E Pros1, M Saigi2, D Alameda3, G Gomez-Mariano4, B Martinez-Delgado4, J J Alburquerque-Bejar1, J Carretero5, R Tonda6, A Esteve-Codina6, I Catala7, R Palmero8, M Jove8, C Lazaro9, A Patiño-Garcia3, I Gil-Bazo10, S Verdura1, A Teulé9, J Torres-Lanzas11, D Sidransky12, N Reguart13, R Pio10, O Juan-Vidal14, E Nadal15, E Felip16, L M Montuenga17, M Sanchez-Cespedes18. 1. Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. 2. Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain. 3. Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain. 4. Molecular Genetics Unit, Rare Diseases Institute of Research (IIER), Health Institute Carlos III, Majadahonda, Madrid, Spain. 5. Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain. 6. CNAG-CRG, Centre for Genomic Regulation (CRG), Institute of Science and Technology (BIST) and University Pompeu Fabra (UPF), Barcelona, Spain. 7. Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain. 8. Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain. 9. Hereditary Cancer Program, Catalan Institute of Oncology, ICO-Oncobell-IDIBELL, Madrid, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain. 10. Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain. 11. Thoracic Surgery Department, Hospital Universitario Virgen de la Arrixaca, El Palmar-Murcia, Spain. 12. Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland. 13. Oncology Department, Thoracic Tumors Unit, Clinic Hospital, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 14. Biomarkers and Precision Medicine Unit, Research Institute La Fe and Department of Medical Oncology, La Fe University Hospital, Valencia, Spain. 15. Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain; Clinical Research in Solid Tumors Group (CReST), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain. 16. Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain. 17. Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain; Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra, Pamplona, Spain. 18. Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. Electronic address: mscespedes@carrerasresearch.org.
Abstract
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.
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.
Authors: Octavio A Romero; Andrea Vilarrubi; Juan J Alburquerque-Bejar; Antonio Gomez; Alvaro Andrades; Deborah Trastulli; Eva Pros; Fernando Setien; Sara Verdura; Lourdes Farré; Juan F Martín-Tejera; Paula Llabata; Ana Oaknin; Maria Saigi; Josep M Piulats; Xavier Matias-Guiu; Pedro P Medina; August Vidal; Alberto Villanueva; Montse Sanchez-Cespedes Journal: Nat Commun Date: 2021-07-14 Impact factor: 14.919