Personalized Prevention of Colorectal Cancer

结直肠癌的个性化预防

• 批准号: 8459022
• 负责人: QI DAI
• 金额: $ 45.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459022
• 关键词: Address; Alleles; Apoptosis; Asians; Biological; Biological Markers; C-reactive protein; Calcium; Cell Proliferation; Clinical; Clinical Trials; Cohort Studies; Colon Carcinoma; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Polyp; Consumption; Depressed mood; Development; Diagnosis; Diet; Dietary intake; Dinoprostone; Enrollment; Ensure; Erythrocytes; Evaluation; Excretory function; Food Interactions; Future; Genes; Genetic Polymorphism; Genotype; Grant; Homeostasis; Hyperplastic Polyp; In Situ Nick-End Labeling; Individual; Inflammation; Intake; Intervention Trial; Lead; Link; Magnesium; Mucous Membrane; Nutrient; Nutritional; PTGS2 gene; Participant; Patients; Placebo Control; Placebos; Plasma; Polyps; Population; Prevention strategy; Randomized; Recruitment Activity; Rectal Cancer; Recurrence; Reporting; Resistance; Risk; S-Phase Fraction; Sample Size; Serum magnesium level observed; Staging; Suggestion; Supplementation; Tennessee; Testing; Tumorigenicity; Variant; Vitamin D; absorption; adenoma; arm; base; calcium intake; cancer prevention; cancer type; carcinogenesis; clinically significant; colorectal cancer prevention; design; follow-up; fortification; high risk; improved; indexing; novel; nutrition related genetics; population based; prevent; prostaglandin M; public health relevance; response; screening; tumorigenesis; urinary

DESCRIPTION (provided by applicant): The original version of this application was previously submitted as a R21 application and received a score of 184. To appropriately address the reviewers' suggestions, we are newly submitting this proposal as a R01 application. High calcium intake and magnesium may protect against colorectal cancer and adenoma, however, results have been inconsistent. Although the mean magnesium intake in the US population is similar to East Asian populations with traditionally low risks of colorectal cancer, the ratio of calcium to magnesium is much higher in the US. We reported recently that magnesium intake is related to a significantly reduced risk of adenoma and hyperplasic polyps. This association primarily appeared among those with a low ratio of calcium to magnesium intakes. We have found similar results for calcium intake. The TRPM7 gene is critically involved in calcium and magnesium (re)absorption and homeostasis. We found that the common Thr1482Ile TRPM7 polymorphism significantly interacted with the calcium/magnesium intake ratio in relation to both adenomatous and hyperplasic polyps. Participants who carried at least one 1482Ile allele and who consumed diets with a high calcium/magnesium ratio were at a higher risk of adenoma and hyperplasic polyps than were participants who did not carry the polymorphism. We propose to conduct an intervention trial of 240 participants to investigate the efficacy of modulating the dietary ratio of calcium to magnesium to change markers directly related to tumorigenesis, including apoptosis biomarkers (e.g. TUNEL and Bax), COX-2 (inflammation), Ki-67 (proliferation index), and TRPM7/TRPM6 in colorectal mucosa as well as total erythrocyte magnesium and urinary excretion of prostaglandin E2 metabolite (PGE-M) as primary endpoints. The progressive resistance to apoptosis is one hallmark for almost all cancer types. The apoptosis index is a strong predictor of future adenoma occurrence. The resistance to apoptosis is accompanied by an elevation in COX-2 expression during tumorigenesis. We found in a population-based cohort study that urinary levels of prostaglandin E2 metabolite (PGE-M) were associated with a substantially increased risk of colon and rectal cancers. Urinary level of PGE- M was also elevated among participants with large adenomas compared to those who had either no or small polyps. The primary aims of this study are to conduct a randomized placebo-controlled intervention trial to test whether reducing the calcium to magnesium intake ratio through supplementation of magnesium has effects on the above-mentioned biomarkers. Furthermore, we will examine whether the effect of modulating dietary intake ratio of calcium to magnesium may be more pronounced among those who carry the 1482Ile allele (GA or AA) compared those who do not carry the 1482Ile (GG). If findings from the study are promising, we will propose to conduct a large-scale clinical trial using recurrence of flat, depressed, and polypoid colorectal adenomas or colorectal cancer as clinical endpoints. The results from our study may ultimately help to develop personalized strategies to prevent the occurrence of colorectal adenoma, and, thus, colorectal cancer.

描述（由申请人提供）：该申请的原始版本之前作为 R21 申请提交，得分为 184。为了适当解决审稿人的建议，我们重新将此提案作为 R01 申请提交。高钙和镁摄入量可以预防结直肠癌和腺瘤，但结果并不一致。尽管美国人口的平均镁摄入量与传统上结直肠癌风险较低的东亚人口相似，但美国的钙与镁的比例要高得多。我们最近报道称，镁摄入量与显着降低腺瘤和增生性息肉的风险有关。这种关联主要出现在钙镁摄入量较低的人群中。我们在钙摄入量方面也发现了类似的结果。 TRPM7 基因在钙和镁的（再）吸收和体内平衡中发挥着重要作用。我们发现常见的 Thr1482Ile TRPM7 多态性与腺瘤性息肉和增生性息肉的钙/镁摄入比例显着相互作用。携带至少一个 1482Ile 等位基因且食用高钙/镁比例饮食的参与者比不携带该多态性的参与者患腺瘤和增生性息肉的风险更高。我们建议对 240 名参与者进行一项干预试验，以研究调节钙镁膳食比例来改变与肿瘤发生直接相关的标志物的功效，包括细胞凋亡生物标志物（例如 TUNEL 和 Bax）、COX-2（炎症）、Ki- 67（增殖指数）、结直肠粘膜中的 TRPM7/TRPM6 以及红细胞总镁和前列腺素 E2 代谢物的尿排泄(PGE-M) 作为主要终点。对细胞凋亡的逐渐抵抗是几乎所有癌症类型的标志之一。细胞凋亡指数是未来腺瘤发生的有力预测因子。对细胞凋亡的抵抗伴随着肿瘤发生过程中 COX-2 表达的升高。我们在一项基于人群的队列研究中发现，尿中前列腺素 E2 代谢物 (PGE-M) 水平与结肠癌和直肠癌风险大幅增加相关。与没有或有小息肉的参与者相比，患有大腺瘤的参与者的尿液 PGE-M 水平也升高。本研究的主要目的是进行一项随机安慰剂对照干预试验，以测试通过补充镁来降低钙镁摄入比例是否对上述生物标志物有影响。此外，我们将研究在携带 1482Ile 等位基因（GA 或 AA）的人群中，与不携带 1482Ile（GG）的人群相比，调节钙镁膳食摄入比例的效果是否更为明显。如果研究结果有希望，我们将建议进行一项大规模临床试验，以扁平、凹陷和息肉状结直肠腺瘤或结直肠癌的复发作为临床终点。我们的研究结果可能最终有助于制定个性化策略来预防结直肠腺瘤的发生，从而预防结直肠癌。