Hematolymphoproliferative malignancies : the impact of lifestyle, organ transplantation and genetic susceptibility

Abstract

During the past decades Non-Hodgkin lymphoma (NHL) has demonstrated an immense increase in incidence globally, among almost all age and race groups as well as in both genders. In the search for causes, none of the known risk factors can alone or together entirely explain this trend. This thesis aims to answer a number of research inquiries with regard to NHL but also other hematolymphoproliferative malignancies. Firstly, we sought to estimate the influence of various forms of tobacco use and body mass index on the risk of NHL, Hodgkin lymphoma (HL), leukemia and multiple myeloma. Secondly, we aimed to disentangle the relative importance of putative determinants of NHL risk in the organ transplant setting, including characteristics of donor and recipient, immunosuppressive medications and infectious complications. Thirdly, our objective was to explore the role of genetic variation in translocation breakpoint genes (BCL2, CCND1), the protooncogene MYC and immunoregulatory genes (TNF, IL-10) in the etiology of NHL.

In a large cohort of more than 330,000 construction workers attending regular health check-ups we employed prospectively gathered exposure information on tobacco use and BMI to analyze the incidence rate ratio (IRR) of NHL and HL in a Cox proportional hazards regression model. Tobacco smoking, oral moist snuff use and BMI were all unrelated to NHL. However, among long term users of oral moist snuff (>30 years), an indication of an excess risk of HL was observed (IRR 3.78, 95% confidence interval [95% CI] 1.23-11.6).

In a subsequent study of the construction workers cohort we computed IRR for acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphatic leukemia (ALL) and multiple myeloma (MM) in relation to tobacco use and BMI, applying essentially the same methods. In this investigation, the study population was restricted to male workers and attained age was used as the time scale in the Cox model. Current smoking was associated with a 50% increased risk of AML (95% CI 1.06-2.11).

Within a cohort (n= 5391) of organ transplant recipients (1970-1997) we designed a nested case control study comprising 37 cases of NHL and 97 controls. Odds ratios (OR) were estimated in a conditional logistic regression model. Treatment with antithymocyte globulin (ATG) conferred a five-fold elevated risk of NHL (95% CI 2.17-14.3). The excess risk was more pronounced for a high average daily dose of ATG. Further, having a herpes virus group infection was associated with a five-fold excess risk of NHL (OR 4.89, 95% CI 1.88-12.7), most likely to be driven by Epstein Barr virus.

In a case-control study of 2410 incident cases of NHL and 1963 matched controls selected from the Swedish and Danish population registers, subjects took part in a telephone interview and provided blood specimens for genotyping. OR and 95% CI were computed in multivariate logistic regression analyses. No relationship between investigated polymorphisms in BCL2, CCND1 or MYC and NHL could be discerned. TNF rs1800629 minor allele homozygocity was associated with a 50% greater risk of NHL (OR 1.52, 95% CI, 1.06-2.18) as well as a two-fold increased risk of T-cell lymphoma and Mantle cell lymphoma, respectively. IL10 rs1800890 minor allele homozygocity conferred a higher risk of diffuse large B-cell lymphoma (OR 1.45, CI 1.10-1.90) and Mantle cell lymphoma (OR 1.83, 95% CI 1.08-3.12).