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). 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. 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. 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. ; This work was supported by the Fundacion Cientifica Asociacion Española Contra el Cancer-AECC (grant number GCB14142170MONT) to LMM, MS-C, and EF; the Spanish Ministry of Economy and Competitivity-MINECO (grant number SAF-2017-82186R to MS-C; Rio Hortega-CM17/00180 to MS; PROYBAR17005NADA to EN); the Health Institute Carlos III-ISCIII, Fondo Europeo de Desarrollo Regional-FEDER (grant Number PT13/0001/0044, PT17/0009/0019, PI16 01821); the Government of Navarra (grant number DIANA project); and the Ramon Areces Foundation (no grant number is applicable) to LMM and RP. ; Sí
FMSR (Austria) ; Fonds de la Recherche Scientifique (FNRS) ; FWO (Belgium) ; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) ; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) ; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) ; MES (Bulgaria) ; CERN (China) ; Chinese Academy of Sciences (CAS) ; MoST (China) ; National Natural Science Foundation of China (NSFC) ; COLCIEN-CIAS (Colombia) ; MSES (Croatia) ; Research Promotion Foundation (RPF) ; Academy of Sciences (Estonia) ; National Institute of Chemical Physics and Biophysics (NICPB) ; Academy of Finland ; ME (Finland) ; Helsinki Institute of Physics (HIP) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA) ; Institut national de physique nucléaire et de physique des particules (IN2P3/CNRS) ; Bundesministerium für Bildung und Forschung (BMBF) ; Deutsche Forschungsgemeinschaft (DFG) ; HGF (Germany) ; General Secretariat for Research and Technology (GSRT) ; Hungarian Scientific Research Fund (OTKA) ; NKTH (Hungary) ; Department of Atomic Energy (DAE) - India ; Department of Science and Technology (DST) - India ; Institute for Research in Fundamental Sciences (IPM) ; Science Foundation Ireland (SFI) ; Istituto Nazionale di Fisica Nucleare (INFN) ; National Research Foundation of Korea (NRF) ; LAS (Lithuania) ; Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV) ; Consejo Nacional de Ciencia y Tecnología (CONACYT) ; SEP (Mexico) ; UASLP-FAI (Mexico) ; Pakistan Atomic Energy Commission (PAEC) ; SCSR (Poland) ; Fundação para a Ciência e a Tecnologia (FCT) ; Joint Institute for Nuclear Research (JINR) ; MST (Russia) ; MAE (Russia) ; MSTDS (Serbia) ; MICINN (Spain) ; Centro Nacional de Física de Partículas, Astropartículas y Nuclear (CPAN) ; Swiss Funding Agencies (Switzerland) ; NSC (Taipei) ; Scientific and Technological Research Council of Turkey (TUBITAK) ; Türkiye Atom Enerjisi Kurumu (TAEK) ; Science and Technology Facilities Council (STFC) ; DOE (USA) ; National Science Foundation (NSF) - USA ; European Union ; Leventis Foundation ; A. P. Sloan Foundation ; Alexander von Humboldt Foundation ; During autumn 2008, the Silicon Strip Tracker was operated with the full CMS experiment in a comprehensive test, in the presence of the 3.8 T magnetic field produced by the CMS superconducting solenoid. Cosmic ray muons were detected in the muon chambers and used to trigger the readout of all CMS sub-detectors. About 15 million events with a muon in the tracker were collected. The efficiency of hit and track reconstruction were measured to be higher than 99% and consistent with expectations from Monte Carlo simulation. This article details the commissioning and performance of the Silicon Strip Tracker with cosmic ray muons.