Common genetic variants in the 9p21 region and their associations with multiple tumours.
BACKGROUND
The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers.


METHODS
We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction.


RESULTS
Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007).


CONCLUSIONS
Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA.
F
F
Gu
R M
RM
Pfeiffer
S
S
Bhattacharjee
S S
SS
Han
P R
PR
Taylor
S
S
Berndt
H
H
Yang
A J
AJ
Sigurdson
J
J
Toro
L
L
Mirabello
M H
MH
Greene
N D
ND
Freedman
C C
CC
Abnet
S M
SM
Dawsey
N
N
Hu
Y-L
YL
Qiao
T
T
Ding
A V
AV
Brenner
M
M
Garcia-Closas
R
R
Hayes
L A
LA
Brinton
J
J
Lissowska
N
N
Wentzensen
C
C
Kratz
L E
LE
Moore
R G
RG
Ziegler
W-H
WH
Chow
S A
SA
Savage
L
L
Burdette
M
M
Yeager
S J
SJ
Chanock
N
N
Chatterjee
M A
MA
Tucker
A M
AM
Goldstein
X R
XR
Yang
D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015201:Meta-Analysis as Topic; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
D014408:Biomarkers, Tumor; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16