Background

Low mitochondrial DNA (mtDNA) copy number is a common feature of renal cell carcinoma (RCC), and may influence tumor development. Results from a recent case-control study suggest that low mtDNA copy number in peripheral blood may be a marker for increased RCC risk. In an attempt to replicate that finding, we measured mtDNA copy number in peripheral blood DNA from a U.S. population-based case-control study of RCC.

Methodology/Principal Findings

Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay using DNA extracted from peripheral whole blood. Cases (n = 603) had significantly lower mtDNA copy number than controls (n = 603; medians 0.85, 0.91 respectively; P = 0.0001). In multiple logistic regression analyses, the lowest quartile of mtDNA copy number was associated with a 60% increase in RCC risk relative to the highest quartile (OR = 1.6, 95% CI = 1.1–2.2; Ptrend = 0.009). This association remained in analyses restricted to cases treated by surgery alone (OR Q1 = 1.4, 95% CI = 1.0–2.1) and to localized tumors (2.0, 1.3–2.8).

Conclusions/Significance

Our findings from this investigation, to our knowledge the largest of its kind, offer important confirmatory evidence that low mtDNA copy number is associated with increased RCC risk. Additional research is needed to assess whether the association is replicable in prospective studies.

The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in NHL, occurring in 70–90% of follicular lymphomas (FL) and 30–50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and −negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (3rd tertile vs. 1st tertile) had elevated risks of t(14;18)-positive DLBCL [odds ratio (OR)=1.8, 95% confidence interval (CI) 1.1–3.0] and FL (OR=1.4, 95%CI 1.0–1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries [13+ versus 0–12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7–2.7; FL OR=1.6, 95%CI 1.1–2.5] and individuals exposed to PCB180 greater than 20.8 ng/g [t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6–2.9; FL OR=1.7, 95%CI 1.0–2.8]. In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes.

Background

Structural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well-characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance.

Results

773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP-array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package.

Conclusions

This study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms.

While severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor (TNF)-α] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein (CRP), sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. Odds ratios (OR) and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR 1.7, 95% CI 1.1–2.8; Ptrend=0.02) and sCD27 (OR 5.3, 95% CI 2.9–9.4; Ptrend<0.0001). These associations remained in analyses of cases diagnosed 6+ years following blood collection (sTNF-R1: OR 2.1, 95% CI 1.0–4.0, Ptrend=0.01; sCD27: OR 4.1, 95% CI 1.9–8.5, Ptrend=0.0001). Elevated levels of IL-10, TNF-α and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis, and were null for cases diagnosed 6+ years post-collection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis.

Immune deficiency is one of the best characterized and strongest known risk factors for non-Hodgkin lymphoma (NHL). We studied the association between single nucleotide polymorphisms (SNPs) in integrin genes that are important components in human innate immunity and the risk of NHL in a population-based case–control study of women in Connecticut, USA. A total of 373 tag SNPs in 33 gene regions were included in the analysis of 448 cases and 525 controls. The ADAM19 rs11466782 SNP was associated with an increased risk of lymphoma (OR, 1.73; 95 % CI, 1.28–2.35; P additive = 0.0004), and the ICAM3 rs2304240 (OR, 0.67; 95 % CI, 0.52–0.86; P additive = 0.002) and the PTGDR rs708486 SNPs (OR, 0.75; 95 % CI, 0.63–0.90; P additive = 0.002) were associated with reduced risk of lymphoma. Two gene regions (ADAM19 (P=0.009) and ICAM3 (P=0.009)) displayed global associations with lymphoma risk at the P<0.01 level. While our results suggest that genetic polymorphisms in integrin genes may play a role in the genesis of lymphoma in women, they should be viewed as exploratory until they are replicated in additional populations.

Abstract

Recent evidence suggests that urinary F2-isoprostanes (F2-IsoPs) are more accurate markers of oxidative stress than other available biomarkers. Most previous studies used unmetabolized F2-IsoPs as a biomarker. Few previous studies measured 15-F2t-IsoP-M, a metabolite of one of the most common F2-IsoPs, 15-F2t-IsoP. Unlike 15-F2t-IsoP, 15-F2t-IsoP-M is not subject to autoxidation and renal production. To our knowledge, no study has compared the associations of age and body mass index (BMI) with F2-IsoPs to those with 15-F2t-IsoP-M. Urinary levels of F2-IsoPs and 15-F2t-IsoP-M were measured using gas chromatography–mass spectrometry for 845 healthy women aged 40–70 years. Both F2-IsoPs and 15-F2t-IsoP-M were elevated among smokers. The level of 15-F2t-IsoP-M increased with age, particularly after menopause, and with BMI. In contrast, F2-IsoPs decreased with age, regardless of menopausal status, and was not related to BMI. The association of 15-F2t-IsoP-M with age or menopausal status did not differ by BMI category, and the association with BMI was also independent of age or menopausal status. 15-F2t-IsoP-M appears to be a valuable biomarker of oxidative stress in age- and obesity-related diseases. Antioxid. Redox Signal. 14, 2453–2460.

Background

Most studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk. However, to our knowledge, no study to date has had quantitative data on historical diesel exposure coupled with adequate sample size to evaluate the exposure–response relationship between diesel exhaust and lung cancer. Our purpose was to evaluate the relationship between quantitative estimates of exposure to diesel exhaust and lung cancer mortality after adjustment for smoking and other potential confounders.

Methods

We conducted a nested case–control study in a cohort of 12 315 workers in eight non-metal mining facilities, which included 198 lung cancer deaths and 562 incidence density–sampled control subjects. For each case subject, we selected up to four control subjects, individually matched on mining facility, sex, race/ethnicity, and birth year (within 5 years), from all workers who were alive before the day the case subject died. We estimated diesel exhaust exposure, represented by respirable elemental carbon (REC), by job and year, for each subject, based on an extensive retrospective exposure assessment at each mining facility. We conducted both categorical and continuous regression analyses adjusted for cigarette smoking and other potential confounding variables (eg, history of employment in high-risk occupations for lung cancer and a history of respiratory disease) to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death (case subjects)/reference date (control subjects). All statistical tests were two-sided.

Results

We observed statistically significant increasing trends in lung cancer risk with increasing cumulative REC and average REC intensity. Cumulative REC, lagged 15 years, yielded a statistically significant positive gradient in lung cancer risk overall (P trend = .001); among heavily exposed workers (ie, above the median of the top quartile [REC ≥ 1005 μg/m3-y]), risk was approximately three times greater (OR = 3.20, 95% CI = 1.33 to 7.69) than that among workers in the lowest quartile of exposure. Among never smokers, odd ratios were 1.0, 1.47 (95% CI = 0.29 to 7.50), and 7.30 (95% CI = 1.46 to 36.57) for workers with 15-year lagged cumulative REC tertiles of less than 8, 8 to less than 304, and 304 μg/m3-y or more, respectively. We also observed an interaction between smoking and 15-year lagged cumulative REC (P interaction = .086) such that the effect of each of these exposures was attenuated in the presence of high levels of the other.

Conclusion

Our findings provide further evidence that diesel exhaust exposure may cause lung cancer in humans and may represent a potential public health burden.