Li, Y., Xiao, X., Bossé, Y. et al. (77 more authors) (2019) Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development. Oncotarget, 10 (19). pp. 1760-1774. ISSN 1949-2553
Abstract
The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand 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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 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), http://creativecommons.org/licenses/by/3.0/ which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Keywords: | epistasis; lung cancer; oncogenesis; functional annotation |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield) > ScHARR - Sheffield Centre for Health and Related Research |
Funding Information: | Funder Grant number CANCER RESEARCH UK C9267/A25152 NATIONAL INSTITUTE FOR HEALTH RESEARCH None NATIONAL INSTITUTE FOR HEALTH RESEARCH ECME FSF 2011/12 CANCER RESEARCH UK C5410/A7315 CANCER RESEARCH UK C5410/A7315. NATIONAL INSTITUTE FOR HEALTH RESEARCH None NATIONAL INSTITUTE FOR HEALTH RESEARCH ECMC CANCER RESEARCH UK C5410/A15588 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST NOne WESTON PARK HOSPITAL CANCER CHARITY CA115 CANCER RESEARCH UK (CRUK) C5410/A7315. CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST 091002 CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST (SPECIAL TRUSTEES) 091002 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST ECMC |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 18 Apr 2019 09:03 |
Last Modified: | 18 Apr 2019 09:24 |
Status: | Published |
Publisher: | Impact Journals |
Refereed: | Yes |
Identification Number: | 10.18632/oncotarget.26678 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:145112 |