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Olle Melander

Principal investigator

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Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

Author

  • Yafang Li
  • Hans Brunnström
  • Jonas Manjer
  • Olle Melander
  • Christopher I Amos

Summary, in English

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10 -11 in overall lung cancer and OR=0.41, p value=9.71x10 -11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10 -12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10 -11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes. Copyright: Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Department/s

  • Improved diagnostics and prognostics of lung cancer and metastases to the lungs
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
  • Tumor microenvironment
  • Surgery
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Cardiovascular Research - Hypertension

Publishing year

2019

Language

English

Pages

1760-1774

Publication/Series

Oncotarget

Volume

10

Issue

19

Document type

Journal article

Publisher

Impact Journals, LLC

Topic

  • Cancer and Oncology
  • Medical Genetics

Keywords

  • Epistasis
  • Functional annotation
  • Lung cancer
  • Oncogenesis

Status

Published

Research group

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

ISBN/ISSN/Other

  • ISSN: 1949-2553