Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR , PTEN , STK11 , RPKAA1 , PRKAG2 , TSC1 , TSC2 , PI3K and Akt1

Abstract

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.

Cancers of the Colon and Rectum: Identical or Fraternal Twins?

“…For example, BRAF mutations occur most commonly in serrated polyps, a specific subtype of colorectal cancer precursor that arises predominantly in the right-side colon (17). Although the link between rectal cancer and the STK11 mutation has not been studied in detail, single-nucleotide polymorphisms in STK11 have been associated with increased risk of developing the disease (18). By contrast, although SRC mutations have been reported in colorectal cancer, the distinct separation between colon cancer and rectal cancer has not been explored (19).…”

Genetic variants in the TGFβ-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue

“…Eukaryotic translation initiation factor 4E (eIF4E) is a translational regulator; expression of eIF4E in human colon cancer cells promotes the TGFβ stimulation of adhesion molecules [23]. Other genes, such as nuclear factor kappa B1 (NFκB1), mammalian target of rapamycin (mTOR), and phosphatase tensin homolog deleted on chromosome 10 (PTEN), are major regulators of inflammation, are associated with colorectal cancer, and influence the TGF-B signaling pathway [24–26]. …”

Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

“…Some arylidene derivatives have been shown previously to work on upstream pathways, such as the involvement of the Akt pathways ras and p53 [17, 28, 29]. It may be further noted that the involvement of various upstream and downstream nodal pathways is characteristic of the source of cancer models [30, 31]. For the first time, we have taken marginal hypoxia, which further mimics the tumor microenvironment into consideration to check its effect on an anti-cancer drug.…”