| 1. |
- Alhamdow, Ayman, et al.
(författare)
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DNA-methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons
- 2018
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 39:7, s. 869-878
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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.
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| 2. |
- Ali, Imran, et al.
(författare)
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Exposure to polychlorinated biphenyls and prostate cancer : population-based prospective cohort and experimental studies
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 37:12, s. 1144-1151
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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.
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| 3. |
- Sinnott, Jennifer A., et al.
(författare)
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Molecular differences in transition zone and peripheral zone prostate tumors
- 2015
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Ingår i: Carcinogenesis. - Oxford, United Kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 36:6, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20-30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research.
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| 4. |
- Stopsack, Konrad H., et al.
(författare)
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Cholesterol uptake and regulation in high-grade and lethal prostate cancers
- 2017
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 38:8, s. 806-811
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Tidskriftsartikel (refereegranskat)abstract
- Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients.
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| 5. |
- Thorgeirsson, Tryggvi, et al.
(författare)
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Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort
- 2016
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Ingår i: Carcinogenesis. - Oxford, United Kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 37:3, s. 262-268
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.
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