Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach.
BACKGROUND
Insulin-like growth factor-1 (IGF1) has been proposed to mediate the obesity-related carcinogenic effects of "Western lifestyle". While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesised to underlie the variation in cancer incidence rates remain ill-defined.


METHODS
We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernising population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study.


RESULTS
We identified a common (minor allele frequency = 0.36) single-nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40% decrease in risk in comparison to genotype CC (odds ratio, 0.59; 95% confidence interval, 0.45 to 0.77). This association was stronger for colon cancer than for rectal cancer (p(heterogeneity)<0.001) and for those who were physically active versus inactive (p(interaction) = 0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk.


CONCLUSIONS
Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer.
Wong
H-L
HL
Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, DDHS, Rockville, Maryland, USA.
Koh
W-P
WP
Probst-Hensch
N M
NM
Van den Berg
D
D
Yu
M C
MC
Ingles
S A
SA
D000368:Aged; D015992:Body Mass Index; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics*; D017124:Conserved Sequence; D015987:Effect Modifier, Epidemiologic; D004734:Energy Metabolism; D019143:Evolution, Molecular; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008019:Life Style; D008297:Male; D008498:Medical Record Linkage; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I