Abstract
BackgroundThe mTOR-PI3K-Akt pathway influences cell metabolism and (malignant) cell growth. We generated sex-specific polygenic risk scores capturing natural variation in 7 out of 10 top-ranked genes in this pathway. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n=120,852). The NLCS has a case-cohort design and 20.3 years of follow-up. Participants completed a baseline questionnaire on diet and cancer in 1986 when 55–69 years old. ~75% of the cohort returned toenail clippings used for DNA isolation and genotyping (n subcohort=3,793, n cases=3,464). To generate the scores, the dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p<1*10−5.ResultsCox regression analyses showed positive associations between the sex-specific polygenic risk scores and colon but not rectal cancer risk in men and women, with hazard ratios for continuously modeled scores close to 1.10. There was no modifying effect observed of the scores on associations between the energy balance-related factors and CRC risk. However, BMI (in men), non-occupational physical activity (in women), and height (in men and women) were associated with the risk of CRC, in particular (proximal and distal) colon cancer, in the direction as expected in the lower tertiles of the sex-specific polygenic risk scores.ConclusionsCurrent data suggest that the mTOR-PI3K-Akt pathway may be involved in colon cancer development. This study thereby sheds more light on colon cancer etiology through use of genetic variation in the mTOR-PI3K-Akt pathway.
Highlights
Altered cell metabolism is considered a cancer hallmark associated with malignant cell growth. [1] Cell metabolism is influenced by the mammalian target of rapamycin-phosphatidylinositide 3-kinases (PI3K)-Akt pathway, which could influence cancer development
Genetic variation in the mammalian target of rapamycin (mTOR)-PI3K-Akt pathway, which captures natural variation in the mTOR-PI3K-Akt pathway in the population, has been associated with cancer risk across organ sites. [3,4,5,6,7,8,9,10,11,12] Differences in associations between cancers may exist as, for example, MTOR rs2295080, a promotor variant associated with transcription [10] and mRNA expression [5] was oppositely associated with leukemia risk than with risk of other cancers. [7, 12, 13] To our knowledge, only one study investigated a potential interaction between MTOR rs2295080 and other variants in the mTOR-PI3K-Akt pathway and a diet risk score, showing evidence of interaction. [14]
The associations observed between the sex-specific polygenic risk scores and the risk of colorectal cancer (CRC) overall, colon cancer risk, suggest that the mTOR-PI3K-Akt pathway is involved in colon cancer development in both men and women
Summary
Altered cell metabolism is considered a cancer hallmark associated with malignant cell growth. [1] Cell metabolism is influenced by the mammalian target of rapamycin (mTOR)-phosphatidylinositide 3-kinases (PI3K)-Akt pathway, which could influence cancer development. Our aim was to extend on the existing evidence by studying mTOR-PI3K-Akt pathway genetic variation in relation to CRC risk and by investigating potential effect modification of mTOR-PI3K-Akt pathway genetic variation on associations between energy balancerelated factors (body mass index, trouser/skirt size, height, physical activity, and early life energy restriction) and CRC risk in the large, prospective Netherlands Cohort Study. A higher body mass index, tallness, and a lack of physical activity are established CRC risk factors [15] which are thought to be associated with a positive energy balance and increased mTOR-PI3K-Akt signaling, stimulating malignant growth. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n= 120,852). The dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p
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