Personalized Prevention of Colorectal Cancer

结直肠癌的个性化预防

• 批准号: 8230802
• 负责人: QI DAI
• 金额: $ 40.29万
• 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/8230802
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: In the general US population, 1 in 18 individuals will develop colorectal cancer over their lifetime and forty percent will die within five years of diagnosis, mainly due to diagnosis at a late stage. Therefore, development of primary preventive strategies for colorectal cancer is very critical. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer through dietary changes or nutritional fortification.

描述（由申请人提供）：此申请的原始版本先前是作为R21申请提交的，并获得了184个分数。为了适当解决审阅者的建议，我们新提交此提案作为R01申请。但是，高钙摄入量和镁可能预防结直肠癌和腺瘤，但是结果不一致。尽管美国人口中的平均镁摄入量与传统上结直肠癌风险低的东亚人群相似，但在美国，钙与镁的比率更高。我们最近报道说，镁摄入量与腺瘤和增生息肉的风险显着降低有关。该关联主要出现在钙与镁摄入量较低的人群中。我们发现了钙摄入量相似的结果。 TRPM7基因与钙和镁（RE）吸收和稳态至关重要。我们发现，与腺瘤和增生息肉有关的常见THR1482IL TRPM7多态性与钙/镁的摄入率显着相互作用。与未携带多态性的参与者相比，携带至少一个1482ile等位基因并消耗高钙/镁比的饮食饮食的参与者具有更高的腺瘤和增生息肉风险。 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前列腺素E2代谢物（PGE-M）作为主要终点的镁和尿排泄。对凋亡的进行性抗性是几乎所有癌症类型的标志。凋亡指数是未来腺瘤发生的有力预测指标。对凋亡的耐药性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，前列腺素E2代谢产物（PGE-M）的尿液水平与结肠和直肠癌的风险大大增加有关。与没有小息肉的人相比，患有大腺瘤的参与者的尿液水平也升高。这项研究的主要目的是进行一项随机的安慰剂对照干预试验，以测试是否通过补充镁来降低钙至镁摄入量对上述生物标志物具有影响。此外，我们将研究调节钙与镁的饮食摄入率的影响是否在携带1482ile等位基因（GA或AA）的人中比不携带1482ile（GG）的人更为明显。如果该研究的结果有希望，我们将建议使用扁平，抑郁和多息肉结直肠腺瘤或结直肠癌作为临床终点进行大规模临床试验。我们研究的结果最终可能有助于制定个性化策略，以防止结直肠腺瘤的发生，从而导致结直肠癌。 公共卫生相关性：在美国普通人群中，一生中有1个人将在诊断后的五年内死亡，四十％将死亡，这主要是由于晚期诊断。因此，制定大肠癌的主要预防策略非常关键。我们研究的结果将有助于鉴定有结直肠腺瘤的高风险的人，并制定个性化策略，以防止发生结直肠腺瘤的发生，从而通过饮食上的改变或营养强化来确定结直肠癌。