Molecular Subtypes of Extra-pulmonary Neuroendocrine Carcinomas Identified by the Expression of Neuroendocrine Lineage-Specific Transcription Factors
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Published:2022-05-24
Issue:3
Volume:33
Page:388-399
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ISSN:1046-3976
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Container-title:Endocrine Pathology
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language:en
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Short-container-title:Endocr Pathol
Author:
Metovic Jasna, La Salvia Anna, Rapa Ida, Napoli Francesca, Birocco Nadia, Pia Bizzi Maria, Garcia-Carbonero Rocio, Ciuffreda Libero, Scagliotti Giorgio, Papotti Mauro, Volante MarcoORCID
Abstract
AbstractExtra-pulmonary neuroendocrine carcinomas (EPNEC) represent a group of rare and heterogenous neoplasms with adverse clinical outcome. Their molecular profile is largely unexplored. Our aim was to investigate if the major transcriptional drivers recently described in high-grade pulmonary neuroendocrine carcinomas characterize distinct molecular and clinical subgroups of EPNEC. Gene expression of ASCL1, NEUROD1, DLL3, NOTCH1, INSM1, MYCL1, POU2F3, and YAP1 was investigated in a series of 54 EPNEC (including 10 cases with mixed components analyzed separately) and in a group of 48 pulmonary large cell neuroendocrine carcinomas (P-LCNEC). Unsupervised hierarchical cluster analysis classified the whole series into four major clusters. P-LCNEC were classified into two major clusters, the first ASCL1/DLL3/INSM1-high and the second (including four EPNEC) ASCL1/DLL3-low but INSM1-high. The remaining EPNEC cases were sub-classified into two other clusters. The first showed INSM1-high and alternative ASCL1/DLL3 or NEUROD1 high expression. The second was characterized mainly by MYCL1 and YAP1 overexpression. In the ten cases with mixed histology, ASCL1, DLL3, INSM1, and NEUROD1 genes were significantly upregulated in the neuroendocrine component. Higher gene-expression levels of NOTCH1 and INSM1 were associated with lower pT stage and negative nodal status. Low INSM1 gene expression was associated with shorter overall survival in the entire case series (p = 0.0017) and with a trend towards significance in EPNEC, only (p = 0.06). In conclusion, our results show that EPNEC possess distinct neuroendocrine-lineage-specific transcriptional profiles; moreover, low INSM1 gene expression represents a novel potential unfavorable prognostic marker in high-grade NECs including those in extra-pulmonary location.
Funder
Associazione Italiana per la Ricerca sul Cancro
Publisher
Springer Science and Business Media LLC
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism,Pathology and Forensic Medicine
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