Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology.
BACKGROUND
Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas.


METHODS
We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele.


RESULTS
The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele.


CONCLUSIONS
A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94107, USA. terri.rice@ucsf.edu
Terri
T
Rice
Shichun
S
Zheng
Paul A
PA
Decker
Kyle M
KM
Walsh
Paige
P
Bracci
Yuanyuan
Y
Xiao
Lucie S
LS
McCoy
Ivan
I
Smirnov
Joseph S
JS
Patoka
Helen M
HM
Hansen
George
G
Hsuang
Joe L
JL
Wiemels
Tarik
T
Tihan
Alexander R
AR
Pico
Michael D
MD
Prados
Susan M
SM
Chang
Mitchel S
MS
Berger
Alissa
A
Caron
Stephanie
S
Fink
Thomas
T
Kollmeyer
Amanda
A
Rynearson
Jesse
J
Voss
Matthew L
ML
Kosel
Brooke L
BL
Fridley
Daniel H
DH
Lachance
Jeanette E
JE
Eckel-Passow
Hugues
H
Sicotte
Brian Patrick
BP
O'Neill
Caterina
C
Giannini
John K
JK
Wiencke
Robert B
RB
Jenkins
Margaret R
MR
Wrensch
D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis
D014408:Biomarkers, Tumor; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human