Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
(2019) In Oncotarget 10(19). p.1760-1774- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/05595499-b514-4827-a203-33df74691d7c
- author
- Li, Yafang ; Brunnström, Hans LU ; Manjer, Jonas LU ; Melander, Olle LU and Amos, Christopher I
- author collaboration
- organization
-
- Improved diagnostics and prognostics of lung cancer and metastases to the lungs (research group)
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Tumor microenvironment
- Surgery (research group)
- EpiHealth: Epidemiology for Health
- EXODIAB: Excellence of Diabetes Research in Sweden
- Cardiovascular Research - Hypertension (research group)
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Epistasis, Functional annotation, Lung cancer, Oncogenesis
- in
- Oncotarget
- volume
- 10
- issue
- 19
- pages
- 15 pages
- publisher
- Impact Journals
- external identifiers
-
- scopus:85062764425
- pmid:30956756
- ISSN
- 1949-2553
- DOI
- 10.18632/oncotarget.26678
- language
- English
- LU publication?
- yes
- additional info
- Export Date: 20 March 2019
- id
- 05595499-b514-4827-a203-33df74691d7c
- date added to LUP
- 2019-03-20 10:15:44
- date last changed
- 2024-01-15 16:20:38
@article{05595499-b514-4827-a203-33df74691d7c, abstract = {{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.}}, author = {{Li, Yafang and Brunnström, Hans and Manjer, Jonas and Melander, Olle and Amos, Christopher I}}, issn = {{1949-2553}}, keywords = {{Epistasis; Functional annotation; Lung cancer; Oncogenesis}}, language = {{eng}}, number = {{19}}, pages = {{1760--1774}}, publisher = {{Impact Journals}}, series = {{Oncotarget}}, title = {{Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development}}, url = {{http://dx.doi.org/10.18632/oncotarget.26678}}, doi = {{10.18632/oncotarget.26678}}, volume = {{10}}, year = {{2019}}, }