Skip to main content
Top
Published in:

Open Access 03-01-2024 | ORIGINAL ARTICLE

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives

Authors: Michele Simbolo, Giovanni Centonze, Anastasios Gkountakos, Valentina Monti, Patrick Maisonneuve, Stela Golovco, Giovanna Sabella, Alessandro Del Gobbo, Stefano Gobbo, Stefano Ferrero, Alessandra Fabbri, Carlotta Pardo, Giovanna Garzone, Natalie Prinzi, Sara Pusceddu, Adele Testi, Luigi Rolli, Alessandro Mangogna, Luisa Bercich, Mauro Roberto Benvenuti, Emilio Bria, Sara Pilotto, Alfredo Berruti, Ugo Pastorino, Carlo Capella, Maurizio Infante, Michele Milella, Aldo Scarpa, Massimo Milione

Published in: Virchows Archiv | Issue 5/2024

Login to get access

Abstract

Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.
Appendix
Available only for authorised users
Literature
3.
go back to reference Dreyer SB, Upstill-Goddard R, Paulus-Hock V, Paris C, Lampraki EM, Dray E, Serrels B, Caligiuri G, Rebus S, Plenker D, Galluzzo Z, Brunton H, Cunningham R, Tesson M, Nourse C, Bailey UM, Jones M, Moran-Jones K, Wright DW, Duthie F, Oien K, Evers L, McKay CJ, McGregor GA, Gulati A, Brough R, Bajrami I, Pettitt S, Dziubinski ML, Candido J, Balkwill F, Barry ST, Grutzmann R, Rahib L, Glasgow Precision Oncology L, Australian Pancreatic Cancer Genome I, Johns A, Pajic M, Froeling FEM, Beer P, Musgrove EA, Petersen GM, Ashworth A, Frame MC, Crawford HC, Simeone DM, Lord C, Mukhopadhyay D, Pilarsky C, Tuveson DA, Cooke SL, Jamieson NB, Morton JP, Sansom OJ, Bailey PJ, Biankin AV, Chang DK (2021) Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology 160:362-377 e313. https://doi.org/10.1053/j.gastro.2020.09.043CrossRefPubMed Dreyer SB, Upstill-Goddard R, Paulus-Hock V, Paris C, Lampraki EM, Dray E, Serrels B, Caligiuri G, Rebus S, Plenker D, Galluzzo Z, Brunton H, Cunningham R, Tesson M, Nourse C, Bailey UM, Jones M, Moran-Jones K, Wright DW, Duthie F, Oien K, Evers L, McKay CJ, McGregor GA, Gulati A, Brough R, Bajrami I, Pettitt S, Dziubinski ML, Candido J, Balkwill F, Barry ST, Grutzmann R, Rahib L, Glasgow Precision Oncology L, Australian Pancreatic Cancer Genome I, Johns A, Pajic M, Froeling FEM, Beer P, Musgrove EA, Petersen GM, Ashworth A, Frame MC, Crawford HC, Simeone DM, Lord C, Mukhopadhyay D, Pilarsky C, Tuveson DA, Cooke SL, Jamieson NB, Morton JP, Sansom OJ, Bailey PJ, Biankin AV, Chang DK (2021) Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology 160:362-377 e313. https://​doi.​org/​10.​1053/​j.​gastro.​2020.​09.​043CrossRefPubMed
7.
go back to reference Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218. https://doi.org/10.1038/nature12213CrossRefPubMedPubMedCentral Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218. https://​doi.​org/​10.​1038/​nature12213CrossRefPubMedPubMedCentral
14.
go back to reference Poulin EJ, Bera AK, Lu J, Lin YJ, Strasser SD, Paulo JA, Huang TQ, Morales C, Yan W, Cook J, Nowak JA, Brubaker DK, Joughin BA, Johnson CW, DeStefanis RA, Ghazi PC, Gondi S, Wales TE, Iacob RE, Bogdanova L, Gierut JJ, Li Y, Engen JR, Perez-Mancera PA, Braun BS, Gygi SP, Lauffenburger DA, Westover KD, Haigis KM (2019) Tissue-specific oncogenic activity of KRAS(A146T). Cancer Discov 9:738–755. https://doi.org/10.1158/2159-8290.CD-18-1220CrossRefPubMedPubMedCentral Poulin EJ, Bera AK, Lu J, Lin YJ, Strasser SD, Paulo JA, Huang TQ, Morales C, Yan W, Cook J, Nowak JA, Brubaker DK, Joughin BA, Johnson CW, DeStefanis RA, Ghazi PC, Gondi S, Wales TE, Iacob RE, Bogdanova L, Gierut JJ, Li Y, Engen JR, Perez-Mancera PA, Braun BS, Gygi SP, Lauffenburger DA, Westover KD, Haigis KM (2019) Tissue-specific oncogenic activity of KRAS(A146T). Cancer Discov 9:738–755. https://​doi.​org/​10.​1158/​2159-8290.​CD-18-1220CrossRefPubMedPubMedCentral
17.
go back to reference Rossi G, Leighl NB, Lu S, Nicholson AG, Smit EF (2021) Large cells carcinoma of the lung. In: Kerr KM, Travis WD (eds) WHO Classification of Tumours. Thoracic Tumours, 5th.edn. IARC, Lyon, pp. 97–99 Rossi G, Leighl NB, Lu S, Nicholson AG, Smit EF (2021) Large cells carcinoma of the lung. In: Kerr KM, Travis WD (eds) WHO Classification of Tumours. Thoracic Tumours, 5th.edn. IARC, Lyon, pp. 97–99
18.
go back to reference Russo A, Franchina T, Ricciardi G, Battaglia A, Picciotto M, Adamo V (2019) Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int J Mol Sci 20. https://doi.org/10.3390/ijms20061431 Russo A, Franchina T, Ricciardi G, Battaglia A, Picciotto M, Adamo V (2019) Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int J Mol Sci 20. https://​doi.​org/​10.​3390/​ijms20061431
21.
go back to reference Thomas A, Takahashi N, Rajapakse VN, Zhang X, Sun Y, Ceribelli M, Wilson KM, Zhang Y, Beck E, Sciuto L, Nichols S, Elenbaas B, Puc J, Dahmen H, Zimmermann A, Varonin J, Schultz CW, Kim S, Shimellis H, Desai P, Klumpp-Thomas C, Chen L, Travers J, McKnight C, Michael S, Itkin Z, Lee S, Yuno A, Lee MJ, Redon CE, Kindrick JD, Peer CJ, Wei JS, Aladjem MI, Figg WD, Steinberg SM, Trepel JB, Zenke FT, Pommier Y, Khan J, Thomas CJ (2021) Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell 39:566-579 e567. https://doi.org/10.1016/j.ccell.2021.02.014CrossRefPubMedPubMedCentral Thomas A, Takahashi N, Rajapakse VN, Zhang X, Sun Y, Ceribelli M, Wilson KM, Zhang Y, Beck E, Sciuto L, Nichols S, Elenbaas B, Puc J, Dahmen H, Zimmermann A, Varonin J, Schultz CW, Kim S, Shimellis H, Desai P, Klumpp-Thomas C, Chen L, Travers J, McKnight C, Michael S, Itkin Z, Lee S, Yuno A, Lee MJ, Redon CE, Kindrick JD, Peer CJ, Wei JS, Aladjem MI, Figg WD, Steinberg SM, Trepel JB, Zenke FT, Pommier Y, Khan J, Thomas CJ (2021) Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell 39:566-579 e567. https://​doi.​org/​10.​1016/​j.​ccell.​2021.​02.​014CrossRefPubMedPubMedCentral
24.
go back to reference Yamada Y, Belharazem-Vitacolonnna D, Bohnenberger H, Weiss C, Matsui N, Kriegsmann M, Kriegsmann K, Sinn P, Simon-Keller K, Hamilton G, Graeter T, Preissler G, Ott G, Scholch S, Nakajima N, Yoshizawa A, Haga H, Date H, Thomas RK, Petrini I, Giaccone G, Strobel P, Marx A (2022) Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities. Cell Death Dis 13:979. https://doi.org/10.1038/s41419-022-05428-xCrossRefPubMedPubMedCentral Yamada Y, Belharazem-Vitacolonnna D, Bohnenberger H, Weiss C, Matsui N, Kriegsmann M, Kriegsmann K, Sinn P, Simon-Keller K, Hamilton G, Graeter T, Preissler G, Ott G, Scholch S, Nakajima N, Yoshizawa A, Haga H, Date H, Thomas RK, Petrini I, Giaccone G, Strobel P, Marx A (2022) Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities. Cell Death Dis 13:979. https://​doi.​org/​10.​1038/​s41419-022-05428-xCrossRefPubMedPubMedCentral
Metadata
Title
Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives
Authors
Michele Simbolo
Giovanni Centonze
Anastasios Gkountakos
Valentina Monti
Patrick Maisonneuve
Stela Golovco
Giovanna Sabella
Alessandro Del Gobbo
Stefano Gobbo
Stefano Ferrero
Alessandra Fabbri
Carlotta Pardo
Giovanna Garzone
Natalie Prinzi
Sara Pusceddu
Adele Testi
Luigi Rolli
Alessandro Mangogna
Luisa Bercich
Mauro Roberto Benvenuti
Emilio Bria
Sara Pilotto
Alfredo Berruti
Ugo Pastorino
Carlo Capella
Maurizio Infante
Michele Milella
Aldo Scarpa
Massimo Milione
Publication date
03-01-2024
Publisher
Springer Berlin Heidelberg
Published in
Virchows Archiv / Issue 5/2024
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-023-03721-4