Patricia Hartge

Fast track — ArticlesGenetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium

BACKGROUNDnCommon genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph).nnnMETHODSnWe selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model.nnnFINDINGSnThe tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083).nnnINTERPRETATIONnCommon polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

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

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

Metabolic gene variants and risk of non-Hodgkin's lymphoma.

Genes involved in metabolism of environmental chemical exposures exhibit sequence variability that may mediate the risk of non-Hodgkins lymphoma. We evaluated associations between non-Hodgkins lymphoma and 15 variants in AHR, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, GSTP1, GSTM3, EPHX1, NQO1, and PON1. Cases were identified from four Surveillance, Epidemiology, and End Results registries in the United States, and population-based controls were identified through random-digit dialing and Medicare eligibility files. Metabolic gene variants were characterized for the 1,172 (89% of total) cases and 982 (93%) controls who provided biological samples for genotyping. Subjects who were heterozygous or homozygous for the cytochrome P450 gene variant CYP1B1 V432L G allele were at slightly greater risk of non-Hodgkins lymphoma [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 0.97-1.65]; these results were consistent across B-cell lymphoma subtypes and among both non-Hispanic White and Black subjects, although not statistically significant. The CYP2E1 −1054T allele was associated with decreased risk of non-Hodgkins lymphoma (CT and TT genotypes combined OR, 0.59; 95% CI, 0.37-0.93), and this pattern was observed among all histologic subtypes. The numbers of cases of particular subtypes were rather small for stable estimates, but we noted that the PON1 L55M AA allele, associated with slightly increased risk of non-Hodgkins lymphoma (variant homozygotes OR, 1.36; 95% CI, 0.96-1.95), was most strongly associated with follicular non-Hodgkins lymphoma and T-cell lymphoma, with ORs for variant homozygotes of 2.12 and 2.93, respectively. There was no overall association with non-Hodgkins lymphoma for the other gene variants we examined. The modest effects we observed may reflect the context of exposures within the general population represented in our study. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1647–53)

Medication use and risk of ovarian carcinoma: a prospective study.

Inflammation and gonadotropins are hypothesized to influence ovarian carcinogenesis. In a prospective study, we evaluated ovarian cancer risk associated with self‐reported use of medications that influence inflammation or gonadotropin levels. The Breast Cancer Detection Demonstration Project Follow‐Up Study enrolled 61,431 women in 1979 and used telephone interviews and 3 mailed questionnaires through 1998 to update risk factor information and identify incident ovarian cancers. The 1992–95 questionnaire ascertained medication use, including duration and frequency of use for aspirin, acetaminophen, other nonsteroidal anti‐inflammatory drugs (NSAIDs), tranquilizers and histamine‐receptor antagonists. A Poisson regression analysis generated rate ratios (RRs) and 95% confidence intervals (CIs) for the 31,364 women who were at risk of ovarian cancer and responded to the questionnaire that queried regular medication use. One hundred sixteen women developed ovarian cancer during follow‐up. None of the anti‐inflammatory medications was associated with ovarian cancer, but the RR for more than 1 aspirin per day for 1 year or longer was 0.56 (95% CI 0.20–1.5) and the RR for more than 5 years of regular “other NSAID” use was 2.0 (95% CI 0.95–4.2). Regular tranquilizer use was not associated with ovarian cancer, but histamine‐receptor antagonists used regularly for more than 5 years (RR = 3.6, 95% CI 1.4–9.1) or more than once daily (RR = 3.1, 95% CI 1.5–6.5) appeared to increase risk. In our study, neither anti‐inflammatory medications nor anti‐psychotic medications were associated with ovarian cancer. Potential associations with histamine‐receptor antagonists may warrant further study.

Determinants of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in house dust samples from four areas of the United States

Determinants of levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) in dust in U.S. homes are not well characterized. We conducted a pilot study to evaluate the relationship between concentrations of PCDD/F in house dust and residential proximity to known sources, including industrial facilities and traffic. Samples from vacuum bag dust from homes of 40 residents of Detroit, Los Angeles, Seattle, or Iowa who participated in a population-based case-control study of non-Hodgkin lymphoma conducted in 1998-2000 were analyzed using high resolution gas chromatography/high resolution mass spectrometry for 7 PCDD and 10 PCDF congeners considered toxic by the U.S. Environmental Protection Agency (EPA). Locations of 10 types of PCDD/F-emitting facilities were obtained from the EPA; however only 4 types were located near study homes (non-hazardous waste cement kilns, coal-fired power plants, sewage sludge incinerators, and medical waste incinerators). Relationships between concentrations of each PCDD/F and proximity to industrial facilities, freight routes, and major roads were evaluated using separate multivariate regression models for each congener. The median (inter-quartile range [IQR]) toxic equivalence (TEQ) concentration of these congeners in the house dust was 20.3 pg/g (IQR=14.3, 32.7). Homes within 3 or 5 km of a cement kiln had 2 to 9-fold higher concentrations of 5 PCDD and 5 PCDF (p<0.1 in each model). Proximity to freight routes and major roads was associated with elevated concentrations of 1 PCDD and 8 PCDF. Higher concentrations of certain PCDD/F in homes near cement kilns, freight routes, and major roads suggest that these outdoor sources are contributing to indoor environmental exposures. Further study of the contribution of these sources and other facility types to total PCDD/F exposure in a larger number of homes is warranted.

Occupation/industry and-risk of non-Hodgkin's lymphoma in the United States

Aims: To identify occupations and industries associated with non-Hodgkin’s lymphoma (NHL) in a large population-based, case-control study in the USA. Methods: Cases (nu200a=u200a1189) of histologically confirmed malignant NHL ages 20–74 were prospectively identified in four geographic areas covered by the National Cancer Institute SEER Program. Controls (nu200a=u200a982) were selected from the general population by random digit dialling (<65 years of age) and from residents listed in Medicare files (65–74 years of age). Odds ratios and 95% confidence intervals for occupations and industries were calculated by unconditional logistic regression analyses, adjusting for age, gender, ethnicity and study centre. Further analyses stratified for gender and histological subtype were also performed. Results: Risk of NHL was increased for a few occupations and industries. Several white collar occupations, with no obvious hazardous exposures, had elevated risks, including purchasing agents and buyers, religious workers, physical therapists and information clerks. Occupations with excesses that may have exposures of interest include launderers and ironers, service occupations, food/beverage preparation supervisors, hand packers and packagers, roofing and siding, leather and leather products, transportation by air, nursing and personal care facilities, and specialty outpatient clinics. Significantly decreased risks of NHL were found for a number of occupations and industries including post-secondary teachers and chemical and allied products. Conclusions: The results of this study suggest that several occupations and industries may alter the risk of NHL. Our results support previously reported increased risks among farmers, printers, medical professionals, electronic workers and leather workers. These findings should be evaluated further in larger studies that have the power to focus on specific exposures and histological subtypes of NHL.

Relationship between interferon regulatory factor 4 genetic polymorphisms, measures of sun sensitivity and risk for non-Hodgkin lymphoma.

ObjectiveSun exposure and sensitivity, including pigmentation, are associated with risk for non-Hodgkin lymphoma (NHL). One variant in the immune regulatory factor 4 (IRF4) gene (rs12203592) is associated with pigmentation, and a different IRF4 variant (rs12211228) is associated with NHL risk. We evaluated the independent roles of these IRF4 polymorphisms and sun sensitivity in mediating NHL risk and explored whether they are confounded or modified by each other.MethodsGenotyping of tag single nucleotide polymorphisms (SNPs) in the IRF4 gene was conducted in 990 NHL cases and 828 controls from a multi-center US study. Measures of sun sensitivity and exposure were ascertained from computer-assisted personal interviews. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL in relation to sun exposures, sun exposures in relation to IRF4 genotypes, and NHL in relation to sun exposures. We further assessed the effects of sun exposures in relation to IRF4 genotypes.ResultsAs previously reported, we found significant associations between IRF4 rs12211228 and NHL and between hair and eye color and NHL. The IRF4 rs12203592 polymorphism (CT/TT genotype) was statistically significantly associated with eye color and particularly with hair color (ORLight Blondexa0=xa00.24, 95% CIxa0=xa00.11–0.50, overall Chi square pxa0=xa00.0002). Analysis of joint effects between eye and hair color with the IRF4 rs12203592 SNP did not reveal statistically significant p-interactions although NHL risk did decline with lighter hair color and presence of the variant IRF4 rs12203592 allele, compared to those without a variant allele and with black/brown hair color.ConclusionsOur data do not statistically support a joint effect between IRF4 and sun sensitivity in mediating risk for NHL. Further evaluation of joint effects in other and larger populations is warranted.

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

Familial cancer can be used to leverage genetic association studies. Recent genome‐wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first‐ or second‐degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty‐one glioma cases and 2,868 cancer‐free controls were identified from four case–control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case–control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A‐CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25–0.61; Bonferroni adjusted ptrend, 1.7 × 10−4). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

Degreasing and risk of non-Hodgkin lymphoma.

Objective: To investigate the relationship between selected solvent-related workplace tasks (degreasing, painting, gluing, stripping paint, staining) and risk of non-Hodgkin lymphoma (NHL). Methods: We analysed occupational data from a large population-based case-control study of NHL conducted in the USA. For participants reporting occupations with possible exposure to organic solvents, job-specific interview modules were administered to elicit in-depth information on solvent-related workplace tasks and other exposure-related factors (225 cases, 189 controls). Unconditional logistic regression models were fit to calculate odds ratios (ORs) and 95% CI for average frequency, maximal frequency and cumulative number of hours having performed each task. Individuals with jobs rated as unexposed to organic solvents in the workplace (180 cases, 213 controls) were used as a reference group. Results: We observed an increased risk of NHL among subjects in the highest category of maximal degreasing frequency (>520 h/year: OR 2.1, 95% CI 0.9 to 4.9, trend test pu200a=u200a0.02). We found similar associations for the highest levels of average frequency and, among men, cumulative number of hours. Other solvent-related tasks were not associated with NHL. Conclusion: Findings from this case-control analysis of solvent-related tasks suggest that frequent degreasing work may be associated with an elevated risk of NHL.

Antibiotic use and risk of non-Hodgkin's lymphoma: a population-based case-control study

Antibiotic use in 759 non-Hodgkins lymphoma (NHL) patients and 589 controls was compared. Neither total antibiotic use (odds ratio=0.7, 95% confidence interval=0.5–1.2), nor antibiotic use by site, was associated with total NHL, or NHL subtypes. There were no trends with frequency or age at first use (P trend=0.23 and 0.26, respectively).