An analysis of growth, differentiation and apoptosis genes with risk of renal cancer.
We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/12(CASP 1/5/4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10-1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04-1.53 and ATG: OR:1.55, 95% CI:1.14-2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value<0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk.
Dong
Linda M
LM
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America. donglm@mail.nih.gov
Brennan
Paul
P
Karami
Sara
S
Hung
Rayjean J
RJ
Menashe
Idan
I
Berndt
Sonja I
SI
Yeager
Meredith
M
Chanock
Stephen
S
Zaridze
David
D
Matveev
Vsevolod
V
Janout
Vladimir
V
Kollarova
Hellena
H
Bencko
Vladimir
V
Schwartz
Kendra
K
Davis
Faith
F
Navratilova
Marie
M
Szeszenia-Dabrowska
Neonila
N
Mates
Dana
D
Colt
Joanne S
JS
Holcatova
Ivana
I
Boffetta
Paolo
P
Rothman
Nathaniel
N
Chow
Wong-Ho
WH
Rosenberg
Philip S
PS
Moore
Lee E
LE
D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors