Richard P. Gallagher

Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium

BACKGROUND Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). METHODS We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. FINDINGS The tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083). INTERPRETATION Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

Dullrazor®: A software approach to hair removal from images

Recently, there has been a growing number of studies applying image processing techniques to analyze melanocytic lesions for atypia and possible malignancy and for total-body mole mapping. However, such lesions can be partially obscured by body hairs. None of these studies has fully addressed the problem of human hairs occluding the imaged lesions. In our previous study we designed an automatic segmentation program to differentiate skin lesions from the normal healthy skin, and learned that the program performed well with most of the images, the exception being those with hairs, especially dark thick hairs, covering part of the lesions. These thick dark hairs confused the program, resulting in unsatisfactory segmentation results. In this paper, we present a method to remove hairs from an image using a pre-processing program we have called DullRazor. This pre-processing step enables the segmentation program to achieve satisfactory results. DullRazor can be downloaded as shareware from http:/(/)www.derm.ubc.ca.

Tanning Beds, Sunlamps, and Risk of Cutaneous Malignant Melanoma

Background: A number of studies have been conducted evaluating the risk of cutaneous malignant melanoma after exposure to sunlamps and/or sunbeds. The proportion of subjects in the individual studies who have reported exposure has, in general, been modest, and the resulting risk estimates for melanoma have been unstable with wide 95% confidence intervals (95% CI). The inconclusive results seen in individual studies have resulted in confusion as to the carcinogenicity of these devices. Methods: We conducted a systematic review and meta-analysis of these studies. A review of the literature from Jan 1, 1984 to April 2004 using MEDLINE identified 12 case-control studies and 1 cohort study which quantitatively evaluated the use of sunlamps and/or sunbeds and subsequent melanoma. After applying exclusion/inclusion criteria, 9 case-control and 1 cohort study provided data for the analysis. Summary odds ratios (OR) and 95% CIs for sunlamp/sunbed use and subsequent melanoma were calculated using a random-effect model. Results: Ten studies provided data for assessment of melanoma risk among subjects who reported “ever” being exposed compared with those “never” exposed. A positive association was found between exposure and risk (summary OR, 1.25; 95% CI, 1.05-1.49). Significant heterogeneity between studies was present. Evaluation of the metrics “first exposure as a young adult” (5 studies) and “longest duration or highest frequency of exposure” (6 studies) also yielded significantly elevated risk estimates (summary OR, 1.69; 95% CI, 1.32-2.18, and 1.61; 95% CI, 1.21-2.12, respectively, with no heterogeneity in either analysis). Conclusions: Results indicate a significantly increased risk of cutaneous melanoma subsequent to sunbed/sunlamp exposure.

Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls

Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude. Methods We performed a pooled analysis of 15 case–control studies (5700 melanoma cases and 7216 controls), correlating patterns of sun exposure, sunburn and solar keratoses (three studies) with melanoma risk. Pooled odds ratios (pORs) and 95% Bayesian confidence intervals (CIs) were estimated using Bayesian unconditional polytomous logistic random-coefficients models. Results Recreational sun exposure was a risk factor for melanoma on the trunk (pOR = 1.7; 95% CI: 1.4–2.2) and limbs (pOR = 1.4; 95% CI: 1.1–1.7), but not head and neck (pOR = 1.1; 95% CI: 0.8–1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR = 1.7; 95% CI: 1.0–3.0). Total sun exposure was associated with increased risk of melanoma on the limbs at low latitudes (pOR = 1.5; 95% CI: 1.0–2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3–1.7), 1.5 (95% CI: 1.3–1.7) and 1.4 (95% CI: 1.1–1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR = 4.0; 95% CI: 1.7–9.1) and limbs (pOR = 4.0; 95% CI: 1.9–8.4). Conclusion Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes.

The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies

The objective of this study was to examine the effects of the intakeof dietary fat upon colorectal cancer risk in a combined analysis of datafrom 13 case-control studies previously conducted in populations withdiffering colorectal cancer rates and dietary practices. Original datarecords for 5,287 cases of colorectal cancer and 10,470 controls werecombined. Logistic regression analysis was used to estimate odds ratios (OR)for intakes of total energy, total fat and its components, and cholesterol.Positive associations with energy intake were observed for 11 of the 13studies. However, there was little, if any, evidence of anyenergy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01,1.02, and 0.92 for quintiles of residuals of total fat intake (P trend =0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (Ptrend = 0.39). The analysis suggests that, among these case-control studies,there is no energy-independent association between dietary fat intake andrisk of colorectal cancer. It also suggests that simple substitution of fatby other sources of calories is unlikely to reduce meaningfully the risk ofcolorectal cancer.

Body site distribution of cutaneous malignant melanoma in relationship to patterns of sun exposure

A study of all newly incident melanoma patients in British Columbia in 1991–1992 was undertaken to test the hypothesis raised by an earlier study, which showed that in younger patients the incidence rate of melanoma per unit area of skin was higher on intermittently exposed skin areas than on continuously exposed areas. Using 1,033 patients and a more detailed body site categorisation than was previously possible, our results confirmed that in both men and women under age 50 the highest melanoma density was on the back. At ages over 50, the greatest density occurred on fully exposed sites, such as the face, though the dorsum of the hand and forearm, likely also to have high exposure, show very low melanoma densities. Differences between males and females correlate well with differences in likely exposure patterns. These results were seen for all invasive cutaneous melanomas combined; the patterns were similar for subtypes and for both invasive and in situ melanoma, with the exception of lentigo maligna melanoma (LMM), which occurs almost exclusively on the face, even at younger ages. Comparison with the earlier study (1976–1979) shows that the age‐standardised rates for melanoma excluding LMM have increased by 60%, with the greatest proportional increase being at younger ages; in the recent data, the age‐standardised rate for intermittently exposed sites exceeds that for usually exposed sites. Our results confirm that intermittent sun exposure has a greater potential for producing melanoma than continuous exposure at ages below about 50, though at older ages melanoma is more common on body sites with continuous sun exposure. Int. J. Cancer 78:276–280, 1998.© 1998 Wiley‐Liss, Inc.

Sunburn, suntan and the risk of cutaneous malignant melanoma--The Western Canada Melanoma Study.

A comparison of interview data on 595 patients with newly incident cutaneous melanoma, excluding lentigo maligna melanoma and acral lentiginous melanoma, with data from comparison subjects drawn from the general population, showed that melanoma risk increased in association with the frequency and severity of past episodes of sunburn, and also that melanoma risk was higher in subjects who usually had a relatively mild degree of suntan compared to those with moderate or deep suntan in both winter and summer. The associations with sunburn and with suntan were independent. Melanoma risk is also increased in association with a tendency to burn easily and tan poorly and with pigmentation characteristics of light hair and skin colour, and history freckles; the associations with sunburn and suntan are no longer significant when these other factors are taken into account. This shows that pigmentation characteristics, and the usual skin reaction to sun, are more closely associated with melanoma risk than are sunburn and suntan histories.

Organochlorines and risk of non-Hodgkin lymphoma

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non‐Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population‐based case–control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin‐like PCB congeners were associated with increased risk of NHL, including dioxin‐like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non‐dioxin‐like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18–2.84). Six pesticide analytes also showed a significant association with NHL; β‐hexachlorocyclohexane, p,p′‐DDE, hexachlorobenzene, mirex, oxychlordane and trans‐nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69–4.24). Our results provide further evidence that organochlorines contribute to NHL risk.

Quality, quantity and harmony: the DataSHaPER approach to integrating data across bioclinical studies

Background Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately ‘harmonized’. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. Methods This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P3G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). Results The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the ‘DataSchema’ and ‘Harmonization Platforms’, together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both ‘prospective’ and ‘retrospective’ harmonization. Conclusion It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.

From consent to institutions: Designing adaptive governance for genomic biobanks

Biobanks are increasingly hailed as powerful tools to advance health research. The social and ethical challenges associated with the implementation and operation of biobanks are equally well-documented. One of the proposed solutions to these challenges involves trading off a reduction in the specificity of informed consent protocols with an increased emphasis on governance. However, little work has gone into formulating what such governance might look like. In this paper, we suggest four general principles that should inform biobank governance and illustrate the enactment of these principles in a proposed governance model for a particular population-scale biobank, the British Columbia (BC) Generations Project. We begin by outlining four principles that we see as necessary for informing sustainable and effective governance of biobanks: (1) recognition of research participants and publics as a collective body, (2) trustworthiness, (3) adaptive management, and (4) fit between the nature of a particular biobank and the specific structural elements of governance adopted. Using the BC Generations Project as a case study, we then offer as a working model for further discussion the outlines of a proposed governance structure enacting these principles. Ultimately, our goal is to design an adaptive governance approach that can protect participant interests as well as promote effective translational health sciences.