Iván Galván-Femenía1, Marta Guindo2, Xavier Duran3, Sílvia Calabuig-Fariñas4, Josep Maria Mercader5, Jose Luis Ramirez6, Rafael Rosell7, David Torrents8, Anna Carreras9, Takashi Kohno10, Eloisa Jantus-Lewintre11, Carlos Camps12, Manuel Perucho13, Lauro Sumoy14, Jun Yokota15, Rafael de Cid16. 1. Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: igalvan@igtp.cat. 2. Barcelona Supercomputing Center (BSC-CNS), Joint BSC-CRG-IRB Research Program in Computational Biology, Carrer de Jordi Girona, 29-31, 08034 Barcelona, Spain. Electronic address: marta.guindomartinez@bsc.es. 3. Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: xduran@igtp.cat. 4. Department of Medical Oncology, Hospital General Universitario de Valencia, Avenida Tres Cruces, 2, 46014, València, Spain; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Avda. Tres Cruces s/n 46014 València, Spain; Department of Pathology, Universitat de València, Av. de Blasco Ibáñez, 13, 46010 València, Spain. Electronic address: calabuix_sil@gva.es. 5. Barcelona Supercomputing Center (BSC-CNS), Joint BSC-CRG-IRB Research Program in Computational Biology, Carrer de Jordi Girona, 29-31, 08034 Barcelona, Spain. Electronic address: mercader@broadinstitute.org. 6. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: jramirez@iconcologia.net. 7. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: rrosell@iconcologia.net. 8. Barcelona Supercomputing Center (BSC-CNS), Joint BSC-CRG-IRB Research Program in Computational Biology, Carrer de Jordi Girona, 29-31, 08034 Barcelona, Spain; ICREA, Catalan Institution for Research and Advanced Studies, Spain. Electronic address: david.torrents@bsc.es. 9. Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: acarreras@igtp.cat. 10. Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tkkohno@ncc.go.jp. 11. Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Avda. Tres Cruces s/n 46014 València, Spain; Department of Pathology, Universitat de València, Av. de Blasco Ibáñez, 13, 46010 València, Spain; Molecular Oncology Laboratory, Fundación Hospital General Universitario de València, Avda. Tres Cruces s/n, 46014 València. Electronic address: jantus_elo@gva.es. 12. Department of Medical Oncology, Hospital General Universitario de Valencia, Avenida Tres Cruces, 2, 46014, València, Spain; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Avda. Tres Cruces s/n 46014 València, Spain; Department of Biotechnology, Universitat Politècnica de València, Camí de Vera, s/n, 46022 València, Spain; Department of Medicine, Universitat de València, Av. de Blasco Ibáñez, 13, 46010 València, Spain. Electronic address: camps_car@gva.es. 13. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: mperucho@igtp.cat. 14. Genomics and Bioinformatics. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: lsumoy@igtp.cat. 15. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: jyokota@igtp.cat. 16. Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institute for Health Science Research Germans Trias i Pujol (IGTP), Can Ruti Biomedical Campus, Crta de Can Ruti, Camí de les Escoles S/N, 08916 Badalona, Barcelona, Spain. Electronic address: rdecid@igtp.cat.
Abstract
OBJECTIVE: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. MATERIALS AND METHODS: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). RESULTS: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients. CONCLUSION: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. MICROABSTRACT: A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy.
OBJECTIVE: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. MATERIALS AND METHODS: We carried out a two-stage genome-wide-association study in non-small-cell lung cancerpatients with platinum-based chemotherapy in an exploratory sample of 181 NSCLCpatients from Caucasian origin, followed by a validation on 356 NSCLCpatients from the same ancestry (Valencia, Spain). RESULTS: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLCpatients. CONCLUSION: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLCpatients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. MICROABSTRACT: A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLCpatients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in humancarcinogenesis as well in resistance to chemotherapy.