Unhee Lim

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (>/= 35) kg/m(2)) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial.

Higher intakes of calcium and dairy products, a major source of dietary calcium, are reported to increase the risk of prostate cancer, potentially due to reductions in circulating vitamin D with increasing calcium intake. We prospectively examined the association of dairy product and calcium intake with prostate cancer risk in 29,509 men, including 1,910 cases, in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We also evaluated the relation of calcium intake with serum 25-hydroxy-vitamin D [25(OH)D] and 1,25-dihydroxy-vitamin D [1,25(OH)2D], in a Prostate, Lung, Colorectal, and Ovarian Trial substudy (n = 275). Dietary intake was assessed using a food frequency questionnaire. Baseline serum 1,25(OH)2D was determined by RIA. Greater intake of dairy products, particularly low-fat dairy products, was weakly associated with increased risk of prostate cancer [relative risk (RR), 1.12; 95% confidence intervals (CI), 0.97-1.30; P trend = 0.06 for >2.75 versus ≤0.98 servings of total dairy/day; 1.23 (1.07-1.41) for low-fat dairy]. Greater dietary calcium intake was associated with increased risk of prostate cancer (RR, 1.34; 95% CI, 0.93-1.94; P trend = 0.02 for >2,000 versus <1,000 mg/day), but greater supplementary calcium intake was not associated with the risk. Associations of dairy product and dietary calcium intake were evident for nonaggressive disease (RR, 1.20; 95% CI, 0.99-1.46; P trend = 0.01 for dairy products; 1.64, 1.04-2.57; P trend = 0.002 for dietary calcium), but not aggressive disease (RR, 1.02; 95% CI, 0.81-1.28 for dairy products; 0.94, 0.49-1.80 for dietary calcium). Calcium intake was not associated with serum 25-hydroxy-vitamin D and 1,25(OH)2D concentration. In this large prospective study in a prostate cancer screening trial, greater dietary intake of calcium and dairy products, particularly low-fat types, may be modestly associated with increased risks for nonaggressive prostate cancer, but was unrelated to aggressive disease. Furthermore, we found no relationship between calcium intake and circulating vitamin D. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2623–30)

Genomic Methylation of Leukocyte DNA in Relation to Colorectal Adenoma Among Asymptomatic Women

BACKGROUND & AIMS Systemic inhibition of DNA methylation causes cancers in animals, in part by inducing genetic instability. Epidemiologic evidence linking low genomic methylation in systemic blood DNA to carcinogenesis is limited, however, specifically to the colorectum, in which genetic instability is a primary etiologic factor. We examined genomic methylation of leukocyte DNA in relation to colorectal adenoma (CRA) among asymptomatic women (40-79 years of age) participating in a multicenter colonoscopy screening study (CONCeRN Study, 2000-2002). METHODS Of all participants who completed self-administered risk factor and food frequency questionnaires, peripheral blood donation, and colonoscopy, 115 pairs of CRA cases and controls with matching age and month of blood draw were studied. Genomic methylation of leukocyte DNA was determined by liquid chromatography mass spectrometry. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS Compared with women in the lowest tertile of genomic methylation, women in the second (OR, 0.72; 95% CI: 0.34-1.52) and third tertiles (OR, 0.17; 95% CI: 0.06-0.49) had lower risk of CRA (P trend = .002). The inverse relationship was stronger for nonadvanced than for advanced adenoma and, less notably, for proximal than for distal adenoma. The association was also moderately more protective with low rather than high total folate intake but did not differ by other nutrients involved in 1-carbon metabolism or colorectal cancer risk factors. CONCLUSIONS Our findings regarding asymptomatic CRA implicate systemic genomic methylation as a potential etiologic factor for an early stage of CRA.

A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma

Mitochondrial DNA (mtDNA) copy number is increased in patients with chronic lymphocytic leukemia (CLL), in Burkitt lymphoma and Epstein-Barr virus-transformed lymphoblastoid cell lines, and in T cells activated via the T-cell receptor. We hypothesized that having a higher mtDNA copy number in peripheral white blood cell DNA from healthy subjects would be associated with future risk of non-Hodgkin lymphoma (NHL). We analyzed mtDNA copy number in 104 incident male NHL cases and 104 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention cohort. There was a dose-response relationship between tertiles of mtDNA copy number and risk of NHL (odds ratio [OR], 95% confidence interval [CI]: 1.0; 1.4 [0.7-2.8]; and 2.4 [1.0-5.5], respectively; P(trend) = .046). The effect was most pronounced for the CLL/small lymphocytic lymphoma (SLL) subtype (OR: 1.0; 3.2 [0.7-15.7]; 14.1 [1.9-103.2]; P(trend) = .009). These results suggest that mtDNA copy number could be associated with the risk of NHL, particularly CLL/SLL.

Consumption of Aspartame-Containing Beverages and Incidence of Hematopoietic and Brain Malignancies

Background: In a few animal experiments, aspartame has been linked to hematopoietic and brain cancers. Most animal studies have found no increase in the risk of these or other cancers. Data on humans are sparse for either cancer. Concern lingers regarding this widely used artificial sweetener. Objective: We investigated prospectively whether aspartame consumption is associated with the risk of hematopoietic cancers or gliomas (malignant brain cancer). Methods: We examined 285,079 men and 188,905 women ages 50 to 71 years in the NIH-AARP Diet and Health Study cohort. Daily aspartame intake was derived from responses to a baseline self-administered food frequency questionnaire that queried consumption of four aspartame-containing beverages (soda, fruit drinks, sweetened iced tea, and aspartame added to hot coffee and tea) during the past year. Histologically confirmed incident cancers were identified from eight state cancer registries. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression that adjusted for age, sex, ethnicity, body mass index, and history of diabetes. Results: During over 5 years of follow-up (1995-2000), 1,888 hematopoietic cancers and 315 malignant gliomas were ascertained. Higher levels of aspartame intake were not associated with the risk of overall hematopoietic cancer (RR for ≥600 mg/d, 0.98; 95% CI, 0.76-1.27), glioma (RR for ≥400 mg/d, 0.73; 95% CI, 0.46-1.15; P for inverse linear trend = 0.05), or their subtypes in men and women. Conclusions: Our findings do not support the hypothesis that aspartame increases hematopoietic or brain cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1654–9)

A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers

Studies indicate that higher sun exposure, especially in the recent past, is associated with reduced risk of non‐Hodgkin lymphoma (NHL). Ultraviolet radiation‐derived vitamin D may be protective against lymphomagenesis. We examined the relationship between prediagnostic serum 25‐hydroxyvitamin D (25(OH)D) and lymphoid cancer risk in a case–control study nested within the Alpha‐Tocopherol Beta‐Carotene Cancer Prevention Study cohort (1985–2002) of 29,133 Finnish male smokers (ages 50–69). We identified 270 incident lymphoid cancer cases and matched them individually with 538 controls by birth‐year and month of fasting blood draw at baseline. In conditional logistic regression models for 10 nmol/L increments or tertile comparisons, serum 25(OH)D was not associated with the risk of overall lymphoid cancers, NHL (n = 208) or multiple myeloma (n = 41). Odds ratios (OR) for NHL for higher tertiles were 0.75 (95% confidence interval (CI), 0.50, 1.14) and 0.82 (95% CI, 0.53, 1.26). The 25(OH)D‐NHL association, however, differed by follow‐up duration at diagnosis. Cases diagnosed less than 7 years from the baseline showed an inverse association (OR for highest vs. lowest tertile = 0.43; 95% CI: 0.23, 0.83; p for trend = 0.01), but not later diagnoses (OR = 1.52; 95% CI: 0.82, 2.80; p for trend = 0.17). The inverse association found for close exposure to diagnosis was not confounded by other risk factors for lymphoma or correlates of 25(OH)D. Although our findings suggest that circulating 25(OH)D is not likely associated with overall lymphoid cancer, they indicate a potentially protective effect on short‐term risk of NHL.

Asian women have greater abdominal and visceral adiposity than Caucasian women with similar body mass index

Background:In the Multiethnic Cohort Study, Japanese Americans (JA) have lower mean body mass index (BMI) compared with Caucasians, but show a higher waist-to-hip ratio at similar BMI values and a greater risk of diabetes and obesity-associated cancers.Objective:We investigated the abdominal, visceral and hepatic fat distribution in these Asian and Caucasian Americans.Design:A cross-sectional sample of 60 female cohort participants (30 JA and 30 Caucasians), of ages 60–65 years and BMIs 18.5–40 kg m−2, underwent anthropometric measurements and a whole-body dual energy X-ray absorptiometry (DXA) scan: a subset of 48 women also had abdominal magnetic resonance imaging (MRI).Results:By design, JA women had similar BMIs (mean 26.5 kg m−2) to Caucasian women (27.1 kg m−2). JA women were found to have a significantly smaller hip circumference (96.9 vs 103.6 cm; P=0.007) but not a significantly lower DXA total fat mass (25.5 vs 28.8 kg; P=0.16). After adjusting for age and DXA total fat mass, JA women had a greater waist-to-hip ratio (0.97 vs 0.89; P<0.0001), DXA trunk fat (15.4 vs 13.9 kg; P=0.0004) and MRI % abdominal visceral fat (23.9 vs 18.5%; P=0.01) and a lower DXA leg fat mass (8.2 vs 10.0 kg; P=<.0001). Their MRI % subcutaneous fat (33.4 vs 30.2%; P=0.21) and % liver fat (5.8 vs 3.8%; P=0.06) did not significantly differ from that of Caucasian women.Conclusions:Our findings build on limited past evidence, suggesting that Asian women carry greater abdominal and visceral fat when compared with Caucasian women with similar overall adiposity. This may contribute to their elevated metabolic risk for obesity-related diseases.

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

Background:Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution.Subjects/Methods:In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case–control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry.Results:In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P<0.01), adiponectin was significantly lower in AA men and women (P=0.02 and P<0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P<0.0001) and CRP (P=0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status.Conclusions:These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

Genetic risk factors for BMI and obesity in an ethnically diverse population: Results from the population architecture using genomics and epidemiology (PAGE) study†‡

Several genome–wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

Circulating 25-Hydroxyvitamin D and Risk of Non-Hodgkin Lymphoma Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Case-control studies generally suggesting an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) have led to speculation that vitamin D may protect against lymphomagenesis. To examine this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D (25(OH)D) and subsequent NHL risk within 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. The authors analyzed measurements from 1,353 cases and 1,778 controls using conditional logistic regression and other methods to estimate the association of 25(OH)D with NHL. No clear evidence of association between categories of 25(OH)D concentration and NHL was observed overall (Ptrend = 0.68) or by sex (men, Ptrend = 0.50; women, Ptrend = 0.16). Findings for other measures (continuous log(25(OH)D), categories of 25(OH)D using sex-/cohort-/season-specific quartiles as cutpoints, categories of season-adjusted residuals of predicted 25(OH)D using quartiles as cutpoints) were generally null, although some measures of increasing 25(OH)D were suggestive of an increased risk for women. Results from stratified analyses and investigations of histologic subtypes of NHL were also null. These findings do not support the hypothesis that elevated circulating 25(OH)D concentration is associated with a reduced risk of NHL. Future research investigating the biologic basis for the sunlight–NHL association should consider alternative mechanisms, such as immunologic effects.