Personalized Prevention of Colorectal Cancer

描述（由申请人提供）：此申请的原始版本先前作为R21申请提交，并获得184分。为了恰当地处理审稿人的建议，我们将此提案作为R01申请重新提交。高钙和镁的摄入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东亚人群相似，而东亚人群患结肠直肠癌的风险传统上较低，但美国人钙镁的比例要高得多。我们最近报道了镁的摄入与显著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比例较低的人群中。我们在钙的摄入上也发现了类似的结果。TRPM7基因在钙和镁（re）的吸收和体内平衡中起关键作用。我们发现，在腺瘤性和增生性息肉中，常见的Thr1482Ile TRPM7多态性与钙/镁摄入比例显著相互作用。携带至少一个1482Ile等位基因且饮食钙镁比高的参与者患腺瘤和增生性息肉的风险高于不携带该多态性的参与者。我们拟开展一项240名参与者的干预试验，研究调节膳食钙镁比对改变与肿瘤发生直接相关的标志物的效果，包括结肠粘膜细胞凋亡生物标志物（如TUNEL和Bax）、COX-2（炎症）、Ki-67（增殖指数）和TRPM7/TRPM6，以及红细胞总镁和前列腺素E2代谢物（PGE-M）的尿排泄作为主要终点。对细胞凋亡的逐渐抵抗是几乎所有癌症类型的一个标志。细胞凋亡指数是预测未来腺瘤发生的重要指标。在肿瘤发生过程中，对细胞凋亡的抵抗伴随着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显著增加相关。与没有息肉或小息肉的受试者相比，大腺瘤患者尿中PGE- M水平也升高。本研究的主要目的是通过一项随机安慰剂对照干预试验来检验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等位基因（GG）的人群相比，调节饮食中钙镁摄入比例的影响是否更为明显。如果研究结果有希望，我们将建议开展一项大规模的临床试验，以复发的扁平型、抑郁型和息肉样结肠腺瘤或结直肠癌为临床终点。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。

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.