Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives
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Published:2024-01-03
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ISSN:0945-6317
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Container-title:Virchows Archiv
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language:en
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Short-container-title:Virchows Arch
Author:
Simbolo Michele, Centonze Giovanni, Gkountakos Anastasios, Monti Valentina, Maisonneuve Patrick, Golovco Stela, Sabella Giovanna, Del Gobbo Alessandro, Gobbo Stefano, Ferrero Stefano, Fabbri Alessandra, Pardo Carlotta, Garzone Giovanna, Prinzi Natalie, Pusceddu Sara, Testi Adele, Rolli Luigi, Mangogna Alessandro, Bercich Luisa, Benvenuti Mauro Roberto, Bria Emilio, Pilotto Sara, Berruti Alfredo, Pastorino Ugo, Capella Carlo, Infante Maurizio, Milella Michele, Scarpa AldoORCID, Milione Massimo
Abstract
AbstractPulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.
Funder
Ministero della Salute Fondazione AIRC per la ricerca sul cancro ETS
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology,General Medicine,Pathology and Forensic Medicine
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