Molecular and Population Genetics Laboratory University of Oxford, Oxford OX3 7BN, UK.
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Old Road Campus, Oxford OX3 7DQ, UK.
Br J Cancer. 2018 Mar 6;118(5):727-732. doi: 10.1038/bjc.2017.486. Epub 2018 Feb 13.
Colorectal cancer (CRC) screening might be improved by using a measure of prior risk to modulate screening intensity or the faecal immunochemical test threshold. Intermediate molecular biomarkers could aid risk prediction by capturing both known and unknown risk factors.
We sampled normal bowel mucosa from the proximal colon, distal colon and rectum of 317 individuals undergoing colonoscopy. We defined cases as having a personal history of colorectal polyp(s)/cancer, and controls as having no history of colorectal neoplasia. Molecular analyses were performed for: telomere length (TL); global methylation; and the expression of genes in molecular pathways associated with colorectal tumourigenesis. We also calculated a polygenic risk score (PRS) based on CRC susceptibility polymorphisms.
Bowel TL was significantly longer in cases than controls, but was not associated with blood TL. PRS was significantly and independently higher in cases. Hypermethylation showed a suggestive association with case:control status. No gene or pathway was differentially expressed between cases and controls. Gene expression often varied considerably between bowel locations.
PRS and bowel TL (but not blood TL) may be clinically-useful predictors of CRC risk. Sample collection to assess these biomarkers is feasible in clinical practice, especially where population screening uses flexible sigmoidoscopy or colonoscopy.
通过使用先前风险的衡量标准来调节筛查强度或粪便免疫化学检测阈值，可能会提高结直肠癌（CRC）的筛查效果。中间分子生物标志物可以通过捕捉已知和未知的风险因素来辅助风险预测。
我们从 317 名接受结肠镜检查的个体的近端结肠、远端结肠和直肠中采集了正常肠黏膜样本。我们将病例定义为有结直肠息肉/癌症的个人病史，将对照定义为无结直肠肿瘤病史。对端粒长度（TL）；整体甲基化；以及与结直肠肿瘤发生相关的分子途径中的基因表达进行了分子分析。我们还根据 CRC 易感性多态性计算了多基因风险评分（PRS）。
病例组的肠道 TL 明显长于对照组，但与血液 TL 无关。PRS 在病例中显著且独立升高。过度甲基化与病例：对照组状态呈显著相关。病例与对照组之间没有差异表达的基因或途径。基因表达在肠道位置之间经常差异很大。
PRS 和肠道 TL（而非血液 TL）可能是 CRC 风险的临床有用预测因子。评估这些生物标志物的样本采集在临床实践中是可行的，特别是在使用软性乙状结肠镜检查或结肠镜检查进行人群筛查的情况下。
