One-Carbon Nutrient Supplements May Boost Risk of Type II Endometrial Cancer

New data suggest that, contrary to expectation, the use of supplements containing one-carbon nutrients like folate and vitamins B2, B6, and B12 appears to be associated with an increased risk of type II endometrial cancer. The investigators said that they had believed that one-carbon nutrients would actually protect against type II endometrial cancer.

Stefano Uccella, MD, with the Mayo Clinic in Rochester, Minnesota, and colleagues estimated the relative risks of type I and II endometrial cancers in 23,356 postmenopausal women according to their intake of one-carbon nutrients. In the United States, endometrial cancer is the most common malignancy of the female reproductive tract. Several risk factors for this cancer have been identified, including obesity, unopposed estrogen, and diabetes. They do not, however, fully explain endometrial cancer risk.

Type I and II endometrial cancer are biologically and clinically distinct. Type II endometrial cancer is frequently associated with p53 mutations, which frequently promote DNA derangement and chromosomal instability. For this reason, the researchers hypothesized that a low intake of nutrients in the one-carbon metabolism pathway (such as folate, methionine, and the enzyme cofactors vitamins B2, B6, and B12), which mediate chromosomal instability and DNA methylation, may protect against type II but not type I endometrial cancer.

In their analysis, the investigators controlled for several risk factors for endometrial cancer, including body mass index, estrogen use, smoking, and alcohol use. Results showed no associations between dietary or supplemental intake of any one-carbon nutrients with type I endometrial cancer.

Contrary to their initial hypothesis, however, positive associations for type II cancer were due to supplemental, rather than dietary, intake of these nutrients: supplemental folate (RR = 1.80 for >228.6 vs 0 μg/day; P trend = .027) and vitamins B2 (RR = 1.94 for >1.70 vs 0 mg/day; P trend = .011), B6 (RR = 2.08 for >2.00 vs 0 mg/day; P trend = .012), and B12 (RR = 2.10 for >3.43 vs 0 μg/day; P trend = .0060).

Uccella and associates said that their finding of an association that is specific for folic acid supplementation and type II endometrial cancer but not type I endometrial cancer may reflect the different characteristics of these two tumor subtypes. They also maintain that their data underscore the need for more rigorous scrutiny of potential negative health consequences of vitamin supplements.

“While mandatory folate fortification of enriched grain products at the population level has led to a decline in the incidence of neural tube defects, this and other recent studies raise concerns about potential negative health effects of excess folic acid and thus need to be fully evaluated,” reported Uccella and colleagues.

Finally, the team cited multiple study strengths, including a prospective cohort design with a well-defined population, the identification of cancer cases using a Surveillance, Epidemiology, and End Results (SEER) cancer database, and minimal loss to follow-up. In addition, dietary assessment was comprehensive and was determined to be “valid and reliable.”

Potential drawbacks include a lack of information on the basal folate status of the women and routine updates of their diet during follow-up. In addition, study participants were older women from the upper Midwest, which makes it difficult to extrapolate the results to other populations.

Uccella S, Mariani A, Wang AH, et al. Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study. Ann Oncol. 2011 Feb 15. doi: 10.1093/annonc/ mdq724. [Epub ahead of print]