Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Case-control investigation of occupational exposure to chlorinated solvents and non-Hodgkin's lymphoma.

OBJECTIVES: Although many studies have investigated the association between trichloroethylene (TCE) exposure and non-Hodgkin's lymphoma (NHL), less is known about other chlorinated solvents. We extended our previous analysis of occupational TCE exposure in a multicentre population-based case-control study of NHL to investigate associations with five additional chlorinated solvents: 1,1,1,-trichloroethane, carbon tetrachloride, chloroform, methylene chloride and perchloroethylene. METHODS: Cases (n=1189) and controls (n=982) provided detailed information on their occupational histories and workplace exposure to chlorinated solvents for selected occupations using job-specific interview modules. An industrial hygienist used this information and a review of the literature to assess occupational exposure to chlorinated solvents. We computed ORs and 95% CIs for different exposure metrics, with the unexposed group as the referent. We also computed ORs by NHL subtype. RESULTS: High cumulative hours exposed to carbon tetrachloride was associated with NHL (>520 hours: OR 1.9; 95% CI 1.0 to 3.6; Ptrend=0.04). This association remained after restricting to jobs with high-intensity exposure (OR 2.0; 95% CI 1.1 to 3.8; P=0.03) and ≥90% exposure probability (OR 2.1; 95% CI 1.0 to 4.3; P=0.03), adjusting for TCE (OR 2.1; 95% CI 1.0- to 4.1; P=0.04) and incorporating a 15-year lag (OR 1.9; 95% CI 1.0 to 3.6; P=0.06). The other evaluated chlorinated solvents were not associated with NHL. CONCLUSIONS: This is the first study using high-quality quantitative exposure assessment methods to identify a statistically significant elevated association between occupational exposure to carbon tetrachloride and NHL. Our findings, although limited by a small number of exposed cases, offer evidence that carbon tetrachloride may be a lymphomagen.

Differential effects of patient-related factors on the outcome of radiation therapy for rectal cancer.

OBJECTIVE: The objective of this study was to investigate whether cancer specific survival in rectal cancer patients is affected by patient-related factors, conditional on radiation treatment. METHODS: 359 invasive rectal cancer patients who consented and provided questionnaire data for a population-based case-control study of colorectal cancer in Metropolitan Detroit were included in this study. Their vital status was ascertained through to the population-based cancer registry. Hazard ratios (HR) for cancer specific and other deaths and 95% confidence intervals (CIs) were calculated according to selected patients' characteristics, stratified by radiation status, using joint Cox proportional hazards models. RESULTS: A total of 159 patients were found to be deceased after the median follow-up of 9.2 years, and 70% of them were considered to be cancer specific. Smoking and a history of diabetes were associated with an increased probability of deaths from other causes (HR 3.20, 95% CI 1.72-5.97 and HR 2.02, 95% CI 0.98-4.16, respectively), while regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was inversely correlated with cancer-specific mortality (HR 0.50, 95% CI 0.30-0.81). Furthermore, the associations of smoking and NSAIDs with the two different types of deaths (cancer vs others) significantly varied with radiation status (P-values for the interactions= 0.014 for both). In addition, we observed a marginally significantly reduced risk of cancer specific deaths in the patients who had the relative ketogenic diet overall (HR=0.49, 95% 0.23-1.02). CONCLUSION: Further research is warranted to confirm these results in order to develop new interventions to improve outcome from radiation treatment.

Polycyclic aromatic hydrocarbons: determinants of residential carpet dust levels and risk of non-Hodgkin lymphoma.

PURPOSE: To investigate the risk of non-Hodgkin lymphoma (NHL) associated with residential carpet dust measurements of polycyclic aromatic hydrocarbons (PAHs). METHODS: We evaluated the relationship between residential carpet dust PAH concentrations (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(a,h)anthracene, and indeno(1,2,3-c,d)pyrene, and their sum) and risk of NHL (676 cases, 511 controls) in the National Cancer Institute Surveillance Epidemiology and End Results multicenter case-control study. As a secondary aim, we investigated determinants of dust PAH concentrations. We computed odds ratios (OR) and 95 % confidence interval (CI) for associations between NHL and concentrations of individual and summed PAHs using unconditional logistic regression, adjusting for age, gender, and study center. Determinants of natural log-transformed PAHs were investigated using multivariate least-squares regression. RESULTS: We observed some elevated risks for NHL overall and B cell lymphoma subtypes in association with quartiles or tertiles of PAH concentrations, but without a monotonic trend, and there was no association comparing the highest quartile or tertile to the lowest. In contrast, risk of T cell lymphoma was significantly increased among participants with the highest tertile of summed PAHs (OR = 3.04; 95 % CI, 1.09-8.47) and benzo(k)fluoranthene (OR = 3.20; 95 % CI, 1.13-9.11) compared with the lowest tertile. Predictors of PAH dust concentrations in homes included ambient air PAH concentrations and the proportion of developed land within 2 km of a residence. Older age, more years of education, and white race were also predictive of higher levels in homes. CONCLUSION: Our results suggest a potential link between PAH exposure and risk of T cell lymphoma and demonstrate the importance of analyzing risk by NHL histologic type.

Investigation of spatio-temporal cancer clusters using residential histories in a case-control study of non-Hodgkin lymphoma in the United States.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is an enigmatic disease with few known risk factors. Spatio-temporal epidemiologic analyses have the potential to reveal patterns that may give clues to new risk factors worthy of investigation. We sought to investigate clusters of NHL through space and time based on life course residential histories. METHODS: We used residential histories from a population-based NHL case-control study of 1300 cases and 1044 controls with recruitment centers in Iowa, Detroit, Seattle, and Los Angeles, and diagnosed in 1998-2000. Novel methods for cluster detection allowing for residential mobility, called Q-statistics, were used to quantify nearest neighbor relationships through space and time over the life course to identify cancer clusters. Analyses were performed on all cases together and on two subgroups of NHL: Diffuse large B-cell lymphoma and follicular lymphoma. These more homogenous subgroups of cases might have a more common etiology that could potentially be detected in cluster analysis. Based on simulation studies designed to help account for multiple testing across space and through time, we required at least four significant cases nearby one another to declare a region a potential cluster, along with confirmatory analyses using spatial-only scanning windows (SaTScan). RESULTS: Evidence of a small cluster in southeastern Oakland County, MI was suggested using residences 10-18 years prior to diagnosis, and confirmed by SaTScan in a time-slice analysis 20 years prior to diagnosis, when all cases were included in the analysis. Consistent evidence of clusters was not seen in the two histologic subgroups. CONCLUSIONS: Suggestive evidence of a small space-time cluster in southeastern Oakland County, MI was detected in this NHL case-control study in the USA.

Analysis of Environmental Chemical Mixtures and Non-Hodgkin Lymphoma Risk in the NCI-SEER NHL Study.

BACKGROUND: There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). OBJECTIVES: We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. METHODS: We conducted a population-based case-control study of NHL in four National Cancer Institute-Surveillance, Epidemiology, and End Results centers--Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington--from 1998 to 2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. RESULTS: The WQS index was statistically significantly associated with NHL overall [odds ratio (OR) = 1.30; 95% CI: 1.08, 1.56; p = 0.006; for one quartile increase] and in the study sites of Detroit (OR = 1.71; 95% CI: 1.02, 2.92; p = 0.045), Los Angeles (OR = 1.44; 95% CI: 1.00, 2.08; p = 0.049), and Iowa (OR = 1.76; 95% CI: 1.23, 2.53; p = 0.002). The index was marginally statistically significant in Seattle (OR = 1.39; 95% CI: 0.97, 1.99; p = 0.071). The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa. CONCLUSIONS: An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk.

Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci.

Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. METHODS: We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). RESULTS: Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. CONCLUSIONS: Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust.

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 five PCB congeners (105, 138, 153, 170, and 180) in carpet dust collected between 1998 and 2000 from 1187 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 PCB 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 [odds ratio (OR) range 1.01-1.04 for each percentage increase] or population density (OR 1.08 for every 1000/mi(2)) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.

Partial associations of dietary iron, smoking and intestinal bacteria with colorectal cancer risk.

Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron-rich luminal environment. We analyzed the data from a population-based case-control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in 2 independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-yr (PY) of cigarette smoking (P value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the U.S. control subjects (P = 0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P = 0.014) and U.S. samples (6.65 vs. 4.37) (P < 0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation.

Residential proximity to industrial combustion facilities and risk of non-Hodgkin lymphoma: a case-control study.

BACKGROUND: Residence near municipal solid waste incinerators, a major historical source of dioxin emissions, has been associated with increased risk of non-Hodgkin lymphoma (NHL) in European studies. The aim of our study was to evaluate residence near industrial combustion facilities and estimates of dioxin emissions in relation to NHL risk in the United States. METHODS: We conducted a population-based case-control study of NHL (1998-2000) in four National Cancer Institute-Surveillance Epidemiology and End Results centers (Detroit, Iowa, Los Angeles, Seattle). Residential histories 15 years before diagnosis (similar date for controls) were linked to an Environmental Protection Agency database of dioxin-emitting facilities for 969 cases and 749 controls. We evaluated proximity (3 and 5 km) to 10 facility types that accounted for >85% of U.S. emissions and a distance-weighted average emission index (AEI [ng toxic equivalency quotient (TEQ)/year]). RESULTS: Proximity to any dioxin-emitting facility was not associated with NHL risk (3 km OR = 1.0, 95% CI 0.8-1.3). Risk was elevated for residence near cement kilns (5 km OR = 1.7, 95% CI 0.8-3.3; 3 km OR = 3.8, 95% CI 1.1-14.0) and reduced for residence near municipal solid waste incinerators (5 km OR = 0.5, 95% CI 0.3-0.9; 3 km OR = 0.3, 95% CI 0.1-1.4). The AEI was not associated with risk of NHL overall. Risk for marginal zone lymphoma was increased for the highest versus lowest quartile (5 km OR = 2.6, 95% CI 1.0-6.8; 3 km OR = 3.0, 95% CI 1.1-8.3). CONCLUSIONS: Overall, we found no association with residential exposure to dioxins and NHL risk. However, findings for high emissions and marginal zone lymphoma and for specific facility types and all NHL provide some evidence of an association and deserve future study.

Household endotoxin levels and the risk of non-Hodgkin lymphoma.

OBJECTIVE: Endotoxin, a component of the outer membrane of gram-negative bacteria, elicits a strong innate and inflammatory immune response associated with the secretion of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α). Because TNF-α polymorphisms that increase TNF-α production are associated with an increased risk of non-Hodgkin lymphoma (NHL), we hypothesized that increased levels of household endotoxin would be associated with an increased NHL risk. METHODS: We evaluated this association in the National Cancer Institute/Surveillance, Epidemiology and End Results (NCI/SEER) NHL multicenter population-based case-control study. Used vacuum cleaner bags were collected from participants during a home interview. Dust samples from the bags of 594 cases and 442 controls were analyzed for endotoxin [endotoxin unit (EU)/mg of dust] using the kinetic chromogenic Limulus amebocyte lysate assay. Multivariable logistic regression was used to estimate the effect of endotoxin on NHL risk adjusted for age, sex, race, education, study center, and farm exposure. RESULTS: Endotoxin was not associated with NHL overall [odds ratio (OR) for highest quartile of endotoxin levels = 0.81, 95 % confidence interval (CI) = 0.55, 1.20; p for trend = 0.35] or with diffuse large B-cell lymphoma (OR = 0.63, 95 % CI = 0.34, 1.16; p = 0.31) or follicular lymphoma (OR = 1.07, 95 % CI = 0.61, 1.89; p = 0.73) subtypes. Both working and living on a farm were associated with higher household endotoxin levels compared to never working (p = 0.009) or living (p = 0.01) on a farm. Excluding farmers from the analysis did not change the results. CONCLUSIONS: We found no evidence of a role for household endotoxin in NHL etiology.

PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium.

Many common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10(-11)), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10(-9)) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

Inherited genetic variation and overall survival following follicular lymphoma.

Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy.In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12,DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results,which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.

Association of dietary quercetin with reduced risk of proximal colon cancer.

Quercetin is a flavonol that appears to be protective against several cancers, but its possible role in prevention of colorectal cancer is not yet well studied. We evaluated dietary intakes of quercetin and risk of colorectal cancer in a large case-control study conducted in metropolitan Detroit, Michigan (N = 2664). The protective effects of quercetin intake, as assessed by a food frequency questionnaire, were confined to risk of proximal colon cancer. Stratified analyses showed that the protective effects of quercetin on risk of proximal colon cancer were significant only when fruit intake or the Healthy Eating Index score was high, or when tea intake was low, with odds ratios (OR) for the highest vs. the lowest quartile of 0.49, 0.44, and 0.51, respectively. Increased quercetin intake had no protective effects when tea intake was high. Interestingly, increased intake of quercetin was associated with increased risk of distal colon cancer when total fruit intake was low (OR for the highest vs. the lowest quartile = 1.99). These results suggest that quercetin can have disparate effects on colon cancer risk depending on whether dietary intakes of fruit or tea are high, and that quercetin had protective effects only on proximal, not distal, colon cancer.

Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.

We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16-96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the 2 years before diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis was associated with an excess risk of NHL (OR = 1.26, 95% CI = 1.01-1.57 based on data from 16 studies); study-specific results indicate significant (I(2) = 51%, p = 0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognized.

Family history of cancer and non-malignant diseases and risk of childhood acute lymphoblastic leukemia: a Children's Oncology Group Study.

BACKGROUND: Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL. METHODS: We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Children's Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders. RESULTS: We found a borderline association of ALL and having a family member with a history of cancer in cases (n=1842) compared to controls (n=1986) (OR=0.98, 95%CI=0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR=0.83, 95%CI=0.73, 0.95) as did family history of rheumatoid arthritis (OR=0.79, 95%CI=0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL. CONCLUSIONS: These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records.

Variation in effects of non-Hodgkin lymphoma risk factors according to the human leukocyte antigen (HLA)-DRB1*01:01 allele and ancestral haplotype 8.1.

Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.

Human leukocyte antigen class I and II alleles and overall survival in diffuse large B-cell lymphoma and follicular lymphoma.

Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01-3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24-4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02-0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20-0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation.