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

M Simbolo; G Centonze; G Ali; G Garzone; S Taormina; G Sabella; C Ciaparrone; A Mafficini; F Grillo; A Mangogna; M Volante; L Mastracci; G Fontanini; S Pilotto; E Bria; M Infante; C Capella; L Rolli; U Pastorino; M Milella; M Milione; A Scarpa

doi:10.1016/j.esmoop.2021.100308

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

ESMO Open. 2022 Feb;7(1):100308. doi: 10.1016/j.esmoop.2021.100308. Epub 2021 Dec 21.

Authors

M Simbolo¹, G Centonze², G Ali³, G Garzone², S Taormina¹, G Sabella⁴, C Ciaparrone¹, A Mafficini⁵, F Grillo⁶, A Mangogna⁷, M Volante⁸, L Mastracci⁶, G Fontanini³, S Pilotto⁹, E Bria¹⁰, M Infante¹¹, C Capella¹², L Rolli¹³, U Pastorino¹³, M Milella⁹, M Milione¹⁴, A Scarpa⁵

Affiliations

¹ Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
² Pathology Unit 1, Pathology and Laboratory Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
³ Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
⁴ Pathology Unit 1, Pathology and Laboratory Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; School of Pathology, University of Milan, Milan, Italy.
⁵ Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy; ARC-Net Research Centre for Applied Research on Cancer, University of Verona, Verona, Italy.
⁶ Department of Surgical and Diagnostic Sciences (DISC), University of Genova and IRCCS S. Martino-IST University Hospital, Genoa, Italy.
⁷ Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy.
⁸ Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Torino, Italy.
⁹ Section of Oncology, Department of Medicine, University of Verona, Verona, Italy.
¹⁰ Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
¹¹ Thoracic Surgery, University and Hospital Trust of Verona, Verona, Italy.
¹² Unit of Pathology, Department of Medicine and Surgery and Research Centre for the Study of Hereditary and Familial tumors, University of Insubria, Varese, Italy.
¹³ Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
¹⁴ Pathology Unit 1, Pathology and Laboratory Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address: massimo.milione@istitutotumori.mi.it.

Abstract

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).

Keywords: combined small-cell lung carcinoma; neuroendocrine carcinoma; next-generation sequencing; small-cell lung cancer; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Neuroendocrine* / genetics
Carcinoma, Neuroendocrine* / pathology
Carcinoma, Small Cell* / genetics
Carcinoma, Small Cell* / pathology
Humans
Lung
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / pathology