Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities
| Autor: | Simbolo, M, Centonze, G, Ali, G, Garzone, G, Taormina, S, Sabella, G, Ciaparrone, C, Mafficini, A, Grillo, F, Mangogna, A, Volante, M, Mastracci, L, Fontanini, G, Pilotto, S, Bria, E, Infante, M, Capella, C, Rolli, L, Pastorino, U, Milella, M, Milione, M, Scarpa, A |
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| Přispěvatelé: | Simbolo, M., Centonze, G., Ali, G., Garzone, G., Taormina, S., Sabella, G., Ciaparrone, C., Mafficini, A., Grillo, F., Mangogna, A., Volante, M., Mastracci, L., Fontanini, G., Pilotto, S., Bria, E., Infante, M., Capella, C., Rolli, L., Pastorino, U., Milella, M., Milione, M., Scarpa, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
combined small-cell lung carcinoma Lung Neoplasms transcriptomics Combined small-cell lung carcinoma neuroendocrine carcinoma next-generation sequencing small-cell lung cancer Carcinoma Small Cell Humans Lung Carcinoma Neuroendocrine Carcinoma Small Cell Small Cell Lung Carcinoma respiratory tract diseases Neuroendocrine Oncology neoplasms Original Research |
| Zdroj: | ESMO Open |
| Popis: | 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). Highlights • We explored 13 C-SCLCs for alterations in 409 genes and transcriptomic profiling of 20 815 genes. • Frequently mutated genes were TP53 and RB1; potentially targetable alterations included two KRAS G12C, two PK3CA, one EGFR. • Transcriptional profiling showed: CoLCNEC clearly NE, CoSQC non-NE, CoADC heterogeneous phenotype. • NE versus non-NE classification and routine EGFR, KRAS and PIK3CA analysis should be extended to C-SCLC. |
| Databáze: | OpenAIRE |
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