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- The Vitamin D Pooling Project: Examining Relationships to Cancer
- DCEG Scientist Appears in NCI Cancer Bulletin Video
- DCEG Gains Two Earl Stadtman Investigators
- Shahinaz Gadalla Receives Merit Award
- DCEG Welcomes Visiting Scholar Ross Prentice
- New Freezer Improves Efficiency and Storage Capacity of DCEG Biospecimen Repository
- DCEG Hosts Distinguished Lecturer David Christiani
- Report Published on DCEG's Research on the Marshall Islands
- Agricultural Health Study Team Members Receive Award
- Workshop on Male Breast Cancer Kicks Off Pooling Project
- Radiation Epidemiology Branch Investigators Present at Conference
- Workshop Tackles Hepatocellular Carcinoma in the Unites States
- Registry Database Studies Working Group
- DCEG Staff Contribute to the Society for Epidemiologic Research Meeting
- Upper Gastrointestinal Cancer Research Group
- NIH Recognizes 2011 FARE Winners
- DCEG Outstanding Research Papers of 2009
- 2010 DCEG Summer Fellows Recognition and Poster Event
- DCEG Investigators Participate in Papillomavirus Conference
- DCEG Staff Win Plain Language Awards
- DCEG Fellows Present at the 2010 NIH Spring Research Festival
- Scientific Highlights
- Major Editorials, Commentaries, and Reviews by DCEG Scientists
- DCEG People in the News
- Stephanie Weinstein Wins Merit Award
- Marianne Henderson Honored by International Repositories Society
- Comings … Goings
- DCEG Participates in Radiation and Health Conference
- Todd Gibson Defends Dissertation
- DCEG Staff Receive NIH Director's Awards
- Memorial Sloan-Kettering Cancer Center Honors Stephen Chanock
The Vitamin D Pooling Project: Examining Relationships to Cancer
Claims regarding the health benefits of vitamin D have increased recently and now include not only benefits for osteoporosis but also for cancer, cardiovascular disease, diabetes, multiple sclerosis, and rheumatoid arthritis. In the specific case of cancer, however, the evidence has been mixed:
- Laboratory-based research indicates tumor suppression by 1,25-dihydroxy-vitamin D3.
- Higher latitude, a surrogate measure for lower levels of ultraviolet B (UVB) solar radiation and lower vitamin D, correlates with higher rates for several cancers.
- Clinical and epidemiologic studies are inconclusive on the relationship between blood vitamin D levels and risks for common cancers, although protective effects on the risk of colorectal cancer and possibly of breast cancer have been suggested in several studies.
Despite the lack of definitive evidence, there have been widespread calls for high-dose vitamin D supplementation, intended to boost its circulating blood levels to various theoretical target thresholds.
NCI launched the Vitamin D Pooling Project (VDPP) in 2007 with the goal of providing reliable estimates of the relative risk of cancer that would fill the gaps in our knowledge of the associations between vitamin D levels and cancer. Through the use of the resources available in the NCI Cohort Consortium and under the leadership of Patricia Hartge, Sc.D., Deputy Director of the Epidemiology and Biostatistics Program, and Virginia Hartmuller, Ph.D., of NCI's Division of Cancer Control and Population Sciences (DCCPS), funding was allocated for measuring circulating 25-hydroxyvitamin D (25[OH]D) in prospectively collected and stored samples of plasma and serum from eight extramural cohorts supported by DCCPS and from two DCEG cohorts.
The VDPP's steering committee, chaired by Dr. Kathy Helzlsouer of Mercy Medical Center in Baltimore, Maryland, included representatives of the 10 participating cohorts, with support from Nonye Harvey, M.P.H. (DCCPS). Stephanie J. Weinstein, Ph.D., Nutritional Epidemiology Branch (NEB), with assistance from Demetrius Albanes, M.D. (NEB), directed the VDPP data coordinating center.
The VDPP made the strategic decision to examine associations between vitamin D and cancer at several less common sites, including cancers of the endometrium, kidney, ovary, pancreas, stomach, and esophagus, as well as non-Hodgkin lymphoma. Limited epidemiological data had suggested associations between these cancers and vitamin D levels, but associations at these sites could not be studied by individual cohorts with sufficient statistical power. The cohorts participating in the VDPP represented a range of geographic latitudes (see Figure 1), vitamin D intake and blood levels, various correlates of exposure, and racial/ethnic populations, enabling robust testing of the vitamin D hypothesis.
As expected when a large pooling effort is carried out across multiple cohorts, the VDPP investigators faced several challenges in data management and analysis, such as how to harmonize the incoming data that were specific to each cohort. Because the concentration of 25(OH)D in the blood may vary substantially by season of the year, when analyzing the data investigators took into consideration when the blood was collected by using techniques that included tight case-control matching on the date of the blood draw, creation of season-specific and season-standardized cutpoints, and stratification by season. In addition, because several clinical definitions are used to assess states of vitamin D “deficiency,” “sufficiency,” or “adequacy” based on blood levels, the VDPP defined overall pooled data-specific cutpoints to standardize these definitions.
The results from the VDPP were published in nine articles in the July 1, 2010, issue of the American Journal of Epidemiology (AJE), including an overview, a description of the project design and methods, findings on the correlates of circulating vitamin D, and six cancer site–specific reports. Investigators found that women and men with higher concentrations of circulating vitamin D did not experience reduced risk for any of the cancers examined during the follow-up periods for the cohorts. The analysis of pancreatic cancer, however, which was led by Rachael Stolzenberg-Solomon, Ph.D., M.P.H., R.D. (NEB), found a significantly elevated risk in a relatively small number of subjects with circulating 25(OH)D greater than 100 nmol/L, which represents approximately the 95th percentile of the U.S. population. These data have prompted concern that in efforts to raise vitamin D levels in the blood, dosages are being prescribed that might expose the population to an increased risk of pancreatic and possibly other tumors. In the aggregate, the observational findings from the VDPP, based on nearly 5,500 cancer cases and 6,700 controls, have provided no evidence of a protective role for higher vitamin D status in the relatively rare cancers that were studied, but they have pointed to a potential adverse effect for pancreatic cancer, which calls for further investigation.
In an accompanying AJE editorial, Mr. Tim Byers of the Colorado School of Public Health concluded that “…even though there was consistency in the overall null observations across most of the cohorts in this pooled analysis, there was some variation. It is easy to imagine that, without this collaborative analysis, we might have been led down several blind alleys derived from analyses of various subgroups and interactions. We all should be grateful to the Vitamin D Pooling Project of Rarer Cancers investigators for having saved us from years of false leads as well as for their vision and skill in carrying out this outstanding collaborative project.”
—Demetrius Albanes, M.D., and Stephanie J. Weinstein, Ph.D.
