Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors

Background: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). Patients and methods...

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Detalles Bibliográficos
Autores: Pros, E, Saigi, M, Alameda, D, Gomez-Mariano, Gema Maria, Martinez-Delgado, Beatriz, Alburquerque-Bejar, J J, Carretero, J, Tonda, R, Esteve-Codina, A, Catala, I, Palmero, R, Jove, M, Lazaro, C, Patiño-García, Ana, Gil-Bazo, I, Verdura, S, Teulé, A, Torres-Lanzas, J, Sidransky, D, Reguart, N, Pio, R, Juan-Vidal, O, Nadal, E, Felip, E, Montuenga, L M, Sanchez-Cespedes, M
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17266
Acceso en línea:http://hdl.handle.net/20.500.12105/17266
Access Level:acceso abierto
Palabra clave:ErbB Receptors
Lung Neoplasms
Adenocarcinoma of Lung
Drug Resistance, Neoplasm
Humans
Microtubule-Associated Proteins
Mutation
Protein Kinase Inhibitors
Retinoblastoma Binding Proteins
Ubiquitin-Protein Ligases
Descripción
Sumario:Background: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). Patients and methods: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. Results: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. Conclusions: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

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