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Epidemiologic and other evidence suggests that vitamin D may be protective against several chronic diseases. Assessing vitamin D status in epidemiologic studies, however, is challenging given finite resources and limitations of commonly used approaches. Using multivariable linear regression, we derived predicted 25-hydroxyvitamin D [25(OH)D] scores based on known determinants of circulating 25(OH)D, including age, race, ultraviolet-B radiation flux at residence, dietary and supplementary vitamin D intakes, body mass index, physical activity, alcohol intake, postmenopausal hormone use (women only), and season of blood draw, in three nationwide cohorts: the Nurses' Health Study (NHS), NHSII, and the Health Professionals Follow-up Study. The model r2 for each cohort ranged from 0.25 to 0.33. We validated the prediction models in independent samples of participants from these studies. Mean measured 25(OH)D levels rose with increasing decile of predicted 25(OH)D score, such that differences in mean measured 25(OH)D between extreme deciles of predicted 25(OH)D were 8.7–12.3 ng/mL. Substituting predicted 25(OH)D scores for measured 25(OH)D in a previously published case-control analysis of colorectal cancer yielded similar effect estimates with odds ratios of approximately 0.8 for a 10-ng/mL difference in either plasma or predicted 25(OH)D. We conclude that these data provide reasonable evidence that a predicted 25(OH)D score is an acceptable marker for ranking individuals by long-term vitamin D status and may be particularly useful in research settings where biomarkers are not available for a majority of a study population.

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10−14), 18q21.33 (BCL2, P = 7.76 × 10−11), 11p15.5 (C11orf21, P = 2.15 × 10−10), 4q25 (LEF1, P = 4.24 × 10−10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10−9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10−8), 18q21.32 (PMAIP1, P = 2.51 × 10−8), 15q15.1 (BMF, P = 2.71 × 10−10) and 2p22.2 (QPCT, P = 1.68 × 10−8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10−18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10−8) and 5p15.33 (TERT, P = 1.92 × 10−7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism

Low vitamin D status is common globally and is associated with multiple disease outcomes. Understanding the correlates of vitamin D status will help guide clinical practice, research, and interpretation of studies. Correlates of circulating 25-hydroxyvitamin D (25(OH)D) concentrations measured in a single laboratory were examined in 4,723 cancer-free men and women from 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, which covers a worldwide geographic area. Demographic and lifestyle characteristics were examined in relation to 25(OH)D using stepwise linear regression and polytomous logistic regression. The prevalence of 25(OH)D concentrations less than 25 nmol/L ranged from 3% to 36% across cohorts, and the prevalence of 25(OH)D concentrations less than 50 nmol/L ranged from 29% to 82%. Seasonal differences in circulating 25(OH)D were most marked among whites from northern latitudes. Statistically significant positive correlates of 25(OH)D included male sex, summer blood draw, vigorous physical activity, vitamin D intake, fish intake, multivitamin use, and calcium supplement use. Significant inverse correlates were body mass index, winter and spring blood draw, history of diabetes, sedentary behavior, smoking, and black race/ethnicity. Correlates varied somewhat within season, race/ethnicity, and sex. These findings help identify persons at risk for low vitamin D status for both clinical and research purposes.

IntroductionUnderstanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models.MethodsData were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (<55, 55–64, and ≥65 years).ResultsMD was positively associated with risk of invasive tumors across all ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55–64 and ≥65 years (Page-interaction = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P’s < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55–64 and ≥65 years (Page-interaction = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group.ConclusionMD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.

Key PointsQuestionWhat is the association between body mass index and risk for breast cancer diagnosed before menopause?FindingIn this large pooled analysis of data on 758 592 premenopausal women, an inverse association of breast cancer risk with body mass index at 18 through 54 years of age was found, most strongly for body mass index at ages 18 through 24 years. The inverse association was strongest for hormone receptor–positive breast cancer, was evident across the entire distribution of body mass index, and did not materially vary by attained age or other characteristics of women.MeaningIncreased adiposity, in particular during early adulthood, may be associated with reductions in the risk of premenopausal breast cancer.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P=2.33×10 −21 ), rs2523607 at 6p21.33 (HLA-B; 2.40×10 −10 ), rs79480871 at 2p23.3 (NCOA1; P=4.23×10 −8 ), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P=9.98×10 −13 and P=3.63×10 −11 , respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL) 1 , has an aggressive clinical course 2 . The risk of DLBCL is increased in individuals with a family history of NHL (odds ratio (OR)=1.4; 95%CI 1.1-2.0) 3 , supporting a genetic contribution. Also, relatives of DLBCL patients are at elevated risk for both DLBCL (RR=9.8, and Hodgkin lymphoma (HL, RR=2.0, 95%CI 1.05-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to: James R. Cerhan, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905, Phone: 507.538.0499, Fax: 507.226.2478, cerhan.james@mayo.edu. 94 These authors contributed equally to this work. 95 These authors jointly directed this work. AUTHORS CONTRIBUTIONSJ.R.C., S.I.B., S.S.W., A.N., A.R.B.-W., Q.L., G. Severi, M. Melbye, L.R.T., M.P.P., C.L., B.M.B., S.L.S., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. organized and designed the study. J.R.C., L.C., L.B., A.H., P.M.B., E.A.H., S.L.S., G. Salles, C.F.S., N.R. and S.J.C. conducted and supervised the genotyping of samples. J.R.C., S.I.B., V.J., Z.W., M.Y., L.C., P.I.W.d.B., D.C., J.G., D. Zhi, Y.W.A., J.H., B.M., J.S., L.L., J.P., C.C.C., N.C., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. contributed to the design and execution of statistical analysis. J.R.C., S.I.B., V.J., H.G., J.M., S.S.W., Z.W., M.Y., L.C., A.N., D.C., A.M., C.R.F., A.J.D.R., C.L., K.E.S., C.F.S., N.R. and S.J.C. wrote the first draft of the manuscript. J.R.C., V.J., H.G., J.M., S.S.W., L.C., A.N., L.B., A.M., A.R.B.-W., Q.L., G. Severi, M. Melbye, J.G., R.D.J., E.K., L.R.T., M.P.P., C.M.V., J.J.S., G.G.G., D.A., R.S.K., M.Z., K.A.B., A.Z.-J., T.M.H., B.K.L., A.J.N., A.D., Y.W.A., M.L., C.A.T., S.M.A., T.E.W., G.J.W., A.S.V., D. Zelenika, H.T., C.H., T.J.M., H.H., B.G., H.-O.A., P.M.B., J.R., M.T.S., E.A.H., W.C., P.H., L.M.M., R.K.S., L.F.T., K.E.N., N.B., Y...

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.