TY - JOUR

T1 - Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

AU - Li, Yafang

AU - Xiao, Xiangjun

AU - Bossé, Yohan

AU - Gorlova, Olga

AU - Gorlov, Ivan

AU - Han, Younghun

AU - Byun, Jinyoung

AU - Leighl, Natasha

AU - Johansen, Jakob S

AU - Barnett, Matt

AU - Chen, Chu

AU - Goodman, Gary

AU - Cox, Angela

AU - Taylor, Fiona

AU - Woll, Penella

AU - Wichmann, H Erich

AU - Manz, Judith

AU - Muley, Thomas

AU - Risch, Angela

AU - Rosenberger, Albert

AU - Han, Jiali

AU - Siminovitch, Katherine

AU - Arnold, Susanne M

AU - Haura, Eric B

AU - Bolca, Ciprian

AU - Holcatova, Ivana

AU - Janout, Vladimir

AU - Kontic, Milica

AU - Lissowska, Jolanta

AU - Mukeria, Anush

AU - Ognjanovic, Simona

AU - Orlowski, Tadeusz M

AU - Scelo, Ghislaine

AU - Swiatkowska, Beata

AU - Zaridze, David

AU - Bakke, Per

AU - Skaug, Vidar

AU - Zienolddiny, Shanbeh

AU - Duell, Eric J

AU - Butler, Lesley M

AU - Houlston, Richard

AU - Artigas, María Soler

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Shepherd, Frances A

AU - Marcus, Michael W

AU - Brunnström, Hans

AU - Manjer, Jonas

AU - Melander, Olle

AU - Muller, David C

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Tumino, Rosario

AU - Liu, Geoffrey

AU - Bojesen, Stig E

AU - Wu, Xifeng

AU - Le Marchand, Loic

AU - Albanes, Demetrios

AU - Bickeböller, Heike

AU - Aldrich, Melinda C

AU - Bush, William S

AU - Tardon, Adonina

AU - Rennert, Gad

AU - Teare, M Dawn

AU - Field, John K

AU - Kiemeney, Lambertus A

AU - Lazarus, Philip

AU - Haugen, Aage

AU - Lam, Stephen

AU - Schabath, Matthew B

AU - Andrew, Angeline S

AU - Bertazzi, Pier Alberto

AU - Pesatori, Angela C

AU - Christiani, David C

AU - Caporaso, Neil

AU - Johansson, Mattias

AU - McKay, James D

AU - Brennan, Paul

AU - Hung, Rayjean J

AU - Amos, Christopher I

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.26678

DO - 10.18632/oncotarget.26678

M3 - Journal article

C2 - 30956756

VL - 10

SP - 1760

EP - 1774

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -