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1.  Rates and Outcomes of Follicular Lymphoma Transformation in the Immunochemotherapy Era: A Report From the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource 
Journal of Clinical Oncology  2013;31(26):3272-3278.
This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use.
Patients and Methods
Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk.
In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001).
Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.
PMCID: PMC3757293  PMID: 23897955
2.  CXCR5 polymorphisms in non-Hodgkin lymphoma risk and prognosis 
CXCR5 [chemokine (C-X-C motif) receptor 5; also known as Burkitt lymphoma receptor 1 (BCR1)] is expressed on mature B-cells, subsets of CD4+ and CD8+ T-cells, and skin-derived migratory dendritic cells. Together with its ligand, CXCL13, CXCR5 is involved in guiding B-cells into the B-cell zones of secondary lymphoid organs as well as T-cell migration. This study evaluated the role of common germline genetic variation in CXCR5 in the risk and prognosis of non-Hodgkin lymphoma (NHL) using a clinic-based study of 1521 controls and 2694 NHL cases including 710 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), 586 diffuse large B-cell lymphoma (DLBCL), 588 follicular lymphoma (FL), 137 mantle cell lymphoma (MCL), 230 marginal zone lymphoma (MZL) and 158 peripheral T-cell lymphoma (PTCL). Of the ten CXCR5 tag SNPs in our study, five were associated with risk of NHL, with rs1790192 having the strongest association (OR=1.19, 95%CI 1.08–1.30; p=0.0003). This SNP was most strongly associated with the risk of FL (OR=1.44, 95%CI 1.25–1.66; p=3.1×10−7), with a lower degree of association with DLBCL (OR=1.16, 95%CI 1.01–1.33; p=0.04) and PTCL (OR=1.29, 95%CI 1.02–1.64; p=0.04) but no association with the risk of MCL or MZL. For FL patients that were observed as initial disease management, the number of minor alleles of rs1790192 was associated with better event-free survival (EFS) (HR=0.64; 95%CI 0.47–0.87; p=0.004). These results provide additional evidence for a role of host genetic variation in CXCR5 in lymphomagenesis, particularly for FL.
PMCID: PMC3758443  PMID: 23812490
non-Hodgkin lymphoma; SNPs; prognosis; prospective cohort; case-control
3.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
PMCID: PMC3699726  PMID: 23733771
4.  Blood Transfusion, Anesthesia, Surgery and Risk of Non-Hodgkin Lymphoma in a Population-Based Case-Control Study 
The incidence of NHL has increased dramatically since at least the 1950s, and during this timeframe there has been a major increase in the use of blood transfusions, invasive surgical procedures, and anesthesia, all of which can impact immune function. We evaluated these factors with NHL risk in a population-based study of 759 cases and 589 frequency-matched controls. Risk factor data were collected during in-person interviews. Unconditional logistic regression was used to estimate ORs and 95% CIs, adjusted for the matching factors. History of transfusion was associated with a 26% higher risk of NHL (95% CI 0.91–1.73), and the elevated risk was specific to transfusions first given 5–29 years before the reference date (OR=1.69; 95% CI 1.08–2.62) and transfusions given for a medical condition (OR=2.09; 95% CI 1.03–4.26). The total number of surgeries and dental procedures (OR=1.53 for 26+ surgeries compared to 0–6; 95% CI 1.02–2.29) and to a lesser extent the total number of exposures to general or local/regional anesthesia (OR=1.35 for 24+ times compared to 0–6; 95% CI 0.91–2.02) were positively associated with risk of NHL. Inclusion of transfusion and surgery or transfusion and anesthesia in the same model did not attenuate these associations. All results were broadly consistent for both DLBCL and follicular subtypes. Blood transfusions were associated with NHL risk, but appear to be a marker for underlying medical conditions. Multiple surgical procedures and/or repeated administration of anesthesia have not been previously reported to be associated with risk of NHL and these exposures warrant further evaluation.
PMCID: PMC3913466  PMID: 18506687
anesthesia; blood transfusion; non-Hodgkin lymphoma; surgery
5.  Farm residence and lymphohematopoietic cancers in the Iowa Women’s Health Study 
Environmental research  2014;133:353-361.
Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women’s Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes.
We analyzed data for a cohort of 37,099 Iowa women aged 55–69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986–2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage.
As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR= 2.23, 95%CI: 1.25–3.99) or rural areas (but not on a farm) (HR= 1.95, 95%CI: 0.89–4.29) compared with women living in towns of > 10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles= 1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage= 1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively.
Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted.
PMCID: PMC4324553  PMID: 25038451
Farm residence; Pesticides; Iowa Women’s Health Study; GIS; Land use
6.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
PMCID: PMC4287989  PMID: 25569183
7.  The Association between Early Life and Adult Body Mass Index and Physical Activity with Risk of non-Hodgkin Lymphoma: Impact of Gender 
Annals of epidemiology  2012;22(12):855-862.
To evaluate the association of body mass index (BMI) and physical activity (PA) during adulthood and at age 18 with risk of non-Hodgkin lymphoma (NHL).
We enrolled 950 newly diagnosed NHL patients and 1146 frequency-matched clinic-based controls. Height, weight, and PA (recent adult and at age 18) were self-reported. Odds ratios (OR), 95% confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression adjusted for age, gender, and residence.
BMI at age 18 was associated with an increased NHL risk (OR=1.38 for highest vs. lowest quartile, p-trend=0.0012), which on stratified analysis was specific to females (OR=1.90, p-trend=0.00025). There was no association of adult BMI with NHL risk. Higher physical activity in adulthood (OR=1.03, p-trend=0.85) or at age 18 (OR=0.88, 95%CI: 0.72–1.07) was not associated with risk, but there was an inverse association for adult physical activity that was specific to females (OR=0.71, p-trend=0.039). Only BMI at age 18 remained significantly associated with NHL risk when modeled together with adult or age 18 physical activity. There was little evidence for heterogeneity in these results for the common NHL subtypes.
Early adult BMI may be of greatest relevance to NHL risk, particularly in females.
PMCID: PMC3513768  PMID: 23146413
body mass index; exercise; lymphoma; non-Hodgkin; etiology; case-control studies
8.  Pretreatment Circulating Serum Cytokines Associated with Follicular and Diffuse Large B-Cell Lymphoma: A Clinic-Based Case-Control Study 
Cytokine  2012;60(3):882-889.
Abnormal immune function is a key factor in predisposition to non-Hodgkin lymphoma (NHL). We evaluated the association of 30 cytokines individually and as a profile with diffuse large B-cell (DLBCL) and follicular (FL) lymphomas.
We used a multiplexed assay to measure 30 cytokine concentrations in pre-treatment serum in a case-control study of 234 FL, 188 DLBCL, and 400 control participants. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age and sex, and polytomous regression was used to evaluate heterogeneity between FL and DLBCL. Principal components analysis (PCA) was used to assess cytokine profiles associated with FL and DLBCL.
In single cytokine modeling, we found that 12 of the 30 circulating serum cytokines were significantly (P<0.05) associated with FL and/or DLBCL after accounting for multiple testing (q<0.05). Soluble IL-2R (sIL-2R) had the strongest association with both FL (OR=6.0 for highest versus lowest tertile, 95% CI 3.8–9.5; p-trend=1.8 × 10−21) and DLBCL (OR=7.6, 95% CI 4.5–13.1; p-trend=7.2 × 10−20). IL1RA and IL-12p40 also showed similar associations for DLBCL and FL. In contrast, HGF, MIG, and MIP-1α had a stronger association with DLBCL compared to FL, and IL-6, IL-8, IL-10, IFN-γ, IP-10, and VEGF were only statistically significantly associated with DLBCL after accounting for multiple testing. However, in PCA modeling, a cytokine profile based on sIL-2R, IL-1RA, MIG, IP-10, IL-8, and IL-12p40 explained most of the variability between controls and both FL and DLBCL.
We identified some single cytokines unique to DLBCL, but overall cytokine associations were more similar than distinct for DLBCL and FL. While these data are limited by concerns of reverse causality, they do suggest cytokines and cytokine profiles that can be prioritized in future studies.
PMCID: PMC3483382  PMID: 23010502
non-Hodgkin lymphoma; biomarkers; cytokines; case-control
9.  Accuracy of Self-Reported Tobacco Use Status among Hematopoietic Stem Cell Transplant (HSCT) Patients 
Bone marrow transplantation  2014;49(7):961-965.
Tobacco use is a risk factor for adverse outcomes among Hematopoietic Stem Cell Transplant (HSCT) patients. Accurate identification of tobacco use offers a vital opportunity to treat this risk factor. The current study compared self-reported tobacco use status to serum cotinine levels among HSCT patients at time of pre-transplant evaluation. A total of 444 participants completed both assessments; 44 participants (9.9%) were classified as tobacco users with serum cotinine concentrations > 2ng/Ml versus 29 with self-report. Sensitivity and specificity of self-report were 65.9% and 100%. Positive predictive and negative predictive values were 100% and 96.4%. Comparing tobacco use documented in the medical record with cotinine, sensitivity and specificity were 51.2% and 99.2%. Factors associated with tobacco use were male gender, single relationship status, less education, and younger age. In summary, utilization of serum cotinine assays increased detection of tobacco use cases more than 50% over self-report. Results are discussed in context of translation to care, including clinical and ethical implications, and current tobacco use treatment guidelines. When cotinine assays are not available, self-report of any tobacco use in the year prior to HSCT should trigger brief advice and cessation or relapse prevention counseling.
PMCID: PMC4162628  PMID: 24732958
Cotinine; Tobacco; Smoking; Transplant; Cancer
10.  A Two-Stage Evaluation of Genetic Variation in Immune and Inflammation Genes with Risk of Non-Hodgkin Lymphoma Identifies New Susceptibility Locus in 6p21.3 Region 
Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology.
To identify susceptibility immune genes, we conducted a 2-stage analysis of single nucleotide polymorphisms (SNPs) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the Odds Ratios (ORs) and 95% confidence intervals (CI).
In the pooled analysis, only the TAP2 coding SNP rs241447 (MAF=0.26; Thr655Ala) at 6p21.3 (OR=1.34, 95%CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (p=3.1 × 10−5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR=1.82, 95%CI 1.46-2.26; p=6.9 × 10−8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR=1.38, 95% CI 1.08-1.77; p=0.011), but not chronic lymphocytic leukemia (OR=1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors.
Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3.
Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
PMCID: PMC3467356  PMID: 22911334
genetics; non-Hodgkin lymphoma; immune function; single nucleotide polymorphisms
11.  Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Study 
Journal of Clinical Oncology  2012;30(27):3368-3375.
The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT).
Patients and Methods
We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database.
Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival.
In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.
PMCID: PMC3675665  PMID: 22915662
While the International Prognostic Score (IPS) is the gold standard for risk-stratifying patients with classical Hodgkin lymphoma (cHL), these criteria do not accurately predict outcome. As cytokines are critically involved in driving cHL, we tested whether pretreatment serum cytokine levels could provide additional prognostic information.
Experimental Design:
Thirty cytokines were measured in pretreatment serum from 140 cHL patients and compared with 50 non-lymphoma controls. Patients were followed for event-free and overall survival, and Cox proportional hazards regression models were used to assess the association of individual cytokines and the cytokine profiles with outcome via unadjusted and IPS-adjusted hazard ratios (HR).
Twelve cytokines (EGF, FGFb, GCSF, HGF, IL-6, IL-8, IL-12, IL-2R, IP-10, MIG, TNFa and VEGF) were significantly (p<0.05) higher in cHL patients than controls; elevated levels of HGF, IL-6, IL-2R, IP-10 and MIG were all associated with poorer event-free survival (EFS). Only IL-2R (p=0.002) and IL-6 (p<0.001) were independently prognostic. Patients with increased IL-6 and IL-2R had a significantly higher risk of early relapse and death, a finding that remained significant even after IPS-based risk stratification. While elevated IL-6 and IL-2R correlated with the IPS, sCD30 and TARC levels, the 2-cytokine model remained independently predictive of prognosis.
Elevated pretreatment serum cytokines are associated with increased disease relapse and inferior survival in cHL. Thus, the pretreatment cytokine profile, particularly serum levels of IL-6 and IL-2R, may be used to identify cHL patients at high risk for early disease relapse.
PMCID: PMC3867576  PMID: 24141626
13.  Food-Frequency Questionnaire Based Estimates of Total Antioxidant Capacity and Risk of Non-Hodgkin Lymphoma 
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
PMCID: PMC3306533  PMID: 22038870
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
14.  Germline Variation in Complement Genes and Event-Free Survival in Follicular and Diffuse Large B-Cell Lymphoma 
American journal of hematology  2012;87(9):880-885.
The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N=107) and DLBCL (N=82) patients enrolled at the Mayo Clinic from 2002–2005. Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (p=0.009), CD55 (p=0.006), CFHR5 (p=0.01), C9 (p=0.02), CFHR1 (p=0.03), and CD46 (p=0.03) were significant at p<0.05, and these genes remained noteworthy after accounting for multiple testing (q<0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (p=0.001) and C7 (p=0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the Regulators of Complement Activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
PMCID: PMC3586263  PMID: 22718493
non-Hodgkin lymphoma; complement pathway; SNPs; prognosis; prospective cohort
15.  The Mayo Clinic Biobank: A building block for individualized medicine 
Mayo Clinic proceedings  2013;88(9):952-962.
To report the design and first three years of enrollment of the Mayo Clinic Biobank.
Preparations for this Biobank began with a 4-day Deliberative Community Engagement with local residents to obtain community input into the design and governance of the biobank. Recruitment, which began in April 2009, is ongoing with a target goal of 50,000. Any Mayo Clinic patient who is 18+ years, able to consent, and a US resident is eligible to participate. Each participant completes a health history questionnaire, provides a blood sample and allows access to existing tissue specimens and all data from their Mayo Clinic medical record (EMR). A Community Advisory Board provides ongoing advice and guidance on complex decisions.
After three years of recruitment, 21,736 subjects have enrolled. Participants were 58% female, 95% of European ancestry, and median age of 62 years. Seventy-four percent lived in Minnesota, 42% from Olmsted County where the Mayo Clinic Rochester is located. The five most commonly self-reported conditions were hyperlipidemia (41%), hypertension (38%), osteoarthritis (30%), any cancer (29%), and gastroesophageal reflux disease (26%). Among self-reported cancer patients, the five most common types were non-melanoma skin cancer (14%), prostate cancer (12% in men), breast cancer (4%), melanoma (3%), and cervical cancer (2% in women). Fifty-six percent of participants had at least 15 years of EMR history. To date, over sixty projects and over 69,000 samples have been approved for use.
The Mayo Clinic Biobank has quickly been established as a valuable resource for researchers.
PMCID: PMC4258707  PMID: 24001487
16.  Sugar-sweetened beverage intake and the risk of type I and type II endometrial cancer among postmenopausal women 
Sugar-sweetened beverage (SSB) intake has been associated with an increased risk of obesity and type II diabetes. However, its association with endometrial cancer is unclear.
We evaluated dietary intake of SSB, fruit juice, sugar-free beverages, sweets/baked goods, starch, and sugars among 23,039 postmenopausal women in the Iowa Women’s Health Study. Incident estrogen-dependent type I and estrogen-independent type II endometrial cancers were identified via linkage with the SEER Registry. Risks of type I and type II endometrial cancers were separately compared by energy-adjusted dietary intake in Cox proportional hazards regression models.
From 1986 to 2010, 506 type I and 89 type II incident endometrial cancers were identified. An increased risk of type I endometrial cancer was observed with increasing SSB intake after adjustment for BMI and other cofounders (ptrend=0.0005). Compared to non-drinkers of SSB, the risk was 78% higher (95% CI=1.32-2.40) among women in the highest quintile of SSB intake. The observed association was not modified by BMI, physical activity, history of diabetes, or cigarette smoking. Higher risk of type I endometrial cancer was also observed with higher intake of sugars. None of the dietary items included in the analysis was associated with type II endometrial cancer risk.
Higher intake of SSB and sugars were associated with an increased risk of type I, but not type II, endometrial cancer.
SSB intake may be a risk factor for type I endometrial cancer regardless of other lifestyle factors.
PMCID: PMC3892378  PMID: 24273064
Sugar-sweetened beverage; endometrial cancer; postmenopausal
17.  The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin’s lymphoma 
American journal of hematology  2013;88(12):997-1000.
There has been an overall decline in the United States incidence of Primary CNS Lymphoma (PCNSL) from 1998 to 2008. This study’s intent was to characterize the cohorts contributing to it. First, calculated the PCNSL incidence rates from nine Surveillance, Epidemiology, and End Results (SEER) registries for time period 1973 to 2008. Second, examined the time trends overall and by age and gender. Third, used 1992–2008 SEER data from the same registries to obtain overall trends for diffuse large B-cell lymphoma (DLBCL). Last, rates were age-adjusted to the 2000 US standard population and reported per 100,000 person-years. Rates continued to increase in women at all ages and men aged 65 and older. In men aged 20–39 and 40–64 years incidence rates peaked in 1995 and then declined dramatically, stabilizing after 1998. The trends in the incidence of PCNSL over this time frame were significantly different from DLBCL for ages 20–39 (P < 0.001) and 40–64 (P < 0.001) years but were not different for the 65 years and older age group (P = 0.99). The overall PCNSL incidence rate declined since 1995 and was driven primarily by the changing incidence in young and middle-aged men. The rate has continued to increase in men aged 65 years and older and in women. The trends in incidence in the younger age groups over this time period did not parallel those observed for DLBCL.
PMCID: PMC4020348  PMID: 23873804
18.  LMO2 protein expression, LMO2 germline genetic variation, and overall survival in diffuse large B-cell lymphoma in the pre-rituximab era 
Leukemia & lymphoma  2012;53(6):1105-1112.
Both LMO2 mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival; however, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (HR=0.55; 95% CI 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p<0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p=0.02). Compared to a model with clinical factors only (c-statistic=0.676), adding the 4 SNPs (c-statistic=0.751) or LMO2 IHC (c-statistic=0.691) increased the predictive ability of the model, while inclusion of all 3 factors (c-statistic=0.754) did not meaningfully add predictive ability above a model with clinical factors and the 4 SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.
PMCID: PMC3575512  PMID: 22066713
Diffuse large B-cell lymphoma; LMO2; prognosis; single nucleotide polymorphisms
19.  Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: Results from two independent cohorts 
Cytokine  2013;64(2):523-531.
Cytokines are important immune mediators of classical Hodgkin lymphoma (CHL) pathogenesis, and circulating levels at diagnosis may help predict prognosis. Germline single nucleotide polymorphisms (SNPs) in immune genes have been correlated with cytokine production and function.
We investigated whether selected germline SNPs in IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629), IL6 (rs1800795), ILRN (rs419598), INFG (rs2430561) and CCL17 (rs223828) were associated with circulating levels of related cytokines at diagnosis and progression-free survival (PFS) in CHL. Patients were from France (GELA, N = 464; median age = 32 years) and the United States (Iowa/Mayo Specialized Program Of Research Excellence [SPORE], N = 239; median age = 38 years); 22% of 346 CHL cases with EBV tumor status were positive.
There was no association with any of the SNPs with cytokine levels. Overall, there was no association of any of the SNPs with PFS. In exploratory analyses by EBV status, TNFA rs1800629 (HRAA/AG = 2.41; 95%CI, 1.17–4.94) was associated with PFS in EBV-negative GELA patients, with similar trends in the SPORE patients (HRAA/AG = 1.63; 95%CI, 0.61–4.40). In a meta-analysis of the two studies, TNFA (HRAA/AG = 2.11; 95%CI, 1.18–3.77; P = 0.01) was statistically significant, and further adjustment for the international prognostic system did not alter this result.
This study showed that germline variation in TNFA was associated with CHL prognosis for EBV-negative patients, which will require confirmation. These results support broader studies on the differential impact of genetic variation in immune genes on EBV-positive vs. EBV-negative CHL pathogenesis.
PMCID: PMC4017856  PMID: 24008079
Hodgkin lymphoma; Cytokines; Polymorphism; TNFA; EBV
20.  FCGR2A and FCGR3A polymorphisms in classical Hodgkin lymphoma by EBV status 
Leukemia & lymphoma  2013;54(11):2571-2573.
PMCID: PMC3999590  PMID: 23597143
FCGR2A; FCGR3A; polymorphism; EBV; Hodgkin Lymphoma
21.  Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust 
Environmental science & technology  2013;47(18):10405-10414.
Polychlorinated biphenyls (PCBs), banned in the United Sates in the late 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of 5 PCB congeners (105, 138, 153, 170, 180) in carpet dust collected between 1998–2000 from 1,187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad, percentage of developed land, number of industrial facilities within 2 km of residences, and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCBs levels (all congeners < maximum practical quantitation limit [MPQL] vs. at least one congener ≥ MPQL to < median concentration vs. at least one congener >median concentration) were positively associated with either percentage of developed land (ORrange: 1.01-1.04 for each percentage increase) or population density (OR: 1.08 for every 1,000/mi2) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and the direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.
PMCID: PMC4076890  PMID: 23952055
22.  Patients with Heart Failure Have an Increased Risk of Incident Cancer 
To evaluate the risk of cancer in patients with heart failure (HF) compared to community controls and its impact on outcome.
HF is associated with excess morbidity and mortality. Non-cardiac causes of adverse outcomes in HF are increasingly recognized but not fully characterized.
In a case-control study, we compared history of cancer among community subjects newly diagnosed with HF from 1979–2002 to age-, sex-, and date-matched community controls without HF (961 pairs). Individuals without cancer at index (596 pairs) were followed for cancer in a cohort design, and the survival of HF patients who developed cancer was assessed.
Before index, 22% of HF cases and 23% of controls had a history of cancer (odds ratio 0.94; 95% CI 0.75–1.17). During 9,203 person-years of follow-up [mean (SD), 7.7 (6.4) years], 244 new cancer cases were identified; HF patients had a 68% higher risk of developing cancer [hazard ratio (HR) 1.68; 95% CI 1.13–2.50] adjusted for body mass index, smoking and comorbidities. The HRs were similar for men and women with a trend toward a stronger association among subjects ≤75 years (P=0.22) and during the most recent time period (P=0.075). Among HF cases, incident cancer increased the risk of death (HR 1.56; 95% CI 1.22–1.99) adjusted for age, sex, year and comorbidities.
HF patients are at increased risk of cancer, which appears to have increased over time. Cancer increases mortality in HF underscoring the importance of non-cardiac morbidity and of cancer surveillance in the management of HF patients.
PMCID: PMC3758775  PMID: 23810869
heart failure; cancer; risk; epidemiology; follow-up studies
23.  Hospitalizations and Emergency Department Use of Mayo Clinic Biobank Participants within the Employee and Community Health Medical Home 
Mayo Clinic proceedings  2013;88(9):963-969.
To evaluate the participants in the Mayo Clinic Biobank for their representativeness to the entire Employee and Community Health (ECH) primary care population with regards to hospital utilization.
Patient and Methods
Participants enrolled in the Mayo Clinic Biobank from April 1, 2009, to December 31, 2010, were linked to ECH panels. Subjects were categorized into risk tiers (0–4) based on the number of health conditions as of December 31, 2010. Outcomes were ascertained through December 31, 2011. Hazard ratios (HR) and 95% confidence intervals (CI) for risk of hospitalization, ER visits, and 30-day re-hospitalization were estimated using Cox regression, accounting for age and sex.
The 8,927 Biobank participants were part of an ECH panel (N=84,872). Compared to all of ECH, the Biobank-ECH participants were more likely to be female (64% vs 55%), older (median age of 58 years vs 47 years), and have a lower percentage in tier 0 (6% vs 24%). There were strong positive associations of tier (4 vs 0/1) with risk of hospitalization (HR=5.8; 95% CI, 4.6–7.5) and ER visits (HR=5.4; 95% CI, 4.2–6.8), among Biobank-ECH participants. Similar associations for risk of hospitalization (HR=8.5; 95% CI, 7.8–9.3) and ER visits (HR=6.9; 95%CI, 6.4–7.5) were observed for all of ECH.
Biobank-ECH participants were older and had more chronic conditions compared to the ECH panel. Nevertheless, the associations of risk tier with utilization outcomes were similar, supporting the use of the Biobank-ECH participants for assessing biomarkers for health care outcomes in the primary care setting.
PMCID: PMC4151531  PMID: 24001488
24.  Associations Between Colorectal Cancer Molecular Markers and Pathways With Clinicopathologic Features in Older Women 
Gastroenterology  2013;145(2):348-356.e2.
Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women’s Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times.
We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest.
Patients’ mean age (P = .03) and tumors’ anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07–2.89, compared with the traditional pathway).
We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.
PMCID: PMC3772766  PMID: 23665275
Molecular Epidemiology; Colon Cancer; Prognostic Factor; Integrated Pathways
25.  Risk of adult acute and chronic myeloid leukemia with cigarette smoking and cessation 
Cancer epidemiology  2013;37(4):10.1016/j.canep.2013.03.012.
Cigarette smoking is an established risk factor for adult myeloid leukemia, particularly acute myeloid leukemia (AML), but less is known about the nature of this association and effects of smoking cessation on risk.
In a large population-based case-control study of myeloid leukemia that included 414 AML and 185 chronic myeloid leukemia (CML) cases and 692 controls ages 20–79 years, we evaluated risk associated with cigarette smoking and smoking cessation using unconditional logistic regression methods and cubic spline modeling.
AML and CML risk increased with increasing cigarette smoking intensity in men and women. A monotonic decrease in AML risk was observed with increasing time since quitting, whereas for CML, the risk reduction was more gradual. For both AML and CML, among long-term quitters (≥30 years), risk was comparable to non-smokers.
Our study confirms the increased risk of myeloid leukemia with cigarette smoking and provides encouraging evidence of risk attenuation following cessation.
PMCID: PMC3819424  PMID: 23643192
Leukemia; Acute myeloid leukemia; Chronic myeloid leukemia; Cigarette smoking; Smoking cessation

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