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Olle Melander

Principal investigator

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Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma


  • Na Qin
  • Yuancheng Li
  • Cheng Wang
  • Meng Zhu
  • Juncheng Dai
  • Tongtong Hong
  • Demetrius Albanes
  • Stephen Lam
  • Adonina Tardon
  • Chu Chen
  • Gary Goodman
  • Stig E. Bojesen
  • Maria Teresa Landi
  • Mattias Johansson
  • Angela Risch
  • H. Erich Wichmann
  • Heike Bickeboller
  • Gadi Rennert
  • Susanne Arnold
  • Paul Brennan
  • John K. Field
  • Sanjay Shete
  • Loic Le Marchand
  • Olle Melander
  • Hans Brunnstrom
  • Geoffrey Liu
  • Rayjean J. Hung
  • Angeline Andrew
  • Lambertus A. Kiemeney
  • Shan Zienolddiny
  • Kjell Grankvist
  • Mikael Johansson
  • Neil Caporaso
  • Penella Woll
  • Philip Lazarus
  • Matthew B. Schabath
  • Melinda C. Aldrich
  • Victoria L. Stevens
  • Guangfu Jin
  • David C. Christiani
  • Zhibin Hu
  • Christopher I. Amos
  • Hongxia Ma
  • Hongbing Shen

Summary, in English

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.


  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Hypertension
  • Department of Clinical Sciences, Malmö
  • Pathology, Lund
  • LUCC - Lund University Cancer Centre
  • Improved diagnostics and prognostics of lung cancer and metastases to the lungs

Publishing year







Frontiers of Medicine





Document type

Journal article




  • Cancer and Oncology


  • function annotation
  • genetic heterogeneity
  • genome-wide association study
  • homologous recombination repair deficiency
  • immune
  • lung cancer



Research group

  • Cardiovascular Research - Hypertension
  • Improved diagnostics and prognostics of lung cancer and metastases to the lungs


  • ISSN: 2095-0217