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DNA methylation profiling of non-small cell lung cancer reveals a COPD-driven immune-related signature
  1. Els Wauters1,2,3,
  2. Wim Janssens3,
  3. Johan Vansteenkiste3,
  4. Herbert Decaluwé4,
  5. Nele Heulens5,
  6. Bernard Thienpont1,2,
  7. Hui Zhao1,2,
  8. Dominiek Smeets1,2,
  9. Xavier Sagaert6,
  10. Johan Coolen7,
  11. Marc Decramer3,
  12. Adrian Liston8,
  13. Paul De Leyn4,
  14. Matthieu Moisse1,2,
  15. Diether Lambrechts1,2
  1. 1Vesalius Research Center (VRC), VIB, KU Leuven, Leuven, Belgium
  2. 2Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium
  3. 3Respiratory Division, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium
  4. 4Department of Thoracic surgery, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium
  5. 5Laboratory of Pneumology, KU Leuven, Leuven, Belgium
  6. 6Centre for Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium
  7. 7Department of Radiology, University Hospital Gasthuisberg, KU Leuven, Belgium
  8. 8Autoimmune Genetics Laboratory, VIB, KU Leuven, Leuven, Belgium
  1. Correspondence to Professor Diether Lambrechts, Vesalius Research Center (VRC), VIB and KU Leuven, Campus Gasthuisberg, Herestraat 49, box 912, Leuven B-3000, Belgium; diether.lambrechts{at}vib-kuleuven.be

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.

  • COPD ÀÜ Mechanisms
  • Innate Immunity
  • Lung Cancer

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