Researchers at the Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine in Nashville, Tennessee, have identified a potential explanation for inconsistent results from prior studies about the association between calcium intake and risk for colorectal adenomas, which are precursors to colorectal cancers.

The findings were presented at the Annual Meeting of the American Association for Cancer Research(AACR), held in Washington, D.C., April 6-10, 2013 and may, according to the researchers, help identify patients who would benefit from higher calcium intake or calcium supplementation.

Reduction in risk
Over the last decades, calcium supplementation has been associated with reduction in the risk of recurrent colorectal adenomas. A report published in JNCI, Journal of the National Cancer Institute (2002) by Wu and Willet examined the association between calcium intake and colon cancer risk in two prospective cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Their study included 87,998 women in NHS and 47,344 men in HPFS. The result from their study showed that the observed risk pattern was consistent with a threshold effect which suggested that calcium intake beyond moderate levels was not associated with a further risk reduction.

A New study
Recent data from the Women?s Health Initiative did also not support the benefit for colorectal cancer after seven years of follow-up, according to Xiangzhu Zhu, M.D., M.P.H., staff scientist in the Division of Epidemiology in the Department of Medicine at Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine in Nashville, Tennessee.

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The two-phase study conducted by Zhu and colleagues investigated whether the associations between risk for colorectal adenoma and intake of calcium and magnesium, as well as the calcium/magnesium ratio, were modified by common changes in 14 genes involved in controlling the amounts of calcium and magnesium in the body.

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The researchers evaluated 1,818 cases and 3,992 controls from the Tennessee Colorectal Polyp Study, a colonoscopy-based case-control study conducted in Nashville. Patients with the highest calcium intake showed no reduction in their risk for colorectal adenoma if they had no changes in either of two of the 14 genes analyzed, the KCNJ1 and SLC12A1 genes, both of which were identified and replicated in the two-phase study and are essential in calcium reabsorption in the kidney.

Highest calcium intake
Fifty-two percent of the study population carried genetic changes in at least one of the two genes, and 13% of the population carried genetic changes in both genes. The highest calcium intake ? patients in the top 33% ? was significantly related to a 39% reduction in adenoma risk for patients who carried a genetic change in one gene and a 69% reduction in adenoma risk among those who carried genetic changes in both genes, according to Zhu. In addition, the corresponding reduction in risk for advanced or multiple adenomas was 89% among those with genetic changes in both genes.

According to Zhu, based on these data, a person with genetic changes in any of the two genes will see an increased risk for adenoma if they consume less than about 1,000 mg of calcium a day, especially if they carry genetic changes in both genes. The risk will increase by more than 50% for an adenoma and by 120% for advanced or multiple adenomas. ?These patients should increase their calcium intake to reduce the risks,? Zhu explained.

As possible explanation
?Our results may provide one possible explanation for the inconsistency in previous studies on calcium intake and colorectal abnormalities because calcium may primarily prevent colorectal cancer in the early stage and reduce risk only among those with genetic changes in calcium reabsorption, which involves KCNJ1 and SLC12A1,?[3] Zhu noted. ?If confirmed in future studies, our findings will be critical for the development of new personalized prevention strategies for colorectal cancer.?

The study was funded by National Institutes of Health (National Center for Complementary and Alternative Medicine/Office of Dietary Supplements) Grant Number 5R01AT004660-04 (PI: Qi Dai). The project was conducted using resources collected from the Tennessee Colorectal Polyp Study, a project of the Vanderbilt Gastrointestinal Cancer Specialized Program of Research Excellence.

For more information:
[1] Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL, Calcium Intake and Risk of Colon Cancer in Women and Men. JNCI J Natl Cancer Inst (2002) 94 (6): 437-446. doi: 10.1093/jnci/94.6.437
[2] TennesseeColorectal Polyp Study
[3]SLC12A1solute carrier family 12 (sodium/potassium/chloride transporters), member 1 [Homo sapiens(human) ]

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