Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/17266
Título
Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors
Autor(es)
Pros, E | Saigi, M | Alameda, D | Gomez-Mariano, Gema Maria ISCIII | Martinez-Delgado, Beatriz ISCIII | Alburquerque-Bejar, J J | Carretero, J | Tonda, R | Esteve-Codina, A | Catala, I | Palmero, R | Jove, M | Lazaro, C | Patiño-Garcia, A | 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
Fecha de publicación
2020-02
Cita
Ann Oncol. 2020 Feb;31(2):274-282.
Idioma
Inglés
Tipo de documento
research article
Resumen
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.
Palabras clave
MESH
ErbB Receptors | Lung Neoplasms | Adenocarcinoma of Lung | Drug Resistance, Neoplasm | Humans | Microtubule-Associated Proteins | Mutation | Protein Kinase Inhibitors | Retinoblastoma Binding Proteins | Ubiquitin-Protein Ligases
Versión en línea
DOI
Aparece en las colecciones
- Investigación > ISCIII > Instituto de Investigación de Enfermedades Raras (IIER)
- Investigación > IIS > IDIBAPS - Instituto de Investigaciones Biomédicas August Pi i Sunyer (Cataluña)
- Investigación > IIS > IDIBELL - Instituto de Investigación Biomédica de Bellvitge (Cataluña)
- Investigación > IIS > IdiSNA - Instituto de Investigación Sanitaria de Navarra (Navarra)
- Investigación > IIS > IIS La Fe - Fundación para la Investigación del Hospital Universitario La Fe (C. Valenciana)