LINE-1 Methylation Levels in Leukocyte DNA and Risk of Renal Cell Cancer

Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84–83.47) compared to 81.67% (IQR: 80.35–83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20−2.81), OR(Q3) = 1.72(1.11−2.65) and OR(Q4) = 2.06(1.34−3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis

Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study

BACKGROUND: The sex hormone-binding globulin (SHBG) is a carrier protein that modulates the bio-availability of serum sex steroid hormones, which may be involved in ovarian cancer. We evaluated whether common genetic variation in SHBG and its 3' neighbor ATP1B2, in linkage disequilibrium, is associated with the risk of epithelial ovarian cancer. METHODS: The study population included 264 women with ovarian carcinoma and 625 controls participating in a population-based case-control study in Poland. Five common single nucleotide polymorphisms (SNPs) in SHGB and five in ATP1B2 were selected to capture most common variation in this region. RESULTS: None of the SNPs evaluated was significantly associated with ovarian cancer risk, including the putative functional SNPs SHBG D356N (rs6259) and -67G>A 5'UTR (rs1799941). However, our data were consistent with a decreased ovarian cancer risk associated with the variant alleles for these two SNPs, which have been previously associated with increased circulating levels of SHBG. CONCLUSION: These data do not support a substantial association between common genetic variation in SHBG and ovarian cancer risk

Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies

International audienceBACKGROUND:Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies.METHODS:We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends.RESULTS:The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women.CONCLUSIONS:Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.)

In-Home Coal and Wood Use and Lung Cancer Risk: A Pooled Analysis of the International Lung Cancer Consortium

10.1289/ehp.1002217Environmental Health Perspectives118121743-174

Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk

Background Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. Methods We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. Results Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after ≥20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after ≥20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. Conclusions Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cance

Exposure to secondhand tobacco smoke and lung cancer by histological type: A pooled analysis of the International Lung Cancer Consortium (ILCCO)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108359/1/ijc28835.pd

A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility

Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk

In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09–1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3′ of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/1/ijc30618-sup-0001-supptables.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/2/ijc30618_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/3/ijc30618.pd

Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk

Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings