Personalized Prevention of Colorectal Cancer

描述(申请人提供)：本申请的原始版本之前是作为R21申请提交的，获得了184分。为了恰当地处理审查员的建议，我们新提交了这份提案作为R01申请。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。尽管美国人口的平均镁摄入量与东亚人口相似，东亚人口患结直肠癌的风险传统上很低，但美国人的钙镁比例要高得多。我们最近报道，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量比例较低的人群中。我们在钙摄入量方面也发现了类似的结果。TRPM7基因与钙和镁(Re)的吸收和动态平衡密切相关。我们发现，常见的Thr1482Ile TRPM7基因多态性与钙/镁摄入量比率显著相关，这与腺瘤性息肉和增生性息肉都有关系。携带至少一个1482Ile等位基因的参与者和食用高钙/镁比饮食的参与者患腺瘤和增生性息肉的风险比不携带该基因的参与者更高。我们建议对240名参与者进行干预试验，以研究调节膳食钙镁比例对改变与肿瘤发生直接相关的标记物的效果，包括大肠粘膜中的凋亡生物标记物(如TUNEL和Bax)、COX-2(炎症)、Ki-67(增殖指数)和TRPM7/TRPM6，以及作为主要终点的红细胞总镁和尿前列腺素E_2代谢物(PGE-M)。对细胞凋亡的渐进性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有力指标。在肿瘤发生过程中，伴随着细胞凋亡抵抗的是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)的水平与结肠癌和直肠癌的风险显著增加有关。与无息肉或小息肉的参与者相比，患有大腺瘤的参与者的尿前列腺素E-M水平也升高。本研究的主要目的是进行一项随机的安慰剂对照干预试验，以测试通过补充镁来降低钙镁摄入量比是否对上述生物标志物产生影响。此外，我们还将研究，在携带1482Ile等位基因(GA或AA)的人群中，调节饮食中钙镁摄入量比例的效果是否会比那些没有携带1482Ile等位基因(GG)的人群更明显。如果研究结果有希望，我们将建议进行一项大规模的临床试验，将扁平、凹陷和息肉样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开发个性化的策略来预防结直肠腺瘤的发生，从而预防结直肠癌的发生。 公共卫生相关性：在普通美国人中，每18个人中就有一个人会在一生中患上结直肠癌，40%的人将在确诊后五年内死亡，主要是由于在晚期确诊。因此，发展结直肠癌的初级预防策略是非常关键的。我们的研究结果将有助于识别结直肠腺瘤的高危人群，并制定个性化的策略，通过改变饮食或营养强化来预防结直肠腺瘤的发生，从而预防结直肠癌的发生。

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.