Simons Colinda C J M, Schouten Leo J, Godschalk Roger W L, van Schooten Frederik-Jan, Stoll Monika, Van Steen Kristel, van den Brandt Piet A, Weijenberg Matty P
Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
Department of Pharmacology and Toxicology, NUTRIM - School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
BioData Min. 2022 Jan 10;15(1):2. doi: 10.1186/s13040-021-00286-3.
The 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.
Cox 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.
Current 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.
mTOR-PI3K-Akt信号通路影响细胞代谢和（恶性）细胞生长。我们生成了性别特异性多基因风险评分，以捕捉该通路中10个排名靠前的基因中7个基因的自然变异。在荷兰队列研究（NLCS）（n = 120,852）中，我们直接研究了这些评分，并研究了它们与能量平衡相关因素（体重指数（BMI）、裤/裙尺寸、身高、身体活动和早年能量限制）的相互作用与结直肠癌（CRC）风险的关系。NLCS采用病例-队列设计，随访20.3年。参与者在1986年55 - 69岁时完成了一份关于饮食和癌症的基线问卷。约75%的队列返回了用于DNA分离和基因分型的趾甲剪（亚队列n = 3,793，病例n = 3,464）。为了生成评分，数据集被分成两部分，风险等位基因根据与另一半数据集中CRC风险的性别特异性关联来定义和加权，因为在之前全基因组关联研究中，排名靠前的基因中没有单核苷酸多态性（SNP）与CRC风险在p < 1×10的显著水平相关。
Cox回归分析显示，性别特异性多基因风险评分与男性和女性的结肠癌风险呈正相关，但与直肠癌风险无关，连续建模评分的风险比接近1.10。未观察到评分对能量平衡相关因素与CRC风险之间关联的修饰作用。然而，BMI（男性）、非职业性身体活动（女性）和身高（男性和女性）与CRC风险相关，特别是（近端和远端）结肠癌风险，在性别特异性多基因风险评分较低三分位数中的方向与预期一致。
目前的数据表明，mTOR-PI3K-Akt信号通路可能参与结肠癌的发生发展。本研究通过利用mTOR-PI3K-Akt信号通路中的基因变异，从而为结肠癌病因学提供了更多的见解。
