Personalized Prevention of Colorectal Cancer

Summary

Principal Investigator: Chang Yu
Abstract: 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.
Funding Period: 2010-04-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer
    Qi Dai
    Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS ONE 6:e18237. 2011
  2. pmc Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III
    Xinqing Deng
    Department of Medicine, Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    BMC Med 11:187. 2013

Detail Information

Publications4

  1. pmc Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer
    Qi Dai
    Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS ONE 6:e18237. 2011
    ..We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk...
  2. pmc Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III
    Xinqing Deng
    Department of Medicine, Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    BMC Med 11:187. 2013
    ....

Research Grants30

  1. Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women
    Joan Lappe; Fiscal Year: 2013
    ..Positive findings will provide support for health policy changes to promote optimal vitamin D levels in the population. ..
  2. Effect of Vitamin D and Omega-3 Fatty Acids on Blood Pressure and Hypertension
    Howard D Sesso; Fiscal Year: 2013
    ..Because high blood pressure is responsible for one out of every six deaths in the United States, the results of this study could possibly improve the health of many people. ..
  3. Colorectal Chemoprevention with Calcium and Vitamin D
    JOHN ANTHONY BARON; Fiscal Year: 2013
    ....
  4. Colorectal Cancer Prevention Through Thyroid Hormone Targets
    ADAM ROBERT BROWN; Fiscal Year: 2013
    ..The successful completion of the study will provide insight into potential age-dependent targets that may lead to the development of new therapies to prevent or treat age-related colorectal cancer. ..
  5. Mechanisms of tumor suppressor gene reactivation in colon cancer by berries
    Li Shu Wang; Fiscal Year: 2013
    ..We now propose to evaluate the anthocyanins in berries for their ability to demethylate and reactivate tumor suppressor genes in colon cancer. ..