Inherited variation in immune genes and pathways and glioblastoma risk.
To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.
Schwartzbaum
Judith A
JA
Division of Epidemiology, College of Public Health, Ohio State University, Columbus, OH 43210, USA. jschwartzbaum@cph.osu.edu
Xiao
Yuanyuan
Y
Liu
Yanhong
Y
Tsavachidis
Spyros
S
Berger
Mitchel S
MS
Bondy
Melissa L
ML
Chang
Jeffrey S
JS
Chang
Susan M
SM
Decker
Paul A
PA
Ding
Bo
B
Hepworth
Sarah J
SJ
Houlston
Richard S
RS
Hosking
Fay J
FJ
Jenkins
Robert B
RB
Kosel
Matthew L
ML
McCoy
Lucie S
LS
McKinney
Patricia A
PA
Muir
Kenneth
K
Patoka
Joe S
JS
Prados
Michael
M
Rice
Terri
T
Robertson
Lindsay B
LB
Schoemaker
Minouk J
MJ
Shete
Sanjay
S
Swerdlow
Anthony J
AJ
Wiemels
Joe L
JL
Wiencke
John K
JK
Yang
Ping
P
Wrensch
Margaret R
MR
D000328:Adult; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
D016207:Cytokines