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Serum 25-hydroxyvitamin D, dietary vitamin D and non-Hodgkin Lymphoma: a Nested Case Control Study in the PLCO Trial

Principal Investigator
Name
Mark Purdue
Degrees
-
Institution
NCI, DCEG, OEEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2005-0021
Initial CDAS Request Approval
Apr 21, 2006
Title
Serum 25-hydroxyvitamin D, dietary vitamin D and non-Hodgkin Lymphoma: a Nested Case Control Study in the PLCO Trial
Summary
There is emerging evidence suggesting that vitamin D may protect against NHL. This hypothesis is supported by epidemiologic findings describing a reduction in NHL risk and mortality with increasing levels of UV exposure and dietary vitamin D intake. Moreover, 1,25-dihydroxyvitamin D3, the active form of vitamin D, has been observed to inhibit proliferation and induce differentiation in lymphocytes and lymphoma cell lines. While these findings offer indirect evidence that vitamin D protects against NHL, no epidemiologic studies have directly evaluated this relationship. To address this question, we propose a nested case-control study (240 cases, 240 controls) to investigate the relationship between NHL and pre-diagnostic levels of 25-hydroxyvitamin D (25(OH)D), the major circulating metabolite of vitamin D and precursor to 1,25-dihydroxyvitamin D3, using T0 serum samples from the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. Levels of 25(OH)D will be measured by radioimmunoassay using 50uL of T0 serum at the laboratory of Dr. Bruce Hollis, Medical University of South Carolina. As well, we will investigate whether NHL is associated with dietary vitamin D intake, calculated from baseline food-frequency questionnaire data. Lastly, we will explore whether the effects of vitamin D differ across levels of other factors that influence vitamin D levels (body mass index) and activity (retinol intake). The association between 25(OH)D levels and case-control status will be estimated using odds ratios (OR) and 95% confidence intervals calculated from conditional logistic regression modeling. This study will have adequate power to detect main-effect associations of moderate size (e.g., above-median OR of 0.6 or less, upper-quartile OR of 0.5 or less). The proposed project has significant implications for improving our understanding of the etiology of NHL, a relatively common yet poorly understood cancer, and in expanding the scope of knowledge regarding the putative anti-cancer effects of vitamin D.Protein and antibody arrays have emerged as a promising technology to study protein expression and protein function in a high throughput manner. As a protein array pioneer company, RayBiotech, Inc. has developed many unique protein and antibody array technologies and products for the research community. These protein and antibody arrays present a new opportunity to profile protein expression levels in cancer patients' samples and identify useful biosignatures for drug development and patient care. Two of most important components in biomarker discovery program are high quality of patients' samples and high-content screening and high-throughput technologies. Therefore, the combination of proven antibody-based detection technology and platforms from RayBiotech and well-characterized samples from PLCO provides a unique and golden opportunity for biomarker discovery. Currently, most ovarian cancer patients are detected at late stages, when survival rates are much lower compared with those detected in early stage. Using our patent-pending antibody array technology, we have identified a new panel of biomarkers for early detection of ovarian cancer. In our preliminary study, 34 ovarian cancer patients and 53 age-matched healthy controls were screened with 174-marker cytokine antibody arrays. Using 3 discrinimant methods, including artificial neural network, classification tree and split point score analysis, a panel of 5 serum protein markers was identified, which can effectively detect ovarian cancer with high specificity (95%) and high sensitivity (100%), with AUC =0.98. Our next step is to validate our identified markers in larger high quality and unbiased samples. PLCO biospecimen is the ideal and essential source. Successful completion of this project may lead to identification novel ovarian cancer biomarkers for early detection. Our long term goal is to identify biomarkers for early detection and personalized medicine of ovarian cancer.
Aims

The primary aim of our proposal is to investigate the relationship between serum levels of 25(OH)D and risk of NHL. Vitamin D has been observed to have antineoplastic properties in in vitro studies of lymphoma and other cancers (1-3), and epidemiologic studies of NHL also indirectly support a protective effect of vitamin D (4,5) (Hartge P, Lim U, personal communication: 2005). Low serum 25(OH)D is considered to be the best indicator of vitamin D status; it represents an integrative measure of both dietary and cutaneous sources of vitamin D. We hypothesize that individuals with low levels of 25(OH)D are at increased risk of NHL. As a secondary aim, we will investigate the relationship between dietary vitamin D intake and NHL risk. A portion of vitamin D is obtained from dietary supplements and a limited number of foods (dairy products, fortified breakfast cereals, oily fish, egg yolk and liver). An estimate of vitamin D intake has been calculated from food-frequency questionnaire data collected at baseline in PLCO. The inclusion of analyses of dietary vitamin D intake, calculated from PLCO baseline food-frequency questionnaire data, will enable us to assess the robustness of the relationship between vitamin D and NHL. As another secondary aim, we will explore whether associations with 25(OH)D and dietary vitamin D intake differ across levels of body mass index and retinol intake. It is plausible that the effects of vitamin D may be modified by body mass index and retinol intake. Higher body mass index has been consistently associated with lower circulating levels of 25(OH)D, probably as a result of greater deposition in body fat (6). Retinol is suspected to antagonize vitamin D effects by binding with the retinoic X receptor, a protein integral to the induction of vitamin D responsive elements (7,8). We will explore the possible existence of such effect modification in our analysis. Epithelial ovarian cancer is the leading cause of death of gynecological cancers. The high mortality rate is due to the difficulty in early detection of ovarian cancer.Currently there is no effective diagnostic method to detect ovarian cancer patients at early stage. Thus, it is very urgent to identify novel biomarkers for early ovarian cancer diagnosis. Protein and antibody arrays, which can detect multiple biomarkers simultaneously with tiny amount of samples, show great promising in identification of novel biomarkers in early cancer detection. As a protein and antibody array pioneer company, we have developed many innovative platforms for biomarker discovery and validation. Our platform allows investigators to seamlessly move from the biomarker discovery phase to validation and clinical phase. From the initial screening phase, we expect to identify a panel of biomarkers which have power to distinguish normal subjects from those with cancer. Then quantitative arrays will be developed to detect the markers identified in the initial screen, and larger sample size will be tested using the quantitative arrays for validation. If the conclusions hold with respect to ovarian cancer patients, using well-designed cohort study, we will test in the serum samples from pre-diagnosed ovarian cancer patients to assess whether the assays have early diagnostic power. From our pilot study, we have profiled the protein expression levels of 174 serum biomarkers using our patent-pending sandwich-based antibody array platform and identified 5 potential ovarian cancer markers which can accurately distinguish cancer patients from healthy controls. In this proposal, our specific aim is to validate the identified 5-marker biomarker in larger number of samples using quantitative arrays. The quantitative arrays will be developed based upon these identified unique signature markers, 100 ovarian cancer patients and 200 age-matched healthy controls will be tested for validation.

Collaborators

Richard Hayes (NCI, DCEG)
Wen-Yi Huang (NCI, DCEG)
Mark Purdue (NCI, DCEG)
Qing Lan (NCI)
Nathaniel Rothman (NCI)
Ruo-Chun Huang (RayBiotech Inc)

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