Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

Radiogenomics in the Era of Advanced Radiotherapy.

Most radiogenomics studies investigate how genetic variation can help to explain the differences in early and late radiotherapy toxicity between individuals. The field of radiogenomics in photon beam therapy has grown rapidly in recent years, carving out a unique translational discipline, which has progressed from candidate gene studies to larger scale genome-wide association studies, meta-analyses and now prospective validation studies. Genotyping is increasingly sophisticated and affordable, and whole-genome sequencing may soon become readily available as a diagnostic tool in the clinic. The ultimate aim of radiogenomics research is to tailor treatment to the individual with a test based on a combination of treatment, clinical and genetic factors. This personalisation would allow the greatest tumour control while minimising acute and long-term toxicity. Here we discuss the evolution of the field of radiogenomics with reference to the most recent developments and challenges.

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

Quantitative apparent diffusion coefficient (ADC) values as an imaging biomarker for fibrosis in pediatric Crohn's disease: preliminary experience.

PURPOSE: To compare histopathology with ADC values in strictured bowel segments in pediatric patients with known Crohn's disease and surgical bowel resection. METHODS: Magnetic resonance enterography (MRE) images of 14 subjects with Crohn's disease who had surgical bowel resection for strictures were retrospectively reviewed. Five of 14 subjects had DWI (b=0, 500, 1000) sequences included in the MRE study. ADC measurements were made by placing ROI's in the strictured bowel wall and compared to full-thickness histologic analysis of resected specimens. ADC values were also compared to control ADC measurements (in normal and inflamed-nonstenotic bowel segments) as well as the mean ADC values of Crohn's patients published in the literature. RESULTS: All five subjects had transmural fibrosis. The mean ADC value with b = 500 was 0.92 ± 0.10 × 10(-3) mm(2)/s and with b = 1000 was 0.8 ± 0.05 × 10(-3) mm(2)/s. There was a significant difference in ADC values between strictures and inflamed-nonstenotic segments (p=0.0143) and between normal and diseased bowel segments (p=0.009-0.0143). CONCLUSIONS: Quantitative ADC measures of transmural fibrosis are lower compared to the reported values of inflammation in Crohn's disease. To our knowledge, this is the first pediatric pilot study to investigate the correlation of quantitative DWI with histology of surgical specimens in pediatric patients with Crohn's disease. Our results are comparable to a recently published study in adult Crohn's patients showing a significant correlation between a decrease in ADC values and fibrosis.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

CT perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia is a significant cause of morbidity and mortality after aneurysmal SAH, leading to poor outcomes. The purpose of this study was to evaluate the usefulness of CTP in determining delayed cerebral ischemia in patients with aneurysmal SAH. MATERIALS AND METHODS: We conducted a systematic review evaluating studies that assessed CTP in patients with aneurysmal SAH for determining delayed cerebral ischemia. Studies using any of the following definitions of delayed cerebral ischemia were included in the systematic review: 1) new onset of clinical deterioration, 2) cerebral infarction identified on follow-up CT or MR imaging, and 3) functional disability. A random-effects meta-analysis was performed assessing the strength of association between a positive CTP result and delayed cerebral ischemia. RESULTS: The systematic review identified 218 studies that met our screening criteria, of which 6 cohort studies met the inclusion criteria. These studies encompassed a total of 345 patients, with 155 (45%) of 345 patients classified as having delayed cerebral ischemia and 190 (55%) of 345 patients as not having delayed cerebral ischemia. Admission disease severity was comparable across all groups. Four cohort studies reported CTP test characteristics amenable to the meta-analysis. The weighted averages and ranges of the pooled sensitivity and specificity of CTP in the determination of delayed cerebral ischemia were 0.84 (0.7-0.95) and 0.77 (0.66-0.82), respectively. The pooled odds ratio of 23.14 (95% CI, 5.87-91.19) indicates that patients with aneurysmal SAH with positive CTP test results were approximately 23 times more likely to experience delayed cerebral ischemia compared with patients with negative CTP test results. CONCLUSIONS: Perfusion deficits on CTP are a significant finding in determining delayed cerebral ischemia in aneurysmal SAH. This may be helpful in identifying patients with delayed cerebral ischemia before development of infarction and neurologic deficits.

Intraplaque high-intensity signal on 3D time-of-flight MR angiography is strongly associated with symptomatic carotid artery stenosis.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage in carotid artery atherosclerotic plaque has been shown to be a marker of risk, associated with prior and future ischemic events, and has been associated with regions of intraplaque high-intensity signal on 3D-TOF MRA. We assessed the association of intraplaque high-intensity signal determined on 3D-TOF MRA with the incidence of prior ipsilateral stroke or TIA. MATERIALS AND METHODS: We assessed intraplaque hemorrhage by evaluating for intraplaque high-intensity signal adapting a recently validated technique on 3D-TOF source images in participants with high-grade (≥ 70%) extracranial carotid stenosis. Logistic regression analyses were used to assess the strength of association between the presence of intraplaque high-intensity signal on routine MRA sequences and prior stroke or TIA. RESULTS: Intraplaque high-intensity signal was present in 22 (41.5%) of 53 carotid arteries studied in 51 patients. Ipsilateral ischemic events occurred in 15 (68.1%) of 22 in the intraplaque high-intensity signal-positive group (10 strokes, 5 TIAs) and in 4 (12.9%) of 31 in the intraplaque high-intensity signal-negative group (3 strokes, 1 TIA). Ischemic events occurred within the 6-month period preceding imaging in 18 (94.7%) of 19 cases. The univariate odds ratio of the association of intraplaque high-intensity signal with any prior ischemic event was 14.5 (95% CI, 3.6-57.6), and the multivariate age- and sex-adjusted odds ratio was 14.2 (95% CI, 3.3-60.5). The association remained present across 1.5 T and 3T magnet field strengths. CONCLUSIONS: Intraplaque high-intensity signal determined from MRA sequences already in place to measure luminal stenosis is strongly associated with prior ipsilateral ischemic events. Prospective validation of these findings to predict outcome in carotid artery stenosis could provide a valuable and widely accessible stroke risk stratification tool.

A review of assistive devices for arm balancing.

Due to neuromuscular disorders (e.g., Duchenne Muscular Dystrophy) people often loose muscle strength and become wheelchair bound. It is important to use muscles as much as possible. To allow this, and to increase independency of patients, an arm orthosis can be used to perform activities of daily life. The orthosis compensates for the gravity force of the arm, allowing people to perform movements with smaller muscle forces. For patients, the aesthetics of the orthosis is one of the critical issues. This paper presents the state-of-the-art in passive and wearable active arm orthoses, and investigates how to proceed towards a suitable structure for a wearable passive arm orthosis, that is able to balance the arm within its natural range of motion and is inconspicuous; in the ideal case it fits underneath the clothes. Existing devices were investigated with respect to the body interface, the volume, and the workspace. According to these evaluation metrics it is investigated to what extent the devices are wearable and inconspicuous. Furthermore, the balancing principle of the devices, the architecture, force transmission through the devices, and alignment with the body joints are investigated. It appears that there is only one wearable passive orthosis presented in literature. This orthosis can perform throughout the natural workspace of the arm, but is still too bulky to be inconspicuous. The other passive orthoses were conspicuous and mounted to the wheelchair. Except one, the wearable active orthoses were all conspicuous and heavy due to a large backpack to enclose the actuators. They also could not achieve the entire natural workspace of the human arm. A future design of an inconspicuous, wearable, passive arm orthoses should stay close to the body, be comfortable to wear, and supports pronation and supination.

Work readiness of graduate health professionals.

BACKGROUND AND AIM: The current exploratory study investigated work readiness among graduate health professionals. DESIGN AND PARTICIPANTS: A critical incident technique was used to elicit perceptions regarding: strategies and skills that constitute work readiness among health professionals and the work readiness factors that help or hinder health graduates' transition and integration into the workplace. Fifteen medical graduates, 26 nursing graduates and five organisational representatives from a regional hospital in Victoria, Australia participated. METHOD: Data were collected via qualitative interviews. RESULTS: Participants discussed a total of 92 critical incidents; 52 related to helping and 40 to hindering work readiness factors that impacted graduates' transition and integration experiences. A follow-up thematic analysis indentified four critical work readiness factors: social intelligence, organisational acumen, work competence and personal characteristics. While graduates and organisational representatives considered each factor important, some differences between the groups emerged. Organisational representative's perceived social intelligence and clinical skills critical graduate competencies, yet graduates were unprepared in these areas. CONCLUSION: The identified work readiness factors were consistent with past research and warrant further investigation of work readiness among a larger group of graduate health professionals in a range of contexts.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.

BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues.

PURPOSE: Recent work has demonstrated an important decrease in breast cancers for women with systemic lupus erythematosus (SLE). The reason behind this phenomenon is unknown. Our purpose was to explore whether the single nucleotide polymorphisms (SNPs) predisposing to SLE might be protective against breast cancer (in women in the general population). METHODS: We focused on loci relevant to 10 SNPs associated with SLE (with a p value of <10(-9)). We determined whether we could establish a decreased frequency of these SNPs in breast cancer cases versus controls, within the general population. To do this we used a large breast cancer genome-wide association study (GWAS) dataset, involving 3,659 breast cancer cases and 4,897 controls. These subjects were all primarily of European ancestry. RESULTS: The population-based GWAS breast cancer data we examined suggested little evidence for important associations between breast cancer and SLE-related SNPs. Within the general population GWAS data, a cytosine(C) nucleotide substitution at rs9888739 (on chromosome 16p11.2) showed a very weak inverse association with breast cancer. The odds ratio (OR) for the rs9888739-C allele was 0.907551 (p value 0.049899) in the GWAS breast cancer sample, compared to controls. There was a slightly stronger, positive, association with breast cancer for rs6445975-G (Guanine) on chromosome 3p14.3, with a breast cancer OR of 1.0911 (p value 0.0097). CONCLUSIONS: Within this large breast cancer dataset, we did not demonstrate important associations with 10 lupus-associated SNPs. If decreased breast cancer risk in SLE is influenced by genetic profiles, this may be due to complex interactions and/or epigenetic factors.

Diagnostic accuracy of 4D-CT for parathyroid adenomas and hyperplasia.

BACKGROUND AND PURPOSE: 4D-CT is a novel method of multiphase CT imaging. When used to localize parathyroid adenomas and hyperplasia, this technique may allow for more robust diagnostic accuracy than traditional sonography and nuclear scintigraphy techniques. The purpose of our study is to assess the accuracy of 4D-CT for localizing pathologically proved parathyroid adenomas and hyperplasia found during surgery. MATERIALS AND METHODS: A total of 35 pathologically proved cases of parathyroid adenoma and hyperplasia were retrospectively reviewed between January 2009 and March 2011. Inclusion criteria were availability of final surgical pathology and performance of preoperative 4D-CT. No cases were excluded. Sensitivity, specificity, and accuracy of 4D-CT were ascertained including both the side and quadrant of the pathologically proved lesion. RESULTS: Of the 35 pathologically proved cases collected over the study period, 32 (sensitivity = 91%) patients were found positive for parathyroid disease using 4D-CT, including 3 cases of multigland disease. For lateralization of single-gland disease, 4D-CT demonstrated an accuracy of 93%. 4D-CT revealed a suboptimal 44% sensitivity, but 100% specificity, for multigland disease. CONCLUSIONS: 4D-CT demonstrated a high diagnostic accuracy for single and multigland disease in our cohort. Importantly, 4D-CT accurately lateralized single-gland adenomas in >90% of cases, allowing the surgeon to employ a directed operative approach. 4D-CT also showed a very high specificity for the detection of multigland disease.

Quantitative analysis of DNA methylation after whole bisulfitome amplification of a minute amount of DNA from body fluids.

Cell-free circulating DNA isolated from the plasma of individuals with cancer has been shown to harbor cancer-associated changes in DNA methylation, and thus it represents an attractive target for biomarker discovery. However, the reliable detection of DNA methylation changes in body fluids has proven to be technically challenging. Here we describe a novel combination of methods that allows quantitative and sensitive detection of DNA methylation in minute amounts of DNA present in body fluids (quantitative Methylation Analysis of Minute DNA amounts after whole Bisulfitome Amplification, qMAMBA). This method involves genome-wide amplification of bisulphite-modified DNA template followed by quantitative methylation detection using pyrosequencing and allows analysis of multiple genes from a small amount of starting DNA. To validate our method we used qMAMBA assays for four genes and LINE1 repetitive sequences combined with plasma DNA samples as a model system. qMAMBA offered high efficacy in the analysis of methylation levels and patterns in plasma samples with extremely small amounts of DNA and low concentrations of methylated alleles. Therefore, qMAMBA will facilitate methylation studies aiming to discover epigenetic biomarkers, and should prove particularly valuable in profiling a large sample series of body fluids from molecular epidemiology studies as well as in tracking disease in early diagnostics.

The use of scoring rubrics to determine clinical performance in the operating suite.

UNLABELLED: This research evolved out of the need to examine the validity and inter-rater reliability of a set of performance-based scoring rubrics designed to measure competencies within the operating suite. METHOD: Both holistic and analytical rubrics were developed aligned to the ACORN Standard [Australian College of Operating Room Nurses Standard NR4, 2004. ACORN Competency Standards for Perioperative Nurses: Standard NR4: The Instrument Nurse in the Perioperative Environment. Australian College of Operating Room Nurses Ltd, Adelaide] and underpinned by the Dreyfus model (1981). Three video clips that captured varying performance of nurses performing as instrument nurses in the operating suite were recorded and used as prompts by expert raters, who judged the performance using the rubrics. RESULTS: The study found that the holistic rubrics led to more consistent judgments than the analytical rubrics, yet the latter provided more diagnostic information for intervention purposes. Despite less consistency, the Analytical Observation Form had sufficient construct validity to satisfy the requirements of criterion referencing as determined by the Item Separation Index (Rasch, 1960), including high internal consistency and greater inter-rater reliability when average ratings were used. CONCLUSION: The study was an empirical investigation of the use of concomitant Analytical and Holistic Rubrics to determine various levels of performance in the operating suite including inter-rater reliability. The methodology chosen was theoretically sound and sufficiently flexible to be used to develop other competencies within the operating suite.

Common variants in mismatch repair genes and risk of colorectal cancer.

BACKGROUND AND AIMS: The mismatch repair (MMR) genes are in charge of maintaining genomic integrity. Mutations in the MMR genes are at the origin of a familial form of colorectal cancer (CRC). This syndrome accounts for only a small proportion of the excess familial risk of CRC. The characteristics of the alleles that account for the remainder of cases are unknown. To assess the putative associations between common variants in MMR genes and CRC, we performed a genetic case-control study using a single-nucleotide polymorphism (SNP) tagging approach. PATIENTS AND METHODS: A total of 2299 cases and 2284 unrelated controls were genotyped for 68 tagging SNPs in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were measured in cases and controls and analysed using univariate analysis. Haplotypes were constructed and analysed using logistic regression. We also carried out a two-locus interaction analysis and a global test analysis. RESULTS: Genotype frequencies were found to be marginally different in cases and controls for MSH3 rs26279 with a rare homozygote OR = 1.31 [95% confidence interval (CI) 1.05 to 1.62], p(trend) = 0.04. We found a rare MLH1 (frequency <5%) haplotype, increasing the risk of colorectal cancer: (OR = 9.76; 95% CI, 1.25 to 76.29; p = 0.03). The two-locus interaction analysis has exhibited signs of interaction between SNPs located in genes MSH6 and MSH2. Global testing has showed no evidence of interaction. CONCLUSION: It is unlikely that common variants in MMR genes contribute significantly to colorectal cancer.

Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers.

BACKGROUND: We chose a set of candidate single nucleotide polymorphisms (SNPs) to investigate gene-environment interactions in three types of cancer that have been related to air pollution (lung, bladder and myeloid leukemia). PATIENTS AND METHODS: The study has been conducted as a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (409 cancer cases and 757 matched controls). We included never and ex-smokers. SNPs were in genes involved in oxidative stress, phase I metabolizing genes, phase II metabolizing genes and methylenetetrahydrofolate reductase (MTHFR). RESULTS: The most notable findings are: GSTM1 deletion and bladder cancer risk [odds ratio (OR) = 1.60; 95% confidence interval 1.00-2.56]; CYP1A1 and leukemia (2.22, 1.33-3.70; heterozygotes); CYP1B1 and leukemia (0.47, 0.27-0.84; homozygotes); MnSOD and leukemia (1.91, 1.08-3.38; homozygotes) and NQO1 and lung cancer (8.03, 1.73-37.3; homozygotes). Other statistically significant associations were found in subgroups defined by smoking habits (never or ex-smokers), environmental tobacco smoke or gender, with no obvious pattern. When gene variants were organized according to the three main pathways, the emerging picture was of a strong involvement of combined phase I enzymes in leukemia, with an OR of 5 (1.63-15.4) for those having three or more variant alleles. The association was considerably stronger for leukemias arising before the age of 55.

Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions.

It is becoming increasingly evident that single-locus effects cannot explain complex multifactorial human diseases like cancer. We applied the multi-factor dimensionality reduction (MDR) method to a large cohort study on gene-environment and gene-gene interactions. The study (case-control nested in the EPIC cohort) was established to investigate molecular changes and genetic susceptibility in relation to air pollution and environmental tobacco smoke (ETS) in non-smokers. We have analyzed 757 controls and 409 cases with bladder cancer (n=124), lung cancer (n=116) and myeloid leukemia (n=169). Thirty-six gene variants (DNA repair and metabolic genes) and three environmental exposure variables (measures of air pollution and ETS at home and at work) were analyzed. Interactions were assessed by prediction error percentage and cross-validation consistency (CVC) frequency. For lung cancer, the best model was given by a significant gene-environment association between the base excision repair (BER) XRCC1-Arg399Gln polymorphism, the double-strand break repair (DSBR) BRCA2-Asn372His polymorphism and the exposure variable 'distance from heavy traffic road', an indirect and robust indicator of air pollution (mean prediction error of 26%, P<0.001, mean CVC of 6.60, P=0.02). For bladder cancer, we found a significant 4-loci association between the BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3'-untranslated region (3'-UTR) polymorphism and the metabolic gene polymorphisms COMT-Val158Met and MTHFR-677C>T (mean prediction error of 22%, P<0.001, mean CVC consistency of 7.40, P<0.037). For leukemia, a 3-loci model including RAD52-2259C>T, MnSOD-Ala9Val and CYP1A1-Ile462Val had a minimum prediction error of 31% (P<0.001) and a maximum CVC of 4.40 (P=0.086). The MDR method seems promising, because it provides a limited number of statistically stable interactions; however, the biological interpretation remains to be understood.