Marco Rais

Risk of malignant lymphoma following viral hepatitis infection

We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin’s lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk.

Risk of lymphoma subtypes and dietary habits in a Mediterranean area

BACKGROUND Previous studies have suggested that diet might affect risk of lymphoma subtypes. We investigated risk of lymphoma and its major subtypes associated with diet in the Mediterranean island of Sardinia, Italy. METHODS In 1998-2004, 322 incident lymphoma cases and 446 randomly selected population controls participated in a case-control study on lymphoma etiology in central-southern Sardinia. Questionnaire interviews included frequency of intake of 112 food items. Risk associated with individual dietary items and groups thereof was explored by unconditional and polytomous logistic regression analysis, adjusting by age, gender and education. RESULTS We observed an upward trend in risk of lymphoma (all subtypes combined) and B-cell lymphoma with frequency of intake of well done grilled/roasted chicken (p for trend=0.01), and pizza (p for trend=0.047), Neither adherence to Mediterranean diet nor a frequent intake of its individual components conveyed protection. We detected heterogeneity in risk associated with several food items and groups thereof by lymphoma subtypes although we could not rule out chance as responsible for the observed direct or inverse associations. CONCLUSIONS Adherence to a Mediterranean diet does not seem to convey protection against the development of lymphoma. The association with specific food items might vary by lymphoma subtype.

GLUCOSE-6-PHOSPHATE DEHYDROGENASE POLYMORPHISM AND LYMPHOMA RISK

AIMS AND BACKGROUND Evidence linking the glucose-6-phosphate dehydrogenase (G6PD) polymorphism and risk of non-Hodgkins lymphoma is conflicting. Risk of non-Hodgkins lymphoma was increased in subjects expressing the G6PD deficient phenotype, whereas subjects under medication with statins, a lipid-lowering class of drugs partially mimicking G6PD deficiency, seemed to enjoy a protective effect. METHODS We conducted a case-control study on lymphoma risk associated with the self-reported G6PD deficient phenotype in 122 lymphoma male cases and 116 male controls in Sardinia, Italy. The association with the GdMed+ genotype, the most frequent variant expressing a deficient enzyme activity, was also tested in 49 male lymphoma cases and 31 controls. The WHO classification was used to identify lymphoma subentities. RESULTS Neither self-reported G6PD deficient phenotype nor the GdMed+ genotype showed an association with lymphoma risk or its subentities. CONCLUSIONS Our results do not confirm an association either positive or negative between the G6PD polymorphism and lymphoma risk.

N-acetyltransferase polymorphisms are associated with risk of lymphoma subtypes

Genes encoding for arylamine N‐acetyltransferase 1 and 2 (NAT1 and NAT2) have been investigated with alternate findings in relation to risk of non‐Hodgkin lymphoma (NHL). We tested functional haplotype‐based NAT1 and NAT2 gene polymorphisms in relation to risk of lymphoma overall and its major B cell subtypes, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). We used allele specific primers and multiplex PCR to detect NAT1 and NAT2 haplotypes in 248 patients with incident lymphoma and 208 population controls. We inferred the NAT1 rapid and slow acetylator and the NAT2 rapid, intermediate or slow acetylator phenotype, based on published functional data on the respective genotypes. Odds ratios and 95% confidence intervals (95% CIs) for lymphoma, B‐NHL, DLBCL, FL, CLL, and other B‐NHL combined associated with the inferred rapid NAT1 acetylator and with the intermediate and slow NAT2 acetylator phenotypes were estimated with unconditional and polytomous logistic regression analysis, adjusting for age, gender and education. NAT1 rapid acetylators showed a 2.8‐fold excess risk (95% CI 1.5–5.2) for lymphoma (all subtypes combined). Risk was highest for CLL and FL, with significant heterogeneity detected across subtypes. Risk also increased with decreasing NAT2 acetylating capacity with no heterogeneity detected across B cell lymphoma subtypes. Risks did not vary by gender. Although poor statistical power was a major limitation in our study, larger studies and pooled analyses are warranted to test whether NAT1 and NAT2 gene polymorphisms might modulate risk of specific lymphoma subtypes through the varying metabolic activity of their products. Copyright

P228 Recreational physical activity and risk of lymphoma subtypes

Background Physical activity is known to protect against several cancers and to improve survival and quality of life in cancer patients. Few studies have addressed the association between physical activity and risk of non Hodgkin lymphoma and its subtypes. Methods During 1998–2004, a case-control study on the aetiology of lymphoma was conducted Sardinia, Italy as part of the European multicentre study EPILYMPH. Information on lifetime recreational physical activity was collected using a standardised questionnaire. Risk of the major lymphoma subtypes associated with ever practicing physical activity and with quartiles of hours of recreational physical activity in the lifetime was calculated with unconditional logistic regression analysis, adjusting by age, gender, education and study centre. Results Risk of lymphoma overall and B-cell lymphoma was not associated with ever practicing recreational physical activity (OR = 0.9, 95% CI: 0.7–1.3). However, a significant protective effect was observed in the upper quartile of hours of recreational physical activity in the lifetime (OR = 0.4, 95% CI: 0.3–0.8). The inverse association was consistent across the major lymphoma subtypes, namely diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia, and multiple myeloma. Conclusions Our results suggest an inverse association between risk of the major lymphoma subtypes and prolonged recreational physical activity.

O04-4 Household pesticides and risk of lymphoma subtypes

Background Evidence from recent studies provides support to the link between exposure to certain pesticide classes and risk of non Hodgkin lymphoma and its subtypes. Whether use of insecticides in the household is also associated with an increased risk is unclear. Methods During 1998–2004, a case-control study on the aetiology of lymphoma was conducted Sardinia, Italy as part of the European multicentre study EPILYMPH. Information on use of insecticides in the household over the residential history of study subjects was collected using a standardised questionnaire. Risk of the major lymphoma subtypes associated with ever use of insecticides indoor and with quartiles of days/year of use was calculated with unconditional logistic regression analysis, adjusting by age, gender, education and study centre. Results Risk of lymphoma overall and B-cell lymphoma was not associated with ever use of indoor insecticide in the household (OR = 0.8, 95% CI: 0.6–1.0), neither we observed an increase in risk associated with increasing quartiles of days/year of indoor use of insecticides: risk in the upper quartile was OR = 0.8 (95% CI: 0.5–1.3) for all lymphomas and OR = 0.8 (95% CI: 0.5–1.4) for B-cell lymphoma. Results were consistent across the major lymphoma subtypes, but multiple myeloma, which showed a modest non significant association, difficult to interpret because of the small number of cases. Conclusions Pyrethroid and carbamate insecticides have been extensively used in different forms as indoor insecticides, particularly in rural areas or nearby water basins. Our results suggest no association between risk of the major lymphoma subtypes and prolonged indoor use of insecticides.

Do matrix metalloproteinase-1 and glucose-6-phosphate dehydrogenase gene polymorphisms interact in promoting lymphoma development?

MMP9 in favoring local invasion and growth of the tumor [13], is also relevant to NHL susceptibility and progression. The MMP1 gene is located in chromosome region 11q22.3, which is amplified in many solid tumors; a single guanine insertion polymorphism (2G) at  1607 bp in the MMP1 promoter region is associated with an increase in MMP1 transcription and local expression of MMP1 [6]. The 2G insertion at MMP1  1607 has also been related to neoplasia susceptibility and invasiveness [13–15]. Therefore, we hypothesized that the 1G allele of the  1607 promoter polymorphism in MMP1, being associated with lower MMP1 expression, might contribute to less proneness to develop NHL, and that such a protective effect might be reinforced by co-occurrence with the G6PD deficient phenotype, due to the impairment in fibroblast metabolic activity and the nitric oxide synthase (NOS) and ROS release associated with the condition. In turn, NOS and ROS could lead to reduced proliferation or induce apoptosis in potentially carcinogenic cells, but could also initiate tumorigenesis via direct DNA damage [16]. We preliminarily tested the hypothesis in 154 male cases of lymphoma, identified in 1998–2004 in two hematology units in Sardinia, Italy, and 182 male population controls, frequency matched to cases by residence area and 5-year age-group. The lymphoma histotypes in our case series were chronic lymphocytic leukemia (CLL; n  36, 23.4%), diffuse large B-cell lymphoma (DLBCL; n  32, 20.8%), follicular lymphoma (FL; n  16, 10.4%), multiple myeloma (MM; n  12, 7.8%), T cell lymphomas (TCL; n  5, 3.2%), Hodgkin lymphoma (HL; n  8, 5.2%) and other rarer B-cell subtypes and NHL of unspecified cell type (n  45; 29.2%). Females were excluded because of the rarity of the homozygotes for the X-linked G6PD deficient variants. Ethical clearance for the overall project, including this preliminary study, was provided by the Ethics Committee of Cagliari University. All subjects provided informed consent before participating in the study. The authors complied with the Declaration