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Sökning: L773:0143 3334 > (2015-2019)

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  • Alhamdow, Ayman, et al. (författare)
  • Cancer-related proteins in serum are altered in workers occupationally exposed to polycyclic aromatic hydrocarbons : : a cross-sectional study
  • 2019
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 40:6, s. 771-781
  • Tidskriftsartikel (refereegranskat)abstract
    • Exposure to some polycyclic aromatic hydrocarbons (PAH) increases the risk of cancer and is common, particularly for workers in occupations such as chimney sweeping. In exposed workers, screening of early cancer-related markers provides important information to identify individuals at risk. Here, we aimed to elucidate the associations between PAH exposure and serum levels of cancer-related proteins in 118 chimney sweeps and 126 occupationally unexposed controls, all non-smoking males from Sweden. Monoydroxylated metabolites of pyrene, phenanthrene, benzo[a]pyrene, and benzo[a]anthracene were measured in urine using LC/MS/MS and 90 cancer-related proteins were measured in serum using a Proximity Extension Assay. Linear regression analysis adjusted for age, BMI, and false discovery rate (FDR) identified 17 serum proteins that were differentially expressed (16 upregulated and 1 downregulated) in chimney sweeps compared with controls (FDR<0.05). Concentrations of the peptidase kallikrein 13 (KLK13) showed significant positive associations with urinary concentrations of the PAH metabolites 3-hydroxybenzo[a]pyrene (B, 95%CI: 0.042, 0.008-0.076) and 3-hydroxybenzo[a]anthracene (B, 95%CI: 0.068, 0.002-0.134). Moreover, dose-response relationships were observed between KLK13 and 3-hydroxybenzo[a]pyrene (trend test P=0.027) and 3-hydroxybenzo[a]anthracene (P=0.035). Pathway and gene ontology analyses showed that cell movement, cell adhesion, and cell migration were the predominant molecular functions associated with the top differentially expressed proteins. In conclusion, we found a number of putative cancer-related proteins differentially expressed in workers exposed to PAH. This warrants effective measure to reduce PAH exposure among workers as well as further investigation to confirm these findings.
  • Alhamdow, Ayman, et al. (författare)
  • DNA-methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons
  • 2018
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 39:7, s. 869-878
  • Tidskriftsartikel (refereegranskat)abstract
    • Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls, and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 μg/g creatinine) followed by chimney sweeps (0.34 μg/g creatinine) and controls (0.05 μg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1% and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B=-2.04; P<0.057, adjusted for smoking and age) and lower average AHRR methylation (B=-2.05; P<0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B=-0.81; P<0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose-response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure.
  • Ali, Imran, et al. (författare)
  • Exposure to polychlorinated biphenyls and prostate cancer population-based prospective cohort and experimental studies
  • 2016
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 37:12, s. 1144-1151
  • Tidskriftsartikel (refereegranskat)abstract
    • Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.
  • Brenner, Darren R, et al. (författare)
  • Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia
  • 2015
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 36:11, s. 1314-1326
  • Tidskriftsartikel (refereegranskat)abstract
    • Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001&gt; P &gt; 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
  • Chen, Dan, et al. (författare)
  • Analysis of the genetic architecture of susceptibility to cervical cancer indicates that common SNPs explain a large proportion of the heritability
  • 2015
  • Ingår i: Carcinogenesis. - 0143-3334 .- 1460-2180. ; 36:9, s. 992-998
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic architecture of susceptibility to cervical cancer is not well-understood. By using a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls with 632 668 single-nucleotide polymorphisms (SNPs), we estimated that 24.0% [standard error (SE) = 5.9%, P = 3.19 x 10(-6)] of variation in liability to cervical cancer is captured by autosomal SNPs, a bit lower than the heritability estimated from family study (27.0%), suggesting that a substantial proportion of the heritability is tagged by common SNPs. The remaining missing heritability most probably reflects incomplete linkage disequilibrium between causal variants and the genotyped SNPs. The variance explained by each chromosome is not related to its length (R-2 = 0.020, P = 0.516). Published genome-wide significant variants only explain 2.1% (SE = 1.5%, P = 0) of phenotypic variance, which reveals that most of the heritability has not been detected, presumably due to small individual effects. Another 2.1% (SE = 1.1%, P = 0.013) of variation is attributable to biological pathways associated with risk of cervical cancer, supporting that pathway analysis can identify part of the hidden heritability. Except for human leukocyte antigen genes and MHC class I polypeptide-related sequence A (MICA), none of the 82 candidate genes/regions reported in other association studies contributes to the heritability of cervical cancer in our dataset. This study shows that risk of cervical cancer is influenced by many common germline genetic variants of small effects. The findings are important for further study design to identify the hiding heritability that has not yet been revealed. More susceptibility loci are yet to be found in GWASs with higher power.
  • Cui, Tao, et al. (författare)
  • Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology
  • 2019
  • Ingår i: Carcinogenesis. - 0143-3334 .- 1460-2180. ; 40:2, s. 269-278
  • Tidskriftsartikel (refereegranskat)abstract
    • Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.
  • Dai, Juncheng, et al. (författare)
  • Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci
  • 2019
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 40:3, s. 432-440
  • Tidskriftsartikel (refereegranskat)abstract
    • DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.
  • Engström, Wilhelm, et al. (författare)
  • The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling
  • 2015
  • Ingår i: Carcinogenesis. - Oxford University Press (OUP): Policy B - Oxford Open Option B. - 0143-3334 .- 1460-2180. ; 36, s. S38-S60
  • Forskningsöversikt (refereegranskat)abstract
    • The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
  • Eriksson, Staffan, et al. (författare)
  • Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
  • 2015
  • Ingår i: Carcinogenesis. - Oxford University Press (OUP): Policy B - Oxford Open Option B. - 0143-3334 .- 1460-2180. ; 36, s. S254-S296
  • Forskningsöversikt (refereegranskat)abstract
    • Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
  • Fahmideh, M. A., et al. (författare)
  • CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility
  • 2015
  • Ingår i: Carcinogenesis. - 0143-3334. ; 36:8, s. 876-882
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p(trend) = 0.022, p(trend) = 0.042, p(trend) = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p(trend) = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p(trend) = 0.009, p(trend) = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways.
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