Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1.
Serine/threonine protein kinase 11 (STK11) and phosphatase tensin homolog deleted on chromosome 10 (PTEN) link insulin sensitivity and metabolic signaling to inflammation and other hormonal factors and colorectal cancer. We evaluate genetic variation in nine genes in a candidate pathway as follows: STK11 (3 tagSNPs), PTEN (9 tagSNPs), FRAP1 (mTOR) (4 tagSNPs), TSC1 (14 tagSNPs), TSC2 (8 tagSNPs), Akt1 (2 tagSNPs), PIK3CA (7 tagSNPs), PRKAA1 (13 tagSNPs) and PRKAG2 (68 tagSNPs) in two population-based case-control studies of colon (n = 1574 cases, 1940 controls) and rectal (n = 91 cases, 999 controls) cancer. FRAP1, PRKAA1, PRKAG2 and TSC2 genes were significantly associated with colon cancer; risk estimates ranged from 1.21 [95% confidence interval (CI) 1.05-1.38] for FRAP1rs1057079 for the AG/GG genotype to 1.51 (95% CI 1.09-2.09) for PRKAG2rs9648723 CC genotype. PIK3CA, PRKAG2, PTEN, STK11 and TSC1 were significantly associated with rectal cancer overall. The strongest association was observed for PIK3CA rs7651265 GG genotype (odds ratio 2.32 95% CI 1.02-5.30). FRAP1 was associated with microsatellite instability (MSI)+ colon tumors; PRKAA1, CpG island methylator phenotype (CIMP)+ and MSI+ colon tumors; PRKAG2 and KRAS2 colon tumors; TSC1 and CIMP+ and MSI+ colon tumors; TSC2 with MSI+ colon tumors; PIK3CA with KRAS2-mutated rectal tumors; PRKAG2 (rs6964824) with KRAS2- and TP53-mutated rectal tumors and with PRKAG2 (rs412396 and rs4725431) with CIMP+ rectal tumors. These data suggest that genetic variation in a predefined candidate pathway for colorectal cancer contributes to both colon and rectal cancer risk. Associations appear to be strongest for CIMP+ and MSI+ tumors.
Slattery
Martha L
ML
Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA. marty.slattery@hsc.utah.edu
Herrick
Jennifer S
JS
Lundgreen
Abbie
A
Fitzpatrick
Francis A
FA
Curtin
Karen
K
Wolff
Roger K
RK
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human; C526223:PRKAG2 protein, human; C109790:STK11 protein, human; C494929:PTEN protein, human