Maryjean Schenk

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes.

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

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 × 10−29 and rs7755224, combined P = 2.00 × 10−19; r2 = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 × 10−9).

A case-control study of self-reported exposures to pesticides and pancreas cancer in Southeastern Michigan

A case‐control study of pancreas cancer in residents, aged 30–79 years, of 18 counties in southeastern Michigan was conducted to investigate the risks of exposure to DDT and related materials in the general population. Sixty‐six people with cytologically diagnosed pancreas cancer were identified using 7 participating hospitals in metropolitan Detroit and Ann Arbor. One hundred and thirty‐one controls were frequency‐matched to the cases on age, sex, ethicity and county of residence by random‐digit dialing. All study participants were administered a questionnaire to assess life‐time exposure to pesticides from both environmental and occupational sources, family history of cancer, past medical history, smoking history and demographic information. A statistically significant increased risk was found for self‐reported exposure to ethylan (1,1‐dichloro‐2,2‐bis(4‐methoxyphenyl) ethane). Increased odds ratios were observed for self‐reported exposures to chloropropylate and DDT, as well as for the summary group of organochlorine pesticides which included all of these materials, though these associations were not significant. Int. J. Cancer 72:62–67, 1997.

New American cancer society process for creating trustworthy cancer screening guidelines

Guidelines for cancer screening written by different organizations often differ, even when they are based on the same evidence. Those dissimilarities can create confusion among health care professionals, the general public, and policy makers. The Institute of Medicine (IOM) recently released 2 reports to establish new standards for developing more trustworthy clinical practice guidelines and conducting systematic evidence reviews that serve as their basis. Because the American Cancer Society (ACS) is an important source of guidance about cancer screening for both health care practitioners and the general public, it has revised its methods to create a more transparent, consistent, and rigorous process for developing and communicating guidelines. The new ACS methods align with the IOM principles for trustworthy clinical guideline development by creating a single generalist group for writing the guidelines, commissioning independent systematic evidence reviews, and clearly articulating the benefits, limitations, and harms associated with a screening test. This new process should ensure that ACS cancer screening guidelines will continue to be a trustworthy source of information for both health care practitioners and the general public to guide clinical practice, personal choice, and public policy about cancer screening.

A Case-Control Study of Occupational Exposure to Trichloroethylene and Non-Hodgkin Lymphoma

Background Previous epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL). Objectives We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods. Methods Cases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group. Results We observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7). Conclusions Our findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.

Environmental medicine content in medical school curricula

BACKGROUND: The Institute of Medicine has recommended basic clinical competence in environmental medicine (EM) for all physicians. However, the amount and content of instruction in EM currently offered in U.S. medical schools is unknown. METHOD: This cross-sectional study was based on responses to a questionnaire regarding the EM curriculum content of U.S. medical schools, mailed in June 1994 with the Association of American Medical Colleges curriculum survey. RESULTS: Of the 126 schools, 119 (94%) responded. Of these, 29 (24%) reported no required EM content in the curriculum. Schools with EM content averaged seven hours of instruction. Eighty-one schools (68%) had faculty with environmental and occupational medicine expertise, primarily within the departments of medicine, preventive medicine, and family medicine. CONCLUSION: There is a need for increased instruction in EM in medical school curricula for students to acquire the knowledge and skills to prevent, diagnose, and treat health problems with an environmental exposure component. For those schools without EM content in the curriculum, the necessary expertise to develop EM curriculum may be available in current faculty.

Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population-based case-control studies.

Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) (CG) = 1.21; OR(CC) = 2.13; P trend = .011); CASP9 rs4661636 (OR(CT) = 0.89; OR(TT) = 0.77; P trend = .011); and CASP1 rs1785882 (OR(AT) = 1.12; OR(AA) = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma

Carcinoma of the pancreas is the fifth leading cancer in the U. S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma‐prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population‐based cohort of patients with malignant melanoma.

Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: A pooled analysis of three population-based case-control studies

The balance between T‐helper 1 (Th1) and T‐helper 2 (Th2) activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non‐Hodgkin lymphoma (NHL). To study the impact of polymorphisms in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population‐based case‐control studies (1946 cases and 1808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene‐based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for rs485497 in IL12A, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen‐specific adaptive immune responses (allele risk OR = 1·17; P(trend) = 0·00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR = 1·26; P(trend) = 0·0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.

A pooled analysis of three studies evaluating genetic variation in innate immunity genes and non-Hodgkin lymphoma risk

Genetic variation in immune‐related genes may play a role in the development of non‐Hodgkin lymphoma (NHL). To test the hypothesis that innate immunity polymorphisms may be associated with NHL risk, we genotyped 144 tag single nucleotide polymorphisms (tagSNPs) capturing common genetic variation within 12 innate immunity gene regions in three independent population‐based case‐control studies (1946 cases and 1808 controls). Gene‐based analyses found IL1RN to be associated with NHL risk (minP = 0·03); specifically, IL1RN rs2637988 was associated with an increased risk of NHL (per‐allele odds ratio = 1·15, 95% confidence interval = 1·05–1·27; Ptrend = 0·003), which was consistent across study, subtype, and gender. FCGR2A was also associated with a decreased risk of the follicular lymphoma NHL subtype (minP = 0·03). Our findings suggest that genetic variation in IL1RN and FCGR2A may play a role in lymphomagenesis. Given that conflicting results have been reported regarding the association between IL1RN SNPs and NHL risk, a larger number of innate immunity genes with sufficient genomic coverage should be evaluated systematically across many studies.