Claire M. Vajdic

Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis

BACKGROUND Only a few types of cancer are recognised as being directly related to immune deficiency in people with HIV/AIDS. Large population-based studies in transplant recipients have shown that a wider range of cancers could be associated with immune deficiency. Our aim was to compare cancer incidence in population-based cohort studies of people with HIV/AIDS and people immunosuppressed after solid organ transplantation. METHODS Two investigators independently identified eligible studies through searches of PubMed and reference lists. Random-effects meta-analyses of log standardised incidence ratios (SIRs) were calculated by type of cancer for both immune deficient populations. FINDINGS Seven studies of people with HIV/AIDS (n=444,172) and five of transplant recipients (n=31 977) were included. For 20 of the 28 types of cancer examined, there was a significantly increased incidence in both populations. Most of these were cancers with a known infectious cause, including all three types of AIDS-defining cancer, all HPV-related cancers, as well as Hodgkins lymphoma (HIV/AIDS meta-analysis SIR 11.03, 95% CI 8.43-14.4; transplant 3.89, 2.42-6.26), liver cancer (HIV/AIDS 5.22, 3.32-8.20; transplant 2.13, 1.16-3.91), and stomach cancer (HIV/AIDS 1.90, 1.53-2.36; transplant 2.04, 1.49-2.79). Most common epithelial cancers did not occur at increased rates. INTERPRETATION The similarity of the pattern of increased risk of cancer in the two populations suggests that it is immune deficiency, rather than other risk factors for cancer, that is responsible for the increased risk. Infection-related cancer will probably become an increasingly important complication of long-term HIV infection.

Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium

Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Cancer incidence and risk factors after solid organ transplantation.

Iatrogenic immunosuppression is a unique setting for investigating immune‐related mechanisms of carcinogenesis. Solid organ transplant recipients have a 3‐fold excess risk of cancer relative to the age‐ and sex‐matched general population. Population‐based studies utilizing cancer registry records indicate that a wide range of cancers, mostly those with a viral etiology, occur at excess rates. To date, cancer risk has predominantly been examined in adult kidney transplant recipients in Western countries. It is yet to be established whether a similar incidence profile exists in the long‐term for other solid organ, pediatric and non‐Western transplant recipients. The cancer incidence profile before and after kidney transplantation strongly suggests a relatively minor contribution by both preexisting cancer risk factors and the conditions underlying end‐stage kidney disease, and points to a causal role for immunosuppression. Within‐cohort risk factor analyses have largely been performed on cohorts with voluntary cancer notification, and very few have incorporated biomarkers of the level of immunosuppression, the current receipt of immunosuppressive agents, or genetic risk factors. Because of their markedly high risk of certain cancers, findings from comprehensive studies in transplant recipients have the potential to raise new avenues for investigation into causal mechanisms and preventive measures against immune‐related and infectious causes of cancer.

Hepatitis C and Non-Hodgkin Lymphoma Among 4784 Cases and 6269 Controls From the International Lymphoma Epidemiology Consortium

BACKGROUND & AIMS Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkins lymphoma (NHL) subtypes after HCV infection. METHODS The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded. RESULTS HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40-2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44-4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68-2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14-5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65-1.60). CONCLUSIONS These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).

Altered Immunity as a Risk Factor for Non-Hodgkin Lymphoma

This review examines the association between disorders of immunity, including immune deficiency, atopy, and autoimmune disease, and non-Hodgkin lymphoma (NHL). Immune deficiency is one of the strongest known risk factors for NHL. Risk is increased whether the immune deficiency is congenital, iatrogenic, or acquired. Risk of NHL increases with degree of immune deficiency, and there is no evidence of a threshold. In the profoundly immune deficient, NHL is frequently caused by infection with the ubiquitous EBV. Whether mild, subclinical immune deficiency is related to increased NHL risk is unknown. There is inconsistent evidence that atopic conditions, such as asthma, hayfever, and eczema, characterized by an immune response that is skewed toward Th2, are associated with a decreased risk of NHL. These data come mainly from case-control studies. Concern has been expressed that the association may be due to reverse causality if early symptoms of NHL include a lessening of atopic manifestations. Case-control and cohort studies of people with autoimmune conditions have generally shown that rheumatoid arthritis, systemic lupus erythematosis, and Sjogrens disease are associated with increased NHL risk. It seems to be the intensity of the inflammatory disease rather than its treatment which is related to increased risk of NHL. The study of altered immunity as a cause of NHL in case-control studies is limited by the fact that development of NHL in itself leads to altered immunity. Cohort studies of the role of altered immunity should be a top priority in epidemiologic studies of NHL etiology. (Cancer Epidemiol Biomarkers Prev 2007;16(3):405–8)

Sun exposure predicts risk of ocular melanoma in Australia

Previous studies examining sun exposure and ocular melanoma have produced inconsistent results. We investigated this association in a population‐based case‐control study in Australia. Cases (n = 290) aged 18–79 years were diagnosed between January 1996 and July 1998. Controls (n = 893) were randomly selected from the electoral rolls and frequency‐matched to cases by age, sex and state. A self‐administered questionnaire and a telephone interview measured sun exposure on weekdays and weekends at 10, 20, 30 and 40 years of age and over the whole of life for specific jobs and recreations. Multivariate logistic regression models of ocular melanoma and sun exposure contained age, sex, region of birth, eye color and measures of ocular and cutaneous sun sensitivity as covariates. Choroid and ciliary body melanoma (n = 246) was positively associated with time outdoors on weekdays and, less persuasively, total time outdoors but not ambient solar irradiance. Odds ratios increased with increasing exposure to OR 1.8 (95% confidence interval 1.1–2.8) for the highest quarter of sun exposure on weekdays up to 40 years of age for men and women together. The strongest positive associations were for total exposure up to 40 years of age, lifetime occupational exposure and total exposure at about 20 years of age in men; all had odds ratios between 2 and 3 in the highest exposure categories. There was inconclusive evidence for an association between sun exposure and iris (n = 25) or conjunctival (n = 19) melanomas. Sun exposure is an independent risk factor for choroidal and ciliary body melanoma in Australia.

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).

The epidemiology of non-Hodgkin lymphoma

Summary Non‐Hodgkin lymphoma (NHL) includes a group of more than 20 different malignant lymphoproliferative diseases that originate from lymphocytes. Rates of NHL have increased dramatically over the past few decades, although the rate of increase has recently slowed. It is now the sixth most common cancer in Australia. Globally, it is somewhat more common in men than in women, and rates are highest in North America and Australia. The causes of the increase in NHL rates are largely unknown. The best described risk factor for NHL is immune deficiency; rates of NHL are greatly increased, with relative risks of 10–100 or more, in people with immune deficiency associated with immune suppressive therapy after transplantation, HIV/AIDS, and congenital conditions. In addition, some NHL subtypes are associated with specific infections. These include immune‐deficiency‐associated central nervous system NHL (Epstein‐Barr virus); gastric mucosa‐associated lymphoid tissue NHL (Helicobacter pylori); adult T‐cell leukemia/lymphoma (human T‐lymphotrophic virus type 1) and body cavity‐based lymphoma (human herpesvirus 8). However, these specific infections account for a very small proportion of total NHL incidence. In addition to immune deficiency and infection, other immune‐related conditions are increasingly being recognised as related to NHL risk. Specific autoimmune conditions, including rheumatoid arthritis, systemic lupus erythema, Sjogrens syndrome, psoriasis and coeliac disease are associated with moderately increased risk of NHL. On the other hand, allergic and atopic conditions and their correlates such as early birth order, appear to be associated with a decreased risk of NHL. A variety of other exposures are less strongly related to NHL risk. These include occupational exposures, including some pesticides, herbicides, and solvents. Recently, two studies have reported that sun exposure is associated with a decreased risk of NHL. Smoking appears to be weakly positively associated with risk of follicular NHL, and alcohol intake is associated with a decreased risk of NHL. The pooled analysis of several case‐control studies of NHL risk that are currently in the field promises to help clarify which of these risk factors are real, and will contribute to the elucidation of the mechanisms of how disorders of the immune system, and other factors, are related to NHL risk.

The pattern of excess cancer in dialysis and transplantation

BACKGROUND After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible. METHODS In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003. RESULTS The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain. CONCLUSIONS In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.

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.