplasms have been associated with MEN1, the role of MEN1 inactivation in rare mesenchymal tumors remains incompletely understood.
Case presentation: We report a woman with genetically confirmed MEN1 carrying the pathogenic germline MEN1 variant c.249_252delGTCT ( p.Ile85Serfs* 33, exon 2), identified in a large MEN1 kindred. The patient presented with primary hyperparathyroidism, a non-functioning pituitary microadenoma, a pancreatic vasoactive intestinal peptide-producing neuroendocrine tumor (VIPoma), and a poorly differentiated gastric neuroendocrine carcinoma. The VIPoma was successfully cured by gastroduodenopancreatectomy, with complete resolution of the WDHA syndrome and normalization of serum VIP levels. In contrast, the gastric neuroendocrine carcinoma followed an aggressive clinical course, leading to disease recurrence and death 30 months after surgery. In addition, the patient developed a recurrent low-grade odontogenic fibromyxosarcoma of the maxilla. Immunohistochemistry demonstrated complete loss of nuclear menin expression in the fibromyxosarcoma, pancreatic VIPoma, and gastric neuroendocrine carcinoma. Molecular analyses of the fibromyxosarcoma revealed allelic imbalance at the MEN1 locus by Sanger sequencing, with apparent absence of the wild-type allele at exon 2 and exclusive detection of the T allele of an informative heterozygous synonymous MEN1 variant ( c.1269C>T ; p.Asp418= , exon 9). Targeted next-generation sequencing confirmed marked enrichment of the mutant MEN1 allele in the fibromyxosarcoma (VAF 81.8%) and demonstrated enrichment of the mutant allele in the VIPoma (VAF 68.2%) and gastric neuroendocrine carcinoma (VAF 70.6%). Together with loss of menin expression by immunohistochemistry, these findings support somatic MEN1 inactivation across all three tumors.
Conclusions: This report provides convergent genetic and immunohistochemical evidence supporting low-grade odontogenic fibromyxosarcoma as a potential MEN1-associated neoplasm. In addition, the demonstration of MEN1 inactivation across three exceptionally rare tumors arising in the same patient provides evidence for a broader role of menin loss across distinct tumor types and supports the possibility that the phenotypic spectrum of MEN1 extends beyond currently recognized manifestations.
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BibTeX
@article{siqueira2026expansion,
title = {{Expansion of the MEN1 tumor spectrum: convergent molecular evidence of MEN1 inactivation in a fibromyxosarcoma, VIPoma, and gastric neuroendocrine carcinoma}},
author = {Nathalia Maria Gonçalves Siqueira and Lucas Santos de Santana and Elisangela Pereira de Souza Quedas and Evandro Sobroza de Mello and Iberê Cauduro Soares and Rodrigo Almeida Toledo and Delmar Muniz Lourenço Junior},
journal = {Frontiers in Endocrinology},
year = {2026},
month = nov,
doi = {10.3389/fendo.2026.1906978},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1906978/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Expansion of the MEN1 tumor spectrum: convergent molecular evidence of MEN1 inactivation in a fibromyxosarcoma, VIPoma, and gastric neuroendocrine carcinoma
AU - Nathalia Maria Gonçalves Siqueira
AU - Lucas Santos de Santana
AU - Elisangela Pereira de Souza Quedas
AU - Evandro Sobroza de Mello
AU - Iberê Cauduro Soares
AU - Rodrigo Almeida Toledo
AU - Delmar Muniz Lourenço Junior
PY - 2026
DA - 2026/11/06
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1906978
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1906978/full
AB - Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor predisposition syndrome primarily characterized by parathyroid, pituitary, and pancreaticoduodenal neuroendocrine tumors. Although several non-endocrine neoplasms have been associated with MEN1, the role of MEN1 inactivation in rare mesenchymal tumors remains incompletely understood. Case presentation: We report a woman with genetically confirmed MEN1 carrying the pathogenic germline MEN1 variant c.249_252delGTCT ( p.Ile85Serfs* 33, exon 2), identified in a large MEN1 kindred. The patient presented with primary hyperparathyroidism, a non-functioning pituitary microadenoma, a pancreatic vasoactive intestinal peptide-producing neuroendocrine tumor (VIPoma), and a poorly differentiated gastric neuroendocrine carcinoma. The VIPoma was successfully cured by gastroduodenopancreatectomy, with complete resolution of the WDHA syndrome and normalization of serum VIP levels. In contrast, the gastric neuroendocrine carcinoma followed an aggressive clinical course, leading to disease recurrence and death 30 months after surgery. In addition, the patient developed a recurrent low-grade odontogenic fibromyxosarcoma of the maxilla. Immunohistochemistry demonstrated complete loss of nuclear menin expression in the fibromyxosarcoma, pancreatic VIPoma, and gastric neuroendocrine carcinoma. Molecular analyses of the fibromyxosarcoma revealed allelic imbalance at the MEN1 locus by Sanger sequencing, with apparent absence of the wild-type allele at exon 2 and exclusive detection of the T allele of an informative heterozygous synonymous MEN1 variant ( c.1269C>T ; p.Asp418= , exon 9). Targeted next-generation sequencing confirmed marked enrichment of the mutant MEN1 allele in the fibromyxosarcoma (VAF 81.8%) and demonstrated enrichment of the mutant allele in the VIPoma (VAF 68.2%) and gastric neuroendocrine carcinoma (VAF 70.6%). Together with loss of menin expression by immunohistochemistry, these findings support somatic MEN1 inactivation across all three tumors. Conclusions: This report provides convergent genetic and immunohistochemical evidence supporting low-grade odontogenic fibromyxosarcoma as a potential MEN1-associated neoplasm. In addition, the demonstration of MEN1 inactivation across three exceptionally rare tumors arising in the same patient provides evidence for a broader role of menin loss across distinct tumor types and supports the possibility that the phenotypic spectrum of MEN1 extends beyond currently recognized manifestations.
SN - 1664-2392
ER -