Els Wauters1, Wim Janssens2, Johan Vansteenkiste2, Herbert Decaluwé3, Nele Heulens4, Bernard Thienpont5, Hui Zhao5, Dominiek Smeets5, Xavier Sagaert6, Johan Coolen7, Marc Decramer2, Adrian Liston8, Paul De Leyn3, Matthieu Moisse5, Diether Lambrechts5. 1. Vesalius Research Center (VRC), VIB, KU Leuven, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium Respiratory Division, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium. 2. Respiratory Division, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium. 3. Department of Thoracic surgery, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium. 4. Laboratory of Pneumology, KU Leuven, Leuven, Belgium. 5. Vesalius Research Center (VRC), VIB, KU Leuven, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium. 6. Centre for Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium. 7. Department of Radiology, University Hospital Gasthuisberg, KU Leuven, Belgium. 8. Autoimmune Genetics Laboratory, VIB, KU Leuven, Leuven, Belgium.
Abstract
INTRODUCTION: Non-small cell lung cancer (NSCLC) is a heterogeneous disorder consisting of distinct molecular subtypes each characterised by specific genetic and epigenetic profiles. Here, we aimed to identify novel NSCLC subtypes based on genome-wide methylation data, assess their relationship with smoking behaviour, age, COPD, emphysema and tumour histopathology, and identify the molecular pathways underlying each subtype. METHODS: Methylation profiling was performed on 49 pairs of tumour and adjacent lung tissue using Illumina 450 K arrays. Transcriptome sequencing was performed using Illumina HiSeq2000 and validated using expression data from The Cancer Genome Atlas (TCGA). Tumour immune cell infiltration was investigated by immunohistochemistry. RESULTS: Unsupervised hierarchical clustering of tumour methylation data revealed two subgroups characterised by a significant association between cluster membership and presence of COPD (p=0.024). Ontology analysis of genes containing differentially methylated CpGs (false discovery rate, FDR-adjusted p<0.05) revealed that immune genes were strongly enriched in COPD tumours, but not in non-COPD tumours. This COPD-specific immune signature was attributable to methylation changes in immune genes expressed either by tumour cells or tumour-infiltrating immune cells. No such differences were observed in adjacent tissue. Transcriptome profiling similarly revealed that genes involved in the immune response were differentially expressed in COPD tumours (FDR-adjusted p<0.05), an observation that was independently replicated using TCGA data. Immunohistochemistry validated these findings, revealing fewer CD4-positive T lymphocytes in tumours derived from patients with COPD. CONCLUSIONS: Lung tumours of patients with COPD differ from those of patients without COPD, with differentially methylated and expressed genes being mainly involved in the immune response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
INTRODUCTION:Non-small cell lung cancer (NSCLC) is a heterogeneous disorder consisting of distinct molecular subtypes each characterised by specific genetic and epigenetic profiles. Here, we aimed to identify novel NSCLC subtypes based on genome-wide methylation data, assess their relationship with smoking behaviour, age, COPD, emphysema and tumour histopathology, and identify the molecular pathways underlying each subtype. METHODS: Methylation profiling was performed on 49 pairs of tumour and adjacent lung tissue using Illumina 450 K arrays. Transcriptome sequencing was performed using Illumina HiSeq2000 and validated using expression data from The Cancer Genome Atlas (TCGA). Tumour immune cell infiltration was investigated by immunohistochemistry. RESULTS: Unsupervised hierarchical clustering of tumour methylation data revealed two subgroups characterised by a significant association between cluster membership and presence of COPD (p=0.024). Ontology analysis of genes containing differentially methylated CpGs (false discovery rate, FDR-adjusted p<0.05) revealed that immune genes were strongly enriched in COPD tumours, but not in non-COPD tumours. This COPD-specific immune signature was attributable to methylation changes in immune genes expressed either by tumour cells or tumour-infiltrating immune cells. No such differences were observed in adjacent tissue. Transcriptome profiling similarly revealed that genes involved in the immune response were differentially expressed in COPD tumours (FDR-adjusted p<0.05), an observation that was independently replicated using TCGA data. Immunohistochemistry validated these findings, revealing fewer CD4-positive T lymphocytes in tumours derived from patients with COPD. CONCLUSIONS: Lung tumours of patients with COPD differ from those of patients without COPD, with differentially methylated and expressed genes being mainly involved in the immune response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
COPD ÀÜ Mechanisms; Innate Immunity; Lung Cancer
Authors: Roby Joehanes; Allan C Just; Riccardo E Marioni; Luke C Pilling; Lindsay M Reynolds; Pooja R Mandaviya; Weihua Guan; Tao Xu; Cathy E Elks; Stella Aslibekyan; Hortensia Moreno-Macias; Jennifer A Smith; Jennifer A Brody; Radhika Dhingra; Paul Yousefi; James S Pankow; Sonja Kunze; Sonia H Shah; Allan F McRae; Kurt Lohman; Jin Sha; Devin M Absher; Luigi Ferrucci; Wei Zhao; Ellen W Demerath; Jan Bressler; Megan L Grove; Tianxiao Huan; Chunyu Liu; Michael M Mendelson; Chen Yao; Douglas P Kiel; Annette Peters; Rui Wang-Sattler; Peter M Visscher; Naomi R Wray; John M Starr; Jingzhong Ding; Carlos J Rodriguez; Nicholas J Wareham; Marguerite R Irvin; Degui Zhi; Myrto Barrdahl; Paolo Vineis; Srikant Ambatipudi; André G Uitterlinden; Albert Hofman; Joel Schwartz; Elena Colicino; Lifang Hou; Pantel S Vokonas; Dena G Hernandez; Andrew B Singleton; Stefania Bandinelli; Stephen T Turner; Erin B Ware; Alicia K Smith; Torsten Klengel; Elisabeth B Binder; Bruce M Psaty; Kent D Taylor; Sina A Gharib; Brenton R Swenson; Liming Liang; Dawn L DeMeo; George T O'Connor; Zdenko Herceg; Kerry J Ressler; Karen N Conneely; Nona Sotoodehnia; Sharon L R Kardia; David Melzer; Andrea A Baccarelli; Joyce B J van Meurs; Isabelle Romieu; Donna K Arnett; Ken K Ong; Yongmei Liu; Melanie Waldenberger; Ian J Deary; Myriam Fornage; Daniel Levy; Stephanie J London Journal: Circ Cardiovasc Genet Date: 2016-09-20
Authors: Wenxin Wu; Wei Zhang; J Leland Booth; David C Hutchings; Xiaoqiu Wang; Vicky L White; Houssein Youness; Cory D Cross; Ming-Hui Zou; Dennis Burian; Jordan P Metcalf Journal: Respir Res Date: 2016-09-07
Authors: Francesca Polverino; Maria Laucho-Contreras; Joselyn Rojas Quintero; Miguel Divo; Victor Pinto-Plata; Lynette Sholl; Juan P de-Torres; Bartolome R Celli; Caroline A Owen Journal: Multidiscip Respir Med Date: 2016-04-04