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Introduction: Circulating fatty acids, which can serve as biomarkers of diet or activity of specific metabolic pathways, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. We performed prospective studies to evaluate red blood cell (RBC) membrane fatty acids as biomarkers of future NHL risk, hypothesizing a positive association for RBC saturated and trans fatty acids and an inverse association for polyunsaturated fatty acids (PUFAs) with risk of NHL and major NHL subtypes. Methods: We conducted a nested case-control study among Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) participants who provided blood samples in 1989-90 (NHS) or 1993-4 (HPFS). We confirmed 583 incident NHL cases through 2010 and matched one control per case on age, gender, race, and blood draw date. By gas chromatography we identified and determined membrane concentrations of 33 individual fatty acids in RBCs. We estimated the odds ratio (OR) and 95% confidence interval (CI) of NHL per 1 standard deviation (SD) increase in RBC level of specific fatty acids using unconditional logistic regression adjusted for matching factors. We also analyzed three common B-NHL subtypes individually (chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma) and examined all B-NHLs in aggregate with and without CLL/SLL. Results: We observed no associations between specific fatty acids and NHL risk overall (data not shown). In subtype-specific analyses, RBC very long chain saturated fatty acid (VLCSFA) levels (including the 20:0, 22:0, 23:0 fatty acids) were inversely associated with the group of all B-NHLs except CLL/SLL, with ORs suggesting 18% to 19% decreases in risk per SD increase in concentration (Table 1). We observed suggestive inverse associations of similar magnitude for follicular lymphoma and DLBCL but no clear association with CLL/SLL for these 3 VLCSFAs (Table 1). These three VLCSFAs had moderate to strong pairwise correlations; Spearman correlations were 0.61 for 20:0 with 22:0, 0.42 for 20:0 with 23:0 and 0.64 for 22:0 with 23:0. PUFAs were also inversely associated with all B-NHL except CLL/SLL, a finding primarily driven by RBC arachidonic acid levels [OR (95%CI) per SD: 0.83 (0.71, 0.90)] and suggestive also for follicular lymphoma [OR, 95% CI per SD: 0.79 (0.61, 1.02)] and DLBCL [OR, 95% CI per SD: 0.82 (0.64, 1.06)]. The remaining RBC fatty acids, including trans fatty acids, had no clear association with any NHL endpoint (data not shown). We did not observe heterogeneity by follow-up interval or age, although we had limited statistical power to detect significant heterogeneity for specific NHL subtypes. Conclusion: RBC levels of VLCSFAs and PUFAs may be associated with lower risk of several types of B-NHL other than CLL/SLL. The specific fatty acids found to be related with NHL risk are not good biomarkers of diet, suggesting that the observed relations may instead be due to endogenous metabolic processes. Investigation is warranted into biologic mechanisms by which circulating fatty acids and their determinants may influence NHL risk, as is further examination of these associations in larger (ideally pooled) study populations. Disclosures No relevant conflicts of interest to declare.

Background: Some, but not all, previous studies have suggested that higher adolescent fiber intake may be associated with a reduced risk of breast cancer. Consistently, adolescent fiber intake has been suggested to reduce breast cancer risk in adulthood in some of the previous studies. To date, there is limited epidemiologic evidence that diet has a strong influence on mammographic density and inconsistency in results for specific dietary factors. While some earlier studies demonstrated an inverse association between adolescent fiber intake and breast density (defined as parenchymal patterns), a more recent study did not find significant associations. We investigated the associations of adolescent fiber intake with mammographic density, a strong and consistent predictor of breast cancer, in premenopausal women. This is by far the largest study that investigated these associations. Methods: This study included 743 premenopausal women within the Nurses’ Health II cohort with no history of breast or other cancer. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammographic images using a computer-assisted thresholding technique. Adolescent and adult diet was assessed with a food frequency questionnaire and energy-adjusted nutrient intakes were estimated for each of the questionnaires. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires, closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusting for age, body mass index, and other known and suspected predictors of mammographic density. Absolute measures were square root-transformed in analyses to improve normality. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts). Results: In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of nuts, fruits, or vegetables nor specific sources of fiber intake (fruits, vegetables, legumes, or cereal) during adolescence were associated with any of the mammographic density phenotypes. Conclusions: Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic density. If observed associations with breast cancer risk are causal, then the effect may not be mediated through mammographic density. Citation Format: Lusine Yaghjyan, Gabriella Ghita, Maryam Farvid, Bernard Rosner, Kimberly A. Bertrand, Rulla Tamimi. Adolescent fiber intake and mammographic breast density in premenopausal women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4346.

Introduction: Relative to white women, African American (AA) women have a disproportionately high incidence of early-onset breast cancer, particularly higher incidence of aggressive breast cancer subtypes such as estrogen receptor (ER) negative tumors. Elucidation of risk factors for early-onset of specific subtypes of breast cancer is needed. Methods: We evaluated associations of reproductive and lifestyle factors with early-onset invasive breast cancer, defined as diagnosis before age 50, in 47,212 AA women ages 21-49 in the Black Women's Health Study (BWHS). The BWHS is an ongoing prospective cohort study in the U.S. that began in 1995. Risk factor information is updated every two years via mailed questionnaires. Incident cases were self-reported on biennial questionnaires or identified through death records and confirmed by medical records and cancer registry data. Through 2013, we identified 192 ER- and 322 ER+ invasive breast cancers diagnosed before age 50. We used multivariable Cox proportional hazards regression, stratified by age, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of family history of breast cancer, age at menarche, parity, age at first birth, years since last birth, lactation, body mass index (recent and at age 18), waist-to-hip ratio, oral contraceptive use, alcohol consumption, smoking history, and physical activity, with risk of ER- and ER+ early-onset breast cancer, separately. Results: The strongest associations were observed for family history of breast cancer, early age at menarche, and lower body mass index at age 18, and these factors were associated with increased incidence of both ER- and ER+ breast cancer. Oral contraceptive use within the past 10 years was also associated with increased risk of both subtypes. High waist-to-hip ratio (HR for top tertile vs. bottom: 1.46, 95% CI: 0.98, 2.19) and high parity (HR for 3+ births vs. 1: 1.43, 95% CI: 0.88, 2.32) were associated with increased risk of ER- breast cancer, while breastfeeding was associated with a reduced risk (HR for ever vs. never: 0.68, 95% CI: 0.47, 0.97). In contrast, higher parity was associated with a reduced risk of ER+ cancer (HR for 3+ births vs. 1: 0.68, 95% CI: 0.45, 1.01). Recent pregnancy (HR for Conclusions: Differential associations of risk factors for ER- vs. ER+ breast cancers in young AA women suggest etiological heterogeneity by tumor subtypes. These differences could explain, in part, disparities in breast cancer incidence and mortality between black and white women. Some identified risk factors are potentially modifiable, suggesting possible opportunities for prevention. Citation Format: Kimberly A. Bertrand, Lynn Rosenberg, Julie R. Palmer. Risk factors for early-onset ER- and ER+ breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1779.

Percent mammographic density (PMD) is a risk factor for estrogen receptor (ER)-positive and ER-negative invasive breast cancer (BC). Gene expression profiling has identified molecular signatures that classify invasive BC into distinct subtypes that vary in their clinical behavior, response to treatment and likely, etiology. Immunohistochemical (IHC) staining of tumor sections using antibody panels can be used to classify these ‘intrinsic’ molecular subtypes. We evaluated whether density measures [PMD, absolute dense area (DA) and non-dense area (NDA)], are associated equally with all ‘intrinsic’ molecular subtypes. Pooled analysis of six cohort or case-control studies included 3492 women with invasive BC and 10,148 without, who underwent screening mammography a median 4 years prior to diagnosis (for cases). PMD, DA, and NDA were assessed from digitized film-screen mammograms using a computer-assisted thresholding technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+ (PMD) or into quartiles (DA and NDA). Receptor status was abstracted from pathology records and supplemented by IHC staining. We classified tumors as Luminal A (ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (TN) (ER-/PR-/HER2-). For TN, we also differentiated basal-like tumors (positive for EGFR and/or CK 5/6) from unclassified (negative on both markers). We used polytomous logistic regression to calculate the odds ratio (OR) of each ‘intrinsic’ subtype of BC by categories of PMD, DA or NDA, adjusting for age, body mass index and study. We tested for statistical heterogeneity of associations by subtype. Of 3492 invasive BC cases, 2217 (63%) were classified as Luminal A, 747 (21%) as Luminal B, 159 (5%) as HER2 expressing, and 369 (11%) as TN. Of TN, 203 were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) unclassified. PMD was associated with BC risk across all subtypes. For Luminal A, compared to women with 11-25% PMD (reference), women with 0-10% had a reduced risk of BC (OR = 0.63 [95% confidence interval: 0.55, 0.74]) while women with 26-50% had an OR = 1.5 [1.3, 1.7] and women with 51%+ had the highest risk, OR = 2.3 [2.0, 2.7]. Similar BC associations were seen across PMD categories when comparing the five subtypes (P-heterogeneity = 0.63). Similar trends were seen for DA and BC across the five subtypes (P-het = 0.25). NDA was inversely associated with BC across subtypes, and there was suggestion of a stronger inverse trend among HER2-expressing BC compared to other subtypes (P-het = 0.09). Our results suggest mammographic density measures are associated with all ‘intrinsic’ molecular subtypes. However, NDA may be more strongly inversely associated with HER2-expressing than other subtypes. Understanding the importance of density measures for BC subtypes has significance for subtype-specific risk models. Citation Format: Aaron D. Norman, Rulla M. Tamimi, Christopher G. Scott, Kimberly A. Bertrand, Matthew R. Jensen, Daniel W. Visscher, Fergus J. Couch, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew Beck, Vernon S. Pankratz, Karla Kerlikowske, Celine M. Vachon. Association of mammographic density measures and breast cancer ‘intrinsic’ molecular subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2593.

Mammographic density is one of the strongest risk factors for breast cancer. The most widely used measure of mammographic density is based on the percentage of dense tissue on a mammogram (percent mammographic density). However, there is additional information in mammographic images not captured by current mammographic density measurements including heterogeneity in patterns of breast density, often referred to as ‘texture’. More recent research suggests that textural features on a mammogram are associated with breast cancer risk independent of percent mammographic density. Therefore, we evaluated an automated measure called V, which measures the grayscale variation within a mammogram, in relation to subsequent breast cancer risk in 834 breast cancer cases (426 premenopausal and 408 postmenopausal) and 1805 controls (978 premenopausal and 827 postmenopausal) from a nested case-control study of breast cancer in the Nurses’ Health Studies (NHS). Among all women, V was modestly correlated with percent mammographic density (r = 0.48, p Citation Format: Megan Rice, Kimberly Bertrand, John Heine, Bernard Rosner, Rulla Tamimi. Texture variation on a mammogram and risk of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2595.

Gene expression profiling has identified molecular subtypes that classify invasive breast cancers into distinct categories that vary in their clinical behavior and response to treatment. These subtypes highlight the many possible biologically and clinically distinct types of breast cancer. Immunohistochemical (IHC) staining of tumor sections using antibody panels has been used as a surrogate for the molecular subtypes identified through gene expression profiling, resulting in a set of intrinsic molecular subtypes. Given the heterogeneity within breast cancer, one might expect that different risk factors influence specific subtypes of breast cancer through various etiologic pathways. We evaluated whether percent mammographic density (MD), the proportion of fibroglandular or white tissue on a mammogram and one of the strongest and most consistent risk factors for breast cancer, is associated equally with all intrinsic molecular subtypes. Data were pooled from six cohort or case-control studies including 3389 women with invasive breast cancer and 9860 without, who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms (for cases, at a median 4 years prior to diagnosis) using a computer-assisted threshold technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+. Receptor status was abstracted from clinical pathology records and supplemented by IHC staining of tumor sections or microarrays. With estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) information, we classified tumors into the intrinsic molecular subtypes: Luminal A ( ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (ER-/PR-/HER2-). For cancers found to be triple negative (TN), we also stained for epidermal growth factor receptor (EGFR) and cytokeratins (CK) 5/6 to differentiate basal-like tumors (positive for EGFR and/or CK 5/6) from the unclassifieds (negative on both EGFR and CK 5/6). We used polytomous logistic regression to calculate the odds (OR) of each of the intrinsic subtypes of breast cancer by categories of percent MD, adjusting for age, BMI and study. Contrasts were constructed and tested within the polytomous model framework to investigate differences in the strength of association of percent MD across subtypes. On average, cases were slightly older (56.4 years [SD=11.3]) than controls (55.8 [10.9]). Of the 3389 invasive breast cancer cases, 2146 (63%) were classified as Luminal A, 709 (21%) as Luminal B, 169 (5%) as HER-2 expressing, and 365(11%) as triple negative (TN). Of the TN tumors, 203 had tumor tissue available and were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) as unclassified. Percent (%) MD was associated with breast cancer risk across all intrinsic subtypes. For Luminal A, compared to women with 11-25% MD (reference), women with 0-10% MD had a reduced risk of breast cancer (OR=0.64 [95% confidence interval (CI): 0.55, 0.74]) while women with 26-50% MD had an OR=1.5 (1.3,1.7) and women with 51%+ MD had the highest risk, OR=2.4 (2.0, 2.8). Similar associations were seen for Luminal B, HER2 expressing, and TN across percent MD categories. The small differences among the percent MD-breast cancer associations observed for the different subtypes were not statistically significant, either when comparing the four (Luminal A, Luminal B, HER-2 expressing and TN; p=0.61) or five categories of subtypes (Luminal A, Luminal B, HER-2 expressing, basal-like, unclassified; p=0.66). Our results suggest percent MD is a risk factor for all intrinsic molecular subtypes. Additional study is needed to examine whether these results hold for younger and older aged women. Understanding the importance of mammographic density measures for subtypes of breast cancer has significance for development of subtype-specific risk models. Citation Format: Celine Vachon, Rulla Tamimi, Yunn-Yi Chen, Christopher Scott, Kimberly Bertrand, Matthew Jensen, Daniel Visscher, Aaron Norman, Fergus Couch, John Shepherd, Bo Fan, Fang-Fang Wu, Lin Ma, Andrew Beck, Steve Cummings, V. Shane Pankratz, Karla Kerlikowske. Mammographic density: A risk factor for all breast cancers or only specific subtypes? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA22.

Background: Animal experiments have suggested that exposure to persistent organic pollutants (POPs) may lead to increased risk of type 2 diabetes. Although recent human studies supported this hypothesis, evidence from prospective investigations is sparse. Objective: To examine the associations of plasma POP concentrations with risk of incident type 2 diabetes in a prospective setting among US women. Methods: Study population was comprised of participants from two independent nested case-control studies in the Nurses’ Health Study, in which major polychlorinated biphenyl (PCB 118, 138, 153, and 180), p-p'- dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyltrichloroethane (DDT), and hexachlorobenzene (HCB) were measured. A non-parametric approach was used to derive standardized scores for plasma concentrations of lipid-adjusted POPs within each study to minimize between-study variation of the POP measurements. Risk of incident type 2 diabetes during the follow-up period (1990-2008) across the tertiles of the scores was examined. Results: Of 1,120 participants, we identified 48 incident type 2 diabetes cases. After adjusting for covariates assessed at blood draw in 1990, including smoking status, body mass index, and total fish intake, plasma HCB concentration was positively associated with type 2 diabetes risk: odds ratio (OR) (95% confidence interval [CI]) was 2.77 (1.17, 6.55, P for trend =0.022) comparing the highest vs. lowest tertile. Other POPs were not significantly associated with diabetes: the ORs (95% CI) were 1.10 (0.51, 2.34, P for trend =0.81) for p-p'-DDE, 0.93 (0.44, 1.95, P for trend =0.86) for DDT, and 0.88 (0.39, 1.97, P for trend =0.76) for sum of the 4 major PCBs, comparing the extreme tertiles. Conclusion: The significant association of plasma HCB concentration with diabetes risk supports a role of POP exposure in the etiology of type 2 diabetes. More prospective data are warranted to confirm these findings.

Epidemiologic evidence suggests that vitamin D may protect against colorectal, prostate, breast, and oropharyngeal cancers(1–6) and other chronic diseases such as cardiovascular disease(6–9), diabetes(6, 9–11), and hip fractures(12–14). Plasma 25-hydroxyvitamin D [25(OH)D], the primary circulating form of vitamin D(6, 15), is an accepted biomarker for measuring vitamin D status in clinical settings(16); however, it is strongly dependent on season of blood draw. Although 25(OH)D is fairly reproducible over 2–3 years(17, 18), one measurement is weaker in characterizing longer term exposure(19, 20). Furthermore, measuring 25(OH)D requires the availability of blood samples and monetary resources for laboratory assays, limiting the feasibility of this approach for many large-scale epidemiologic studies. Individual determinants of vitamin D status, such as latitude and regional estimates of solar radiation(21–23) or dietary assessment(24–26), have been used as surrogates of vitamin D exposure, but each alone contributes a small proportion of 25(OH)D. An alternative approach to assess vitamin D status is to combine known determinants of circulating 25(OH)D to derive a predicted score from questionnaire data using measurements of plasma 25(OH)D available for a subset of the study population; reported r2 from such predictive models have ranged from 0.21 to 0.42(18, 27–29). Although the r2 between predicted and measured 25(OH)D has been used to assess the “validity” of the predicted 25(OH)D approach, the r2 in this context has limitations given that a single measure is not a true gold standard of long-term average 25(OH)D concentration. Such an “alloyed” or imperfect gold standard will underestimate true “validity”(30–32). More importantly, a comparison of high versus low circulating 25(OH)D level in the population, which may be estimated by high and low predicted 25(OH)D, may be the more relevant factor for testing exposure-disease hypotheses in epidemiologic studies. In this paper, we describe the development and validation of regression models to predict 25(OH)D based on determinants of vitamin D status in three cohorts: the Nurses' Health Study (NHS), the Nurses' Health Study II (NHSII), and the Health Professionals Follow-Up Study (HPFS). Predicted 25(OH)D scores have been used in several analyses within these cohorts(8, 18, 33, 34) but, with the exception of HPFS(18), no formal validation has been conducted previously and the specific prediction models varied with each analysis. We also evaluated reproducibility of plasma 25(OH)D over 10–11 years in NHS participants.

Case–control studies suggest increased sun exposure reduces non-Hodgkin lymphoma (NHL) risk. Evidence from prospective cohort studies, however, is limited and inconsistent. We evaluated the association between ambient ultraviolet radiation (UV) exposure and NHL in a nationwide cohort of women, the Nurses’ Health Study (NHS). Between 1976 and 2006, we identified 1064 incident NHL cases among 115,482 women in the prospective NHS. Exposures assessed included average annual UV-B flux based on residence at various times during life, vitamin D intake, and predicted plasma 25-hydroxyvitamin D levels. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of all NHL and histologic subtypes using Cox proportional hazards models. NHL risk was increased for women residing in areas of high ambient UV radiation (UV-B flux >113 R–B count × 10−4) compared to those with lower exposure (

Severe immunosuppression is an established risk factor for non-Hodgkin lymphoma (NHL), but an association with subclinical immune dysfunction is unclear. We conducted a case-control study nested in the Physicians' Health Study and the Nurses' Health Study cohorts to determine whether patterns of antibody response to Epstein-Barr virus (EBV) were associated with NHL risk. We measured antibody titers against viral capsid antigen, early antigen, and Epstein-Barr nuclear antigen (EBNA-1 and EBNA-2) in blood samples collected before diagnosis from 340 cases and 662 matched controls. Using conditional logistic regression, we estimated rate ratios (RRs) and 95% confidence intervals (CIs) for elevated versus normal titers and the ratio of anti–EBNA-1 to anti–EBNA-2 titers (≤ 1.0 vs > 1.0). We found no association between EBV serostatus, elevated titers, or an EBNA-1/EBNA-2 ratio ≤ 1.0 and NHL risk overall. For chronic lymphocytic leukemia/small lymphocytic lymphoma, suggestive associations were noted for elevated anti–EBNA-2 (RR, 1.74; 95% CI, 0.99-3.05), anti–viral capsid antigen (RR, 1.58; 95% CI, 0.79-3.14), and EBNA-1/EBNA-2 ratio ≤ 1.0 (RR, 1.52; 95% CI, 0.91-2.55). There was no evidence of heterogeneity by subtype. Overall, we found no evidence that EBV antibody profile predicts NHL risk in immunocompetent persons, with the possible exception of chronic lymphocytic leukemia/small lymphocytic lymphoma.

Vital statistics for the lymphoid malignancies obtained from the Surveillance, Epidemiology and End Results (SEER) Program have seldom been directly compared to data from alternative national databases. While SEER is recognized as the standard, some lymphoid malignancies-especially the chronic ones--may be underreported. We compared the incidence, all-cause and cause-specific mortality for Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) in SEER to that in the Nurses' Health Study (NHS), a national cohort study of 121,700 female registered nurses, matching for age and race. In over 2.5 million person-years, the incidence of HL was the same as in SEER (SIR=1.01 [0.75, 1.26]), while the incidence of NHL, CLL and MM were slightly higher. All-cause mortality was lower for the lymphoid malignancies except for MM, which was the same; there were no differences in cause-specific mortality, except for MM (HR=1.26 [1.07, 1.48]). Our analysis suggests that, at least among white women, SEER is a reliable data source with respect to lymphoid malignancies.

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 (P(trend) = 0.68) or by sex (men, P(trend) = 0.50; women, P(trend) = 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.

Incidence rates for non-Hodgkin lymphoma have nearly doubled since the 1970s, although with no further rise since the mid-1990s.1,2 The increase in non-Hodgkin lymphoma incidence over time cannot be fully explained by improvements in diagnosis, the rise in AIDS-related non-Hodgkin lymphoma diagnoses, or other known risk factors.3,4 Possible reasons may include secular trends in the exposure to environmental factors. Polychlorinated biphenyls (PCBs) and organochlorine pesticides such as dichlorodiphenyl trichloroethane (DDT) have been the focus of recent studies of non-Hodgkin lymphoma.5-8 PCBs were first produced in the U.S. in 1929 and were used for a variety of industrial purposes in hydraulic fluids, flame retardants, paints, plasticizers, pesticides, and wood preservatives, and as coolants or lubricants in transformers and capacitors. Although manufacturing of PCBs was banned in the U.S. in 1977, these compounds persist in air, water, and soil, and accumulate in fish. Moreover, PCBs are still being introduced into the environment through improperly maintained industrial waste sites and illegal dumping. PCBs are lipid-soluble and are stored in adipose tissue and in the lipid components of blood and breast milk. Because PCBs are not easily metabolized and have long half-lives, the concentrations of PCBs in tissue or breast milk provide reasonable estimates of cumulative exposures over time.9 DDT was manufactured and used as an insecticide in the U.S. from 1945 until it was banned in 1972. Like PCBs, DDT is an environmentally persistent pollutant and accumulates in fish. In addition, some developing countries still use DDT, and foods imported from these countries may be contaminated.10 These compounds are ubiquitous in the environment, and exposure to low levels of DDT, its metabolites, and PCBs among the general U.S. population continues today.9,10 Organochlorines have been classified as probable human carcinogens by the U.S. Environmental Protection Agency (EPA) and the International Agency for Research on Cancer (IARC), based largely on animal evidence.11,12 In addition to their carcinogenic properties, organochlorines also exhibit immunotoxic effects.9,13,14 Recent epidemiologic evidence suggests that exposure to certain PCBs and p,p′-dichlorodiphenyl dichloroethane (p,p′-DDE), the major metabolite of DDT, may increase the risk of non-Hodgkin lymphoma, with relative risks generally ranging from two to four.6,7,15-17 Other case-control studies have reported no association between PCBs and non-Hodgkin lymphoma.5,18 Among the studies with positive findings overall, results for individual PCB congeners have been inconsistent. To date, only three studies have reported associations with organochlorine levels measured in blood collected before diagnosis.7 Only two retrospective case-control studies have had sufficient sample size to examine associations by the major histologic subtypes of non-Hodgkin lymphoma.5,6 To test the hypothesis that higher blood levels of PCBs and p,p′-DDE are associated with a subsequent increased risk of non-Hodgkin lymphoma, we measured concentrations of organochlorines in blood samples collected prospectively in 205 men with non-Hodgkin lymphoma and 409 matched controls in the Physicians’ Health Study. We also evaluated these associations with subtypes of non-Hodgkin lymphoma based on the World Health Organization (WHO) classification of lymphomas.19

Introduction: Periodontal disease has been associated with several chronic diseases, including cancer. In an earlier prospective cohort analysis within the HPFS, we observed a 31% higher risk of NHL among participants who reported severe periodontitis at baseline (Michaud et al. Lancet Oncology 2008). Herein, we examined this novel association with an additional 8 years of follow-up, updated periodontal disease status, and analyzed association by subtype of NHL. Methods: The HPFS is a prospective cohort of male health professionals, aged 45-65 years, recruited throughout the US in 1986 using mail questionnaires. Periodontal status was reported at baseline and biennially thereafter. Incident cases of NHL diagnosed between 1986-2012 are included in this analysis; subtypes of NHL were determined through medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models adjusting for age, race, number of teeth, body mass index, diabetes, smoking and geographic region. An 8-year lag analysis was performed evaluating periodontal status 8-years prior to diagnosis (including follow-up years 1994-2012, n=514 cases). Results: During 16 years of follow-up, 876 cases of NHL were ascertained. Subtypes with sufficient numbers for analysis included chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n=281), diffuse large B-cell lymphoma (DLBCL) (n=83) and follicular lymphoma (FL) (n=91). Significant associations for periodontal disease at baseline were noted for total NHL, which includes B- and T-cell subtypes (HR = 1.25, 95% CI: 1.05-1.49) and CLL/SLL (HR = 1.37, 95% CI: 1.01-1.86) (Table). With updated periodontal status, similar associations were observed for periodontal disease and risk of total NHL (HR = 1.30, 95% CI: 1.11-1.52) and CLL/SLL (HR = 1.40, 95% CI: 1.06-1.83). In the baseline and updated analyses, associations for DLBCL were similar to those for all NHLs, however, no association was noted for FL. Associations remained elevated in an 8-year lag analysis for total NHL (HR = 1.23, 95% CI = 1.00-1.52), and for CLL/SLL (HR = 1.48, 95% CI = 1.04-2.09). Conclusion: These data show that the association for periodontitis and NHL has persisted over time in the HPFS. Furthermore, the long latency period between periodontal disease status and NHL diagnosis suggests that the association is not a consequence of the cancer. In addition, the association with periodontal disease appeared strongest for CLL/SLL and DLBCL. Mechanistic and prospective study of this association are warranted. Table 1. Periodontal disease and risk of NHL in the HPFS, 1986-2012. Total NHL CLL/SLL DLBCL Follicular Baseline periodontal status 876 cases 281 cases 83 cases 91 cases No hx periodontal dx 1.0 1.0 1.0 1.0 Periodontal dx 1.25 (1.05-1.49) 1.38 (1.02-1.87) 1.36 (0.77-2.40) 0.67 (0.34-1.32) 25-32 teeth 1.0 1.0 1.0 1.0 17-24 teeth 0.76 (0.60-0.95) 0.50 (0.31-0.79) 1.33 (0.71-2.51) 0.81 (0.38-1.70) 0-16 teeth 0.83 (0.61-1.13) 0.60 (0.32-1.09) 0.43 (0.10-1.87) 1.85 (0.81-4.22) Updated periodontal status No hx periodontal dx 1.0 1.0 1.0 1.0 Periodontal dx 1.30 (1.11-1.52) 1.40 (1.08-1.84) 1.40 (0.85-2.30) 0.93 (0.55-1.59) Disclosures No relevant conflicts of interest to declare.

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.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Background Mammographic density (MD) is a strong intermediate risk factor for breast cancer (BC) and, having both genetic and environmental determinants, may account for the over 6-fold international variations in BC incidence rates. The International Pooling Project of Mammographic Density is a worldwide collaborative project of MD targeting populations spanning the BC incidence range. The aims of the project are to (i) describe international variations in overall and age-specific distributions of MD, (ii) assess whether international variations in MD are explained by variations in the distributions of individual-level determinants of this marker and (iii) examine whether international variations in MD correlate with corresponding BC incidence rates. Methods Each contributing study provided comparable data on MD risk factors and mammographic images from a random sample of ˜ 400 general population women, who had undergone screening mammography. Images were transferred in digitised screen-film, full-field or computed radiography digital DICOM format (raw or processed). Images were randomly allocated into batches for MD reading using the Cumulus 6 thresholding software, by experienced readers who were blinded to study and individual-level factors. Data on MD determinants were pooled and linked with MD readings. Results are calibrated according to type of digital image (raw to processed), and adjusted for image type. Results 22 countries and approximately 12,000 women are included, spanning populations with age-standardised BC incidence rates (ASR) of 25.8 (India) to 99 (The Netherlands) per 100,000 woman-years. To date, for 9,635 participants data have been pooled (results will be updated). The MD risk factors vary greatly across populations, for example: mean age at menarche (in years) was 14.3 (95% CI 14.1–14.5) in Korean women and 12.6 (12.5–12.8) in Mexican women; mean parity was 3.8 (3.6–4.1) in Egyptian women and 1.3 (1.1–1.4) in those from Hong Kong; and mean BMI (in kg/m 2 ) was 33.7 (33.1–34.3) in Egyptian women compared to 22.3 (21.6–22.9) in those from India. Differences in MD according to these distributions will be presented. Discussion The international perspective of this study generated large exposure heterogeneity enabling a wider investigation of MD determinants and the extent to which MD is an intermediate marker of BC risk, both within and between populations.

As we discussed in our recent manuscript, our findings of modest but significant positive associations between ambient ultraviolet (UV) radiation and non-Hodgkin lymphoma (NHL) risk in the Nurses’ Health Study (NHS) were unexpected and inconsistent with most of the prior literature on this topic [1]. Dr. Grant offers alternative explanations for our results. In response to his comments, we have conducted additional data analyses. First, Dr. Grant questions whether a majority of NHS participants reside in regions of relatively low total and UV-B radiation. We agree that results from the NHS may not be generalizable to other populations, particularly those in the areas of higher UV radiation. Because nurses originally were recruited from 11 US states (i.e., California, Connecticut, Florida, Maryland, Massachusetts, Michigan, New Jersey, New York, Ohio, Pennsylvania, and Texas) [2], a majority of participants (59%) resided in the Northeast at baseline in 1976. A similar proportion of women reported Northeast residence at birth, age 15, and age 30. Over the course of 30 years of follow-up, 55% of the person-time included residence in the northeast region of the USA. We used the distribution of average annual UV-B flux values in our study population, which ranged from 93 to 196 (in R-B counts 910) as nurses changed residence over the 30 years of follow-up, to guide our choice of cutpoints for analysis. We reported that NHL risk was increased among women who resided in regions with UV-B flux[113 compared to those with lower exposure (\113) [1]. In response to Dr. Grant’s comment, we dichotomized the top category of UV-flux at its median value (164) and re-analyzed the data using this 4-category variable. Our findings were similar to the results presented in the manuscript, with increased risks most apparent in the highest category of ambient UV-B exposure. For example, the multivariable-adjusted rate ratio (RR) for NHL associated with UV-B flux [164 at age 15, which included residence in Texas, Florida, Arizona, New Mexico, and Louisiana, compared to UV-B flux\113 was 1.72 (95% confidence interval (CI): 1.30, 2.29). Further, it is important to note that we observed statistically significant linear trends for the association of average annual UV-B flux, assessed at various time points and considered as a continuous variable, and risk of NHL (p-trend\0.05). Moreover, we found no evidence of departure from linearity when restricted cubic splines were examined. Second, Dr. Grant suggests that the association between UV-B radiation and NHL risk may differ by latitude because of differences in the relative amount of UV-B and UV-A radiation. We speculated in our paper that increased risks of NHL could plausibly be mediated through immunosuppressive effects of UV exposure. As previously discussed, modest increased risks were most apparent for individuals living in areas of higher UV-B radiation (i.e., outside of the northeast). Unfortunately, data on ambient UV-A levels were not available for analysis, and therefore, we could not evaluate the relative effects of UV-A vs. UV-B exposure nor could we directly evaluate the immunosuppression K. A. Bertrand (&) F. Laden Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA e-mail: kbertran@hsph.harvard.edu

Introduction: Severe immune compromise is a strong risk factor for non-Hodgkin lymphoma (NHL), and serum B-cell activation and inflammation markers predicted AIDS-NHL risk in HIV+ persons. We performed a nested case-control analysis in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts to characterize pre-diagnosis plasma immune marker profiles associated with risk of HIV-unrelated NHL and major histologic subtypes. Methods: The NHS formed in 1976 with 121,701 female US registered nurses. The HPFS enrolled 51,529 male health professionals in 1986. Both cohorts are followed via biennial questionnaires and confirm cancer diagnoses by medical record review and National Death Index follow-up. Among participants who contributed peripheral blood samples in 1989-90 (NHS) or 1993-4 (HPFS), we confirmed incident primary NHL diagnoses in 345 women and 255 men with no other cancer history. We matched one control per case on cohort (gender), age, race and time of blood draw among persons with no cancer history as of the index date. We determined plasma concentrations of 13 cytokines, soluble receptors and immune activation markers using multiplexed Luminex assays (R & D Systems). In preliminary cohort-specific analyses we calculated matching factor-adjusted odds ratios (OR) and 95% confidence intervals (CI) using logistic regression to estimate the relative risk of NHL per standard deviation (SD) increase in assay batch-adjusted natural log-transformed biomarker concentration. We examined associations for NHL overall and for more common World Health Organization-defined histologic subtypes, including chronic lymphocytic leukemia (CLL; 78 female/70 male cases), follicular lymphoma (FL; 61/24), diffuse large B-cell lymphoma (DLBCL; 69/37) and T-cell NHL (all histologic types, 18/10). Results: The mean (range) years from blood draw to NHL diagnosis was 11 (0.2-22) in women and 7 (0.1-17) in men. In both cohorts, pre-diagnosis levels of the immune activation markers soluble interleukin-2 receptor-α (sIL-2Rα) and sCD30, the B cell chemokine CXCL13, and the inflammatory marker soluble tumor necrosis factor receptor-2 (sTNF-R2) were significantly positively associated with risk of NHL overall (Table 1). Table 1.Association of pre-diagnosis plasma immune marker level with risk of NHL overallBiomarkerWomen, OR [95% CI] per SD, p-valueMen, OR [95% CI] per SD, p-valuesIL-2Rα1.41 [1.23, 1.61], p In subtype analyses, risk of CLL was significantly increased in association with increased levels of sIL-2Rα (OR [95% CI] per SD, women: 1.57 [1.26, 1.96], p Discussion: These findings support an etiologic role for immune activation and inflammation in HIV-unrelated NHL. Apparent gender differences in associations may be due to chance (sparse data); statistical heterogeneity by gender will be evaluated and, if appropriate, data will be pooled to improve stability of estimates. Further evaluation by follow-up interval may lend additional insights on the immune milieu that promotes lymphomagenesis and on potential markers of longer- or shorter-term NHL risk. Disclosures No relevant conflicts of interest to declare.

Background: The incidence rate of non-Hodgkin lymphoma (NHL) has more than doubled over the last few decades, but the reason for this increase has been largely unexplained. The long-term effect of blood donation on cancer incidence is not well investigated despite its potentially large impact on the population. Immune deficiency is associated with increased risk of NHL. Blood donation may influence subsequent NHL development via temporary immune system alterations following blood donation, which have been demonstrated in several human studies. A large nested case-control study within a cohort of blood donors in Sweden and Denmark showed an increased odds ratio (OR) of NHL among frequent plasma donors comparing to non-donors (OR 2.14, 95% confidence interval (CI) 1.22-3.74) [Edgren G et al., 2008]. Results of this and other studies have been difficult to interpret because of the possible influence of healthy donor effects or different baseline characteristics among blood donors compared to general population. To test the hypothesis that frequent blood donation is associated with an increased risk of NHL and its most common histologic subtypes in a general, non-immune compromised population, we conducted a prospective study in the Health Professional Follow-up Study (HPFS) cohort. Methods: We followed 36,580 men in the HPFS cohort, who in 1992 had no prior diagnosis of cancer and provided information on frequency of blood donation in the past 30 years. Throughout follow-up of the HPFS cohort, participants completed questionnaires about lifestyle and medical history every two years. Non-respondents were followed through the National Death Index. Identified diagnoses of cancer were confirmed by medical record review. The present analysis included all confirmed incident diagnoses of NHL through January 2008. Person-time accrued for each participant from January 1992 to the earliest among dates of NHL diagnosis, death, or January 2008. Cox proportional hazards regression was used to calculate hazards ratios (HR) and 95% CIs for the risk of all NHL and major NHL histologic subtypes associated with number of blood donations (1-5, 6-9, 10-19, or >20, vs. none), stratifying by age in months and follow-up cycle. Potential confounding by putative NHL risk factors (i.e. smoking, alcohol, BMI, height, physical activity, race) was evaluated by including these factors in multivariable models. Results: During 482,008 person-years of follow-up, 484 incident cases of NHL were confirmed. Participant characteristics were similar at baseline among blood donors and non-donors with respect to age, race, and selected lifestyle factors. In the age-adjusted model, there was no significant association between blood donation frequency and incidence of NHL (HR 1.12, 95% CI 0.82-1.55, comparing >20 donations vs. 0 donations over 30 years, p for trend = 0.44) or of any major NHL subtypes. Adjustment for potential confounders did not notably change the effect estimates for all NHL or any NHL subtypes. Conclusion: In this prospective study, there was no evidence that frequent blood donation is associated with incidence of all NHL or any major subtypes. Disclosures No relevant conflicts of interest to declare.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. Relatives of DLBCL patients are at elevated risk for DLBCL. In small genome-wide association studies (GWAS) in which all NHL subtypes were combined, no conclusive loci for DLBCL have been previously identified in individuals of European background, whereas a recent study conducted in East Asia identified a locus at 3q27. Methods: To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new GWAS and one prior scan, totaling 3,857 DLBCL cases and 7,666 controls of European ancestry. Imputation was used to combine all the data using the 1000 Genomes Project release v3 and IMPUTE2. Based on these findings, we selected 6 promising SNPs for genotyping in an additional 202 cases and 3,431 controls, which were then included in a second meta-analysis. SNPTEST was used to estimate odds ratios (ORs), using the additive model and adjusting for age, gender and significant eigenvectors. Results: In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; OR=2.33, P=1.60x10-20), rs13255292 and rs4733601 at 8q24.21 (PVT1; OR=1.23, P=4.86x10-12 and OR=1.18, P=1.63x10-8, respectively), rs2523607 at 6p21.33 (HLA-B; OR=1.34, 3.35x10-9) and rs2681416 at 3q13.33 (CD86; OR=1.20, P=6.04x10-9). The two 8q24.21 SNPs displayed minimal linkage disequilibrium (r2=0.03) and conditional analysis supported their independence. We did not observe a notable signal for a locus previously reported for DLBCL on 3q27 in East Asia, rs6773854 (OR=1.06, P=0.81). We estimated that common SNPs, including but not limited to the loci discovered in this study, explain approximately 16% of the variance for DLBCL risk overall. Discussion: The susceptibility locus at 6p25.3 maps near a plausible DLBCL candidate gene, EXOC2 (exocyst complex component 2), which interacts with Ral proteins, and disruption of the Ral-exocyst regulatory node impacts cellular and developmental processes associated with malignant transformation and progression. The two 8q24.21 variants are approximately 1Mb telomeric to the 8q24 region linked with multiple cancers including CLL. Both variants are positioned in close proximity to PVT1, which is a non-coding RNA implicated in the MYC activation, and MYC is known to be deregulated in some DLBCLs. The locus at 3q13.33 maps to CD86 (B7-2), a B-7 family member that along with CD80 (B7-1) is essential in cognate interactions between T- and B-lymphocytes; both play key roles in immunodeficiency, autoimmune diseases, and in anti-tumor immunity. Finally, we had multiple signals in the HLA region, the strongest of which was at 6p21.33 near HLA-B. HLA-B encodes the HLA class I heavy chain paralogue, which heterodimerizes with a light chain (β2 microglobulin) and plays a central role in presenting intracellularly processed self or foreign antigens to CD8+ cytotoxic T lymphocytes. Class I molecules have been extensively linked to the risk of a variety of immune-mediated diseases and cancers including DLBCL. Conclusions: 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. Citation Format: James R. Cerhan, Sonja I. Berndt, Joseph Vijai, Hervé Ghesquières, James McKay, Sophia S. Wang, Zhaoming Wang, Meredith Yeager, Alexandra Nieters, David Cox, Alain Monnereau, Christopher Flowers, Anneclaire J. De Roos, Angela R. Brooks-Wilson, Qing Lan, Gianluca Severi, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark Purdue, Claire Vajdic, Demetrius Albanes, Kimberly A. Bertrand, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Paolo Vineis, Susan L. Slager, Karin E. Smedby, Gilles Salles, Christine F. Skibola, Nathaniel Rothman, Stephen J. Chanock, on behalf of the NHL GWAS Project. Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-272. doi:10.1158/1538-7445.AM2014-LB-272

Introduction: We recently reported the percentage of mammographic density (MD) to be a breast cancer risk factor across tumor characteristics and age groups. Yet, we noted stronger associations for tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages Methods: Data were pooled from six studies including 3517 women with invasive breast cancer and 8558 without. Dense area and non-dense area were assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We standardized dense and non-dense area measurements made within each study and categorized into quartiles based on the control distribution for pooled analyses. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (ER, PR) status by age ( Results: Absolute dense area was associated with increased breast cancer risk [odds ratios (ORs) Q1 vs Q2: 0.67, Q3 vs Q2: 1.25, Q4 vs Q2: 1.62] and non-dense area was associated with decreased breast cancer risk (ORs: Q1 vs Q2: 1.44, Q3 vs Q2: 0.89, Q4 vs Q2: 0.71) overall and across all age groups. Positive associations for absolute dense area were observed across all invasive tumor characteristics. Stronger associations were noted for larger tumors across all ages (p-trend Conclusion: These results suggest the strong association we previously observed of high percent MD and ER-negative disease in women Citation Format: Kimberly A. Bertrand, Christopher G. Scott, Rulla M. Tamimi, Matthew R. Jensen, V. Shane Pankratz, Aaron Norman, John Shepherd, Yunn-Yi Chen, Karla Kerlikowske, Celine M. Vachon. Dense and non-dense mammographic area and risk of breast cancer by age and tumor characteristics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2014-3279

Background. Follicular lymphoma (FL) is an indolent B-cell malignancy with a variable clinical course that may transform to more aggressive forms of lymphoma. Previous modestly powered GWAS have reported multiple FL susceptibility loci in the HLA class I and II regions at 6p21.32-33, but novel non-HLA susceptibility loci and the genetic architecture of FL associations in the HLA region remain to be elucidated. Methods. We conducted the largest GWAS of FL to date consisting of 2,142 cases and 6,221 controls of European ancestry from 22 studies scanned on the Illumina OmniExpress. After imputation of common SNPs using IMPUTE2 and 1,000 Genomes Project v3 data, we conducted a meta-analysis of these data with two previous FL GWAS (n=586 cases, 1,537 controls) and replicated top hits in an additional 629 cases and 4,283 controls. Expression quantitative trait loci (eQTL) analyses were performed to evaluate the effects of associated variants on gene expression. Classical HLA allele imputations and stepwise regression analyses are underway to further characterize the HLA associations. Results. In the joint meta-analysis, the strongest association with FL risk was observed in the HLA region, where a large number of SNPs showed genome-wide significance (P Conclusions. This large GWAS provides further support for the important role of common genetic variation in non-HLA genes and further evidence of the key role that HLA immune-regulatory genes play in the pathogenesis of FL. Citation Format: Christine F. Skibola, Sonja I. Berndt, James R. Cerhan, Zhaoming Wang, Joseph Vijai, Lucia Conde, Paul de Bakker, Sophia S. Wang, Claire M. Vajdic, Brenda M. Birmann, Susan L. Slager, James McKay, Paige M. Bracci, Alexandra Nieters, Qing Lan, Angela R. Brooks-Wilson, Martha S. Linet, Demetrius Albanes, John J. Spinelli, Roel C.H. Vermeulen, Mark P. Purdue, Meredith Yaeger, Lauren R. Teras, Silvia de Sanjose, Alain Monnereau, Simon Crouch, Jia Nee Foo, Henrik Hjalgrim, Gianluca Severi, Brian K. Link, Kimberly A. Bertrand, Yawei Zhang, Karin E. Smedby, Stephen J. Chanock, Nathaniel Rothman, NHL GWAS Consortium. Meta-analysis of genome-wide association studies identifies novel susceptibility loci for follicular lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5072. doi:10.1158/1538-7445.AM2014-5072

Marginal zone lymphomas (MZL) are a group of indolent non-Hodgkin's B-cell lymphomas (NHL) comprising extranodal MZL of mucosa-associated lymphoid tissue (MALT) type, splenic MZL and nodal MZL. MZL comprises 7-12% of adult NHLs. The genetic etiology of MZL is poorly understood. To better understand the genetic risk factors for MZL, we conducted the first genome-wide association study (GWAS) of this lymphoid malignancy. The GWAS included 824 MZL cases and 6,220 controls of European ancestry from 22 studies of NHL. Genotyping was carried out at the Cancer Genomics Research Laboratory (CGR) of NCI using Illumina Human OmniExpress arrays. Standard genotyping quality controls were performed. Imputation of common SNPs was performed using IMPUTE2 software and 1000 Genomes Project release version 3 data. Association testing was subsequently performed using SNPTEST, assuming a log-additive genetic model adjusting for age, gender and three significant eigenvectors. We identified one locus at 6p21.32 within the HLA class II region that attained genome-wide significance (P Citation Format: Joseph Vijai, Zhaoming Wang, Sonja I. Berndt, Susan L. Slager, James R. Cerhan, Christine Skibola, Sophia S. Wang, Angela R. Brooks-Wilson, Silvia de Sanjose, Paige M. Bracci, Mads Melbye, Bengt Glimelius, Rebecca D. Jackson, Wendy Cozen, Nikolaus Becker, Lauren R. Teras, John J. Spinelli, Jenny Turner, Qing Lan, Mark P. Purdue, Kimberly A. Bertrand, Kenneth Offit, Paolo Vineis, Brian K. Link, Graham G. Giles, Anne Zelenuich-Jacquotte, Alain Monnereau, Maria Grazia Ennas, Demetrius Albanes, Laurie Burdett, Nathaniel Rothman, Stephen J. Chanock, Alexandra Nieters, On behalf of the NHL GWAS Consortium. A genome-wide association study suggests evidence of variants at 6p21.32 associated with marginal zone lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2014-5071

Background: The etiology of non-Hodgkin lymphoma (NHL) is poorly understood, especially regarding modifiable risk factors that could inform prevention messages. Obesity and diet are potentially modifiable risk factors that may contribute to lymphomagenesis by influencing inflammation or carcinogen exposure. Prospective data on obesity, diet, and NHL risk are limited and inconsistent. After 14 years of follow-up in the Nurses' Health Study (NHS), we observed significant associations of fat and vegetable intake with NHL risk. We expanded these analyses to further examine the roles of obesity and diet in NHL etiology in the NHS and Health Professionals Follow-up Study (HPFS) cohorts after substantially longer follow-up. Methods: The NHS was established in 1976, when 121,700 female nurses aged 30–55 years completed a self-administered questionnaire on lifestyle behaviors and medical history. The HPFS comprises 51,529 male dentists and other health professionals aged 40–75 years at baseline in 1986. Biennial questionnaires are sent to participants to update risk factor information and identify new diagnoses and have included a validated semiquantitative food frequency questionnaire (FFQ) to assess diet every 2 to 4 years since 1980 in the NHS and 1986 in the HPFS. The present analyses included 91,227 women who completed the 1980 NHS-FFQ and 47,542 men who completed the 1986 HPFS-FFQ and had no prior history of cancer. We confirmed 966 incident diagnoses of NHL among women through 2008 and 566 cases among men through 2006. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risk of NHL associated with current and young adult (NHS, age 18; HPFS, age 21) body mass index (BMI) and selected dietary factors (i.e., total fat, animal fat, vegetable fat, saturated fat, trans fat, fruits, and vegetables). We examined updated cumulative average food and energy-adjusted nutrient intakes. Multivariable models controlled for potential confounding by age, race, BMI, height, smoking history, physical activity, and total energy intake. Results: Young adult BMI was positively associated with NHL risk in both women (p-trend=0.02) and men (p-trend=0.002) in multivariable models. Women with BMI ≥30 kg/m2 at age 18 (vs. Conclusions: These preliminary analyses in two large prospective cohorts support the hypothesis that obesity in young adulthood predicts increased risk of all NHL in both men and women. We also observed a suggested positive association of NHL risk with trans fat intake in women and a modest inverse association with vegetable intake in men and women, consistent with our earlier reports. It is plausible that there is etiologic heterogeneity across the >30 NHL histologic subtypes. Ongoing analyses to examine the relationship of obesity and diet with major NHL histologic subtypes in the NHS and HPFS may yield further insights into their roles in NHL etiology and prevention. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A73.

Objective: Vitamin D deficiency and insufficiency are common globally. Because low circulating 25-hydroxyvitamin D [25(OH)D] concentrations measured during adulthood have been associated with several disease outcomes, it is important to understand correlates of circulating 25(OH)D, especially in certain at-risk populations. Methods: Circulating 25(OH)D was assayed in 4,723 adult men and women with no diagnosed cancer from ten cohorts in the United States, Finland and China participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Data on potential correlates were obtained and harmonized by a central data coordinating center. Serum/plasma samples were assayed for 25(OH)D at Heartland Assays, Inc. using the DiaSorin LIAISON 25(OH)D TOTAL assay, a direct, competitive chemiluminescence immunoassay. We used stepwise linear regression and polytomous logistic regression to identify demographic and lifestyle correlates of circulating 25(OH)D. Results: Vitamin D deficiency (defined as 25 kg/m2, and low physical activity were associated with greater risk of vitamin D deficiency ( Conclusions: Vitamin D deficiency and insufficiency were common in this population. Multiple modifiable and non-modifiable factors were correlated with circulating 25(OH)D. These findings help identify individuals at risk for low vitamin D status, which may be useful for both clinical and research purposes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2776.

Background: Results from several recent case-control studies suggest that increased sun exposure may reduce risk of non-Hodgkin lymphoma (NHL). Vitamin D synthesis is hypothesized as one possible mechanism, since solar ultraviolet-B (UV-B) radiation exposure triggers endogenous vitamin D production in the skin. To date, no prospective studies of UV and NHL have been conducted. Methods: We identified 1057 incident cases of NHL through 2006 in the Nurses’ Health Study (NHS), a cohort study of approximately 121,700 women who have been followed since 1976. Ambient UV radiation exposure, as measured by average annual UV-B flux (in R-B counts x 10-4), was estimated for all participants based on residence at various times during life and categorized as 113. Vitamin D intake from food and supplements was calculated based on responses to food frequency questionnaires with follow-up beginning in 1980. Using plasma 25-hydroxyvitamin D (25(OH)D) measurements available for a subset of the NHS population, we developed a linear regression model to predict plasma 25(OH)D levels for the entire cohort based on multiple determinants of vitamin D status, including dietary intake and UV-B flux. Cox proportional hazards models were used to estimate incidence rate ratios (RRs) and 95% confidence intervals (CIs). The main analyses included all cases of NHL; we also performed separate analyses for the most common NHL subtypes [i.e., chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL)]. Results: For most measures of ambient UV-B flux, the risk of NHL was increased for women in the highest category of exposure (i.e., > 113) compared to the lowest (i.e., 113 ranged from 1.10 (95% CI: 0.94, 1.29) for UV-B flux based on residence in 1976 to 1.21 (95% CI: 1.00, 1.47) for UV-B flux at age 15. Positive linear trends were observed for all measures. We observed stronger associations for CLL/SLL than for FL and no association for DLBCL with most measures of UV-B flux. The RR for the highest quintile of total vitamin D intake versus the lowest, after adjusting for age, body mass index, smoking, height, multivitamin use, and intake of retinol, calcium, and total calories, was 1.02 (95% CI: 0.71, 1.46). There was no association between predicted 25(OH)D score and risk of NHL. There did not appear to be differences in effect estimates for vitamin D intake by NHL subtype. Conclusions: Our findings of weak but statistically significant positive associations between UV-B flux assessed at various time points and risk of NHL in this prospective cohort study do not support the hypothesis of a protective effect of sunlight exposure. We found no association between vitamin D intake and risk of NHL, suggesting that if UV exposure is ultimately found to reduce the risk of this cancer, the effect may not act through vitamin D. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2820.

Findings from several epidemiologic studies suggest that exposure to solar ultraviolet radiation may be associated with a reduced risk of non-Hodgkin lymphoma (NHL). These observations have led to speculation that vitamin D may protect against lymphomagenesis. To investigate this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D [25(OH)D] and subsequent NHL risk within ten cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Prediagnostic samples of serum or plasma from 1,353 cases and 1,778 controls were assayed for 25(OH)D by immunoassay at a single laboratory. Odds ratios (ORs) and 95% confidence intervals (CIs) relating categories of 25(OH)D concentration with NHL risk were calculated using conditional logistic regression models, with 50- Overall, no evidence of association with NHL risk was observed for either low 25(OH)D concentration ( Analyses of other measures of 25(OH)D {continuous log[25(OH)D], categories of 25(OH)D using sex/cohort/season-specific cutpoints, categories of season-adjusted residuals of predicted 25(OH)D} were similarly null, as were results from stratified analyses and investigations of histologic subtypes of NHL. These findings do not support the hypothesis that elevated circulating 25(OH)D levels are associated with reduced NHL risk. Future research investigating the biologic basis for the sunlight-NHL association should consider alternative mechanisms, such as immunologic effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2805.

6599 Background: Health literacy, often defined as the degree to which an individual can obtain and understand information needed to make appropriate health decisions, may lead to a decreased incidence and improved mortality for some cancers by promoting risk factor modification and adherence to treatment. As a result, nurses, who presumably possess a higher level of health literacy and access to care than the general population, might be expected to manifest a lower incidence of and better survival for the hematologic malignancies. Methods: We assessed the incidence, all-cause, and cause-specific mortality for Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) in the NHS, an ongoing cohort study of 121,700 female registered nurses aged 30–55 years at entry who have been followed for 30 years. We compared these outcomes to those in the SEER program of the National Cancer Institute, matching for age and race. Results: In over 2.5 million person-years, the incidence of HD in the NHS was the same as in SEER. The incidence of NHL, CLL and MM was slightly increased. All-cause mortality was better in the NHS when compared to SEER for HD (HR= 0.62, 95% CI: [0.38, 1.0]) and NHL (HR= 0.81, 95% CI: [0.71, 0.91]). There were no differences in cause-specific mortality, except for MM, which was worse in the NHS (HR= 1.27, 95% CI: [1.07, 1.52]). Conclusion: The incidence of hematologic malignancy is not reduced in nurses, possibly because preventable risk factors for these cancers have yet to be elucidated. To the contrary, the slight increase in incidence for NHL, MM and CLL may be due to higher levels of overall health vigilance and/or occupational exposures. The fact that cancer-related mortality is similar for nurses as compared to age and race-matched SEER controls casts doubt on the roles of health literacy and access to care in improving survival for these disorders. No significant financial relationships to disclose. [Table: see text]

Background Several studies have shown that mammographic texture features are associated with breast cancer risk independent of the contribution of breast density. Thus, texture features may provide novel information for risk stratification. We examined the association of a set of established texture features with breast cancer risk by tumor type and estrogen receptor (ER) status, accounting for breast density. Methods This study combines five case–control studies including 1171 breast cancer cases and 1659 controls matched for age, date of mammogram, and study. Mammographic breast density and 46 breast texture features, including first- and second-order features, Fourier transform, and fractal dimension analysis, were evaluated from digitized film-screen mammograms. Logistic regression models evaluated each normalized feature with breast cancer after adjustment for age, body mass index, first-degree family history, percent density, and study. Results Of the mammographic features analyzed, fractal dimension and second-order statistics features were significantly associated (p

Background High mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently. Methods Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses’ Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD. Results In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p

Introduction Overweight and obesity in childhood and adolescence are associated with reduced breast cancer risk, independent of adult body mass index (BMI). These associations may be mediated through breast density. Methods We prospectively examined associations of early life body fatness with adult breast density measured by MRI in 182 women in the Dietary Intervention Study in Children (DISC) who were ages 25–29 at follow-up. Height, weight, and other factors were measured at baseline (ages 8–10) and annual clinic visits through adolescence. We used linear mixed-effects models to quantify associations of percent breast density and dense and non-dense breast volume at ages 25–29 with quartiles of age-specific youth body mass index (BMI) Z-scores, adjusting for clinic, treatment group, current adult BMI, and other well-established risk factors for breast cancer and predictors of breast density. Results We observed inverse associations between age-specific BMI Z-scores at all youth clinic visits and percent breast density, adjusting for current adult BMI and other covariates (all p values

Background Vitamin D deficiency, which has been linked to an increased risk of colorectal cancer, is particularly common among African Americans. Previous studies of vitamin D status and breast cancer risk, mostly conducted in white women, have had conflicting results. We examined the relationship between predicted vitamin D status and incidence of breast cancer in a cohort of 59,000 African American women. Methods Participants in the Black Women’s Health Study have been followed by biennial mail questionnaires since 1995, with self-reported diagnoses of cancer confirmed by hospital and cancer registry records. Repeated five-fold cross-validation with linear regression was used to derive the best 25-hydroxyvitamin D (25(OH)D) prediction model based on measured 25(OH)D in plasma specimens obtained from 2856 participants in 2013–2015 and questionnaire-based variables from the same time frame. In the full cohort, including 1454 cases of incident invasive breast cancer, Cox proportional hazards models were used to compute the incidence rate ratio (IRR) for each quartile of predicted vitamin D score relative to the highest quartile. Predicted vitamin D score for each two-year exposure period was a cumulative average of predicted scores from all exposure periods up to that time. Results Twenty-two percent of women with measured 25(OH)D were categorized as “deficient” (

Background To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women. Methods This study included 743 cancer-free premenopausal women (mean age, 44.9 years) within the Nurses’ Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts). Results In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake (fruits, vegetables, or nuts) during adolescence were associated with any of the mammographic density phenotypes. Conclusions Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density.