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oai:repisalud.isciii.es:20.500.12105/172662025-05-05T14:56:02Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16961col_20.500.12105_16962col_20.500.12105_16968col_20.500.12105_16975col_20.500.12105_19616

00925njm 22002777a 4500 dc Pros, E author Saigi, M author Alameda, D author Gomez-Mariano, Gema Maria author Martinez-Delgado, Beatriz author Alburquerque-Bejar, J J author Carretero, J author Tonda, R author Esteve-Codina, A author Catala, I author Palmero, R author Jove, M author Lazaro, C author Patiño-García, Ana author Gil-Bazo, I author Verdura, S author Teulé, A author Torres-Lanzas, J author Sidransky, D author Reguart, N author Pio, R author Juan-Vidal, O author Nadal, E author Felip, E author Montuenga, L M author Sanchez-Cespedes, M author 2020-02 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. Ann Oncol. 2020 Feb;31(2):274-282. 10.1016/j.annonc.2019.09.001 1569-8041 Annals of oncology : official journal of the European Society for Medical Oncology 31959344 http://hdl.handle.net/20.500.12105/17266 Nonsmokers Lung adenocarcinoma EGFR RB1 Tyrosine kinase inhibitors Whole-exome sequencing Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors