期刊
ESMO OPEN
卷 7, 期 1, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.esmoop.2021.100308
关键词
combined small-cell lung carcinoma; small-cell lung cancer; neuroendocrine carcinoma; next-generation sequencing; transcriptomics
类别
资金
- Italian Ministry of Health [ERP-2017-23671129]
- Associazione Italiana per la Ricerca sul Cancro [12182, AIRC 5x 1000]
- Universita Cattolica del Sacro Cuore (UCSC) [D1-2020]
- AIRC IG [20583]
- FIRC-AIRC fellowship for Italy [25422]
- Fondazione IRCCS Istituto Nazionale Tumori Milano 5x 1000 Funds-grant 'Integrative molecular analysis of pure and combined lung large-cell neuroendocrine carcinoma (LCNEC)'
Thirteen cases of combined small-cell lung cancer (C-SCLC) were evaluated, showing potential targetable alterations and distinct transcriptomic profiles, which could be classified into different subtypes based on NE or non-NE lineage.
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).
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