Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications
- Creators
- Simbolo M.
- Centonze G.
- Giudice L.
- Grillo F.
- Maisonneuve P.
- Gkountakos A.
- Ciaparrone C.
- Cattaneo L.
- Sabella G.
- Giugno R.
- Bossi P.
- Spaggiari P.
- Del Gobbo A.
- Ferrero S.
- Mastracci L.
- Fabbri A.
- Filugelli M.
- Garzone G.
- Prinzi N.
- Pusceddu S.
- Testi A.
- Monti V.
- Rolli L.
- Mangogna A.
- Bercich L.
- Benvenuti M. R.
- Bria E.
- Pilotto S.
- Berruti A.
- Pastorino U.
- Capella C.
- Infante M.
- Milella M.
- Scarpa A.
- Milione M.
- Others:
- Simbolo, M.
- Centonze, G.
- Giudice, L.
- Grillo, F.
- Maisonneuve, P.
- Gkountakos, A.
- Ciaparrone, C.
- Cattaneo, L.
- Sabella, G.
- Giugno, R.
- Bossi, P.
- Spaggiari, P.
- Del Gobbo, A.
- Ferrero, S.
- Mastracci, L.
- Fabbri, A.
- Filugelli, M.
- Garzone, G.
- Prinzi, N.
- Pusceddu, S.
- Testi, A.
- Monti, V.
- Rolli, L.
- Mangogna, A.
- Bercich, L.
- Benvenuti, M. R.
- Bria, E.
- Pilotto, S.
- Berruti, A.
- Pastorino, U.
- Capella, C.
- Infante, M.
- Milella, M.
- Scarpa, A.
- Milione, M.
Description
Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. Results: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. Conclusions: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.
Additional details
- URL
- https://hdl.handle.net/11567/1108936
- URN
- urn:oai:iris.unige.it:11567/1108936
- Origin repository
- UNIGE