Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities

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M. Simbolo¹  G. Centonze²  G. Ali³  G. Garzone²  S. Taormina¹  G. Sabella²  C. Ciaparrone¹  A. Mafficini¹  F. Grillo⁶  A. Mangogna⁷  M. Volante⁸  L. Mastracci⁶  G. Fontanini³  S. Pilotto⁹  E. Bria^1,10  M. Infante^1,11  C. Capella^1,12  L. Rolli^1,13  U. Pastorino^1,13  M. Milella⁹  M. Milione²  A. Scarpa¹ 

[1] Section of Pathology, Department of Diagnostics and Public Health, University of Verona;Pathology Unit 1, Pathology and Laboratory Department, Fondazione IRCCS Istituto Nazionale dei Tumori;Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa;School of Pathology, University of Milan;ARC-Net Research Centre for Applied Research on Cancer, University of Verona;Department of Surgical and Diagnostic Sciences ,(DISC), University of Genova and IRCCS S. Martino-IST University Hospital;Institute for Maternal and Child Health;Department of Oncology, University of Turin at San Luigi Hospital;Section of Oncology, Department of Medicine, University of Verona;Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore;Thoracic Surgery, University and Hospital Trust of Verona;Unit of Pathology, Department of Medicine and Surgery and Research Centre for the Study of Hereditary and Familial tumors, University of Insubria;Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori

关键词: combined small-cell lung carcinoma;    small-cell lung cancer;    neuroendocrine carcinoma;    next-generation sequencing;    transcriptomics;   

DOI  :  10.1016/j.esmoop.2021.100308

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC.Materials and methods Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes.Results All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern.Conclusions These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).

【 授权许可】

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