Personalized Prevention of Colorectal Cancer

描述（由申请人提供）：本申请的原始版本先前作为R21申请提交，并获得184分。为了适当地解决评审人员的建议，我们新将该提案作为R 01申请提交。高钙摄入和镁可以预防结直肠癌和腺瘤，然而，结果并不一致。尽管美国人群的平均镁摄入量与传统上结直肠癌风险较低的东亚人群相似，但美国的钙镁比例要高得多。我们最近报道，镁的摄入量与腺瘤和增生性息肉的风险显著降低有关。这种关联主要出现在钙镁摄入比例低的人群中。我们发现钙摄入量也有类似的结果。TRPM 7基因与钙和镁的（再）吸收和体内平衡密切相关。我们发现，常见的Thr 1482 Ile TRPM 7多态性与腺瘤性和增生性息肉的钙/镁摄入比例显着相互作用。携带至少一个1482 Ile等位基因和高钙/镁比饮食的参与者比不携带该多态性的参与者有更高的腺瘤和增生性息肉风险。我们建议对240名参与者进行干预试验，以调查调节膳食钙镁比例以改变与肿瘤发生直接相关的标志物（包括凋亡标志物）的疗效（如TUNEL和Bax）、考克斯-2（炎症），Ki-67（增殖指数），和TRPM 7/TRPM 6以及总红细胞镁和前列腺素E2代谢产物（PGE-M）的尿排泄作为主要终点。对细胞凋亡的进行性抗性是几乎所有癌症类型的一个标志。细胞凋亡指数是未来腺瘤发生的强有力预测指标。在肿瘤发生过程中，对凋亡的抵抗伴随着考克斯-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显著增加相关。与没有息肉或有小息肉的参与者相比，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产生影响。此外，我们还将研究与不携带1482 Ile（GG）的人相比，在携带1482 Ile等位基因（GA或AA）的人中，调节膳食钙镁摄入比例的效果是否更明显。如果这项研究的结果是有希望的，我们将建议进行一项大规模的临床试验，使用复发的扁平，凹陷，息肉样结直肠腺瘤或结直肠癌作为临床终点。我们的研究结果可能最终有助于制定个性化的策略来预防结直肠腺瘤的发生，从而预防结直肠癌。 公共卫生相关性：在一般美国人群中，每18个人中就有1人会在其一生中患上结直肠癌，40%的人会在诊断后5年内死亡，主要是由于晚期诊断。因此，制定结直肠癌的一级预防策略至关重要。我们的研究结果将有助于识别结直肠腺瘤的高风险人群，并制定个性化的策略来预防结直肠腺瘤的发生，从而通过饮食改变或营养强化来预防结直肠癌。

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.