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Open access

Barbara Senk, Katja Goricar, Viljem Kovac, Vita Dolzan and Alenka Franko

Abstract

Background

Malignant mesothelioma (MM) is an asbestos related aggressive tumor with poor prognosis. The aim of this study was to investigate if aquaporin 1 (AQP1) genetic polymorphisms influence the risk of MM and the response to cisplatin based MM treatment.

Patients and methods

The case-control study included 231 patients with MM and a control group of 316 healthy blood donors. All subjects were genotyped for three AQP1polymorphisms (rs1049305, rs1476597 and rs28362731). Logistic and Cox regression were used in statistical analysis.

Results

AQP1 rs1049305 polymorphism was significantly associated with MM risk in dominant model adjusted for gender and age (OR = 0.60, 95% CI = 0.37–0.96, Padj = 0.033). This polymorphism was also significantly associated with cisplatin based treatment related anaemia (unadjusted: OR = 0.49, 95% CI = 0.27–0.90, P = 0.021; adjusted: for CRP: OR = 0.52, 95% CI = 0.27–0.99, P = 0.046), with leukopenia (OR = 2.09, 95% CI = 1.00–4.35, P = 0.049) in dominant model and with thrombocytopenia (OR = 3.06, 95% CI = 1.01–9.28, P = 0.048) and alopecia (OR = 2.92, 95% CI = 1.00–8.46, P = 0.049) in additive model. AQP1 rs28362731 was significantly associated with thrombocytopenia (unadjusted: OR = 3.73, 95% CI = 1.00–13.84, P = 0.049; adjusted for pain: OR = 4.63, 95% CI = 1.13–19.05, P = 0.034) in additive model.

Conclusions

AQP1 may play a role in the risk of MM. Furthermore, AQP1 genotype information could improve the prediction of MM patients at increased risk for cisplatin toxicity.

Open access

Kristina Levpuscek, Katja Goricar, Viljem Kovac, Vita Dolzan and Alenka Franko

Abstract

Background

Malignant mesothelioma (MM) is a rare aggressive tumour of mesothelium caused by asbestos exposure. It has been suggested that the genetic variability of proteins involved in DNA repair mechanisms affects the risk of MM. This study investigated the influence of functional polymorphisms in ERCC1 and XRCC1 genes, the interactions between these polymorphisms as well as the interactions between these polymorphisms and asbestos exposure on MM risk.

Patients and methods

In total, 237 cases with MM and 193 controls with no asbestos-related disease were genotyped for ERCC1 and XRCC1 polymorphisms.

Results

ERCC1 rs3212986 polymorphism was significantly associated with a decreased risk of MM (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.41–0.91; p = 0.014). No associations were observed between other genetic polymorphisms and MM risk. Interactions between polymorphisms did not significantly influence MM risk. Interaction between ERCC1 rs11615 and asbestos exposure significantly influenced MM risk (OR = 3.61; 95% CI = 1.12–11.66; p = 0.032). Carriers of polymorphic ERCC1 rs11615 allele who were exposed to low level of asbestos had a decreased risk of MM (OR = 0.40; 95% CI = 0.19–0.84; p = 0.016). Interactions between other polymorphisms and asbestos exposure did not significantly influence MM risk.

Conclusions

Our findings suggest that the genetic variability of DNA repair mechanisms could contribute to the risk of developing MM.

Open access

Viljem Kovac, Metoda Dodic-Fikfak, Niko Arneric, Vita Dolzan and Alenka Franko

Abstract

Background. Fibulin-3 is a new potential biomarker for malignant mesothelioma (MM). This study evaluated the potential applicability of fibulin-3 plasma levels as a biomarker of response to treatment and its prognostic value for progressive disease within 18 months. The potential applicability of fibulin-3 in comparison with or in addition to soluble mesothelin-related peptides (SMRP) was also assessed.

Patients and methods. The study included 78 MM patients treated at the Institute of Oncology Ljubljana between 2007 and 2011. Fibulin-3 levels in plasma samples obtained before treatment and in various responses to treatment were measured with the enzyme-linked immunosorbent assay.

Results. In patients evaluated before the treatment, fibulin-3 levels were not influenced by histopathological sub-types, tumour stages or the presence of metastatic disease. Significantly higher fibulin-3 levels were found in progressive disease as compared to the levels before treatment (Mann-Whitney [U] test = 472.50, p = 0.003), in complete response to treatment (U = 42.00, p = 0.010), and in stable disease (U = 542.00, p = 0.001). Patients with fibulin-3 levels exceeding 34.25 ng/ml before treatment had more than four times higher probability for developing progressive disease within 18 months (odds ratio [OR] = 4.35, 95% confidence interval [CI] 1.56–12.13). Additionally, patients with fibulin-3 levels above 34.25 ng/ml after treatment with complete response or stable disease had increased odds for progressive disease within 18 months (OR = 6.94, 95% CI 0.99–48.55 and OR = 4.39, 95% CI 1.63–11.81, respectively).

Conclusions. Our findings suggest that in addition to SMRP fibulin-3 could also be helpful in detecting the progression of MM.

Open access

Alenka Franko, Vita Dolžan, Niko Arnerić and Metoda Dodič-Fikfak

Asbestosis and Catalase Genetic Polymorphism

Catalase (CAT) is part of the enzymatic defense system against reactive oxygen species (ROS), known to be involved in the pathogenesis of asbestosis. This study investigates whether CAT -262 C>T genetic polymorphism influences the risk of asbestosis in workers occupationally exposed to asbestos.

The nested case-control study included 262 cases with asbestosis and 265 controls with no asbestos-related disease. Data on cumulative asbestos exposure and smoking were available. A real-time PCR assay was introduced for genotyping CAT -262 C>T promoter polymorphism.

A slightly elevated risk of asbestosis was observed in subjects with the CAT -262 TT genotype compared to others (OR=1.36, CI 0.70-2.62). This risk did not change substantially after adjustment by sex, age, and smoking, but the involvement of cumulative asbestos exposure changed the OR to 1.91 (CI 0.93-3.91). These findings indicate that the CAT -262 TT genotype may be slightly associated with an increased risk of asbestosis. No synergistic effect was found between cumulative asbestos exposure and the CAT -262 TT genotype, but cumulative asbestos exposure acted as a confounder. These results are an important contribution to understanding the interactions between genetic and environmental factors that may modify the risk of asbestosis.

Open access

Alenka Franko, Katja Goricar, Viljem Kovac, Metoda Dodic-Fikfak and Vita Dolzan

Summary

Background

This study aimed to investigate the association between NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms and the risk of developing pleural plaques, asbestosis, and malignant mesothelioma (MM), and to study the influence of the interactions between polymorphisms and asbestos exposure on the risk of developing these diseases.

Methods

The case-control study included 416 subjects with pleural plaques, 160 patients with asbestosis, 154 subjects with MM and 149 subjects with no asbestos disease. The NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms were determined using real-time PCR-based methods. In the statistical analysis, standard descriptive statistics was followed by univariate and multivariate logistic regression modelling.

Results

Asbestos exposure (medium and high vs low) was associated with the risk for each studied asbestos-related disease. An increased risk of pleural plaques was found for CARD8 rs2043211 AT + TT genotypes (OR = 1.48, 95% CI 1.01–2.16, p = 0.042). When the analysis was performed for MM patients as cases, and pleural plaques patients as controls, a decreased MM risk was observed for carriers of CARD8 rs2043211 TT genotype (OR = 0.52, 95% CI 0.27–1.00, p = 0.049). The interactions between NLRP3 rs35829419 and CARD8 rs2043211 genotypes did not influence the risk of any asbestos-related disease. However, when testing interactions with asbestos exposure, a decreased risk of asbestosis was found for NLRP3 CA+AA genotypes (OR = 0.09, 95% CI 0.01–0.60, p = 0.014).

Conclusions

The results of our study suggest that NLRP3 and CARD8 polymorphisms could affect the risk of asbestos-related diseases.

Open access

Alenka Franko, Nika Kotnik, Katja Goricar, Viljem Kovac, Metoda Dodic-Fikfak and Vita Dolzan

Abstract

Background

Malignant mesothelioma is a rare cancer with poor outcome, associated with asbestos exposure. Reactive oxygen species may play an important role in the mechanism of carcinogenesis; therefore, genetic variability in antioxidative defence may modify an individual’s susceptibility to this cancer. This study investigated the influence of functional polymorphisms of NQO1, CAT, SOD2 and hOGG1 genes, gene-gene interactions and gene-environment interactions on malignant mesothelioma risk.

Patients and methods

In total, 150 cases with malignant mesothelioma and 122 controls with no asbestos-related disease were genotyped for NQO1, CAT, SOD2 and hOGG1 polymorphisms.

Results

The risk of malignant mesothelioma increased with smoking, odds ratio (OR) 9.30 [95% confidence interval (CI): 4.83–17.98] and slightly with age, OR 1.10 (95% CI: 1.08–1.14). Medium and high asbestos exposures represented 7-times higher risk of malignant mesothelioma compared to low exposure, OR 7.05 (95% CI 3.59–13.83). NQO1 rs1800566 was significantly associated with increased malignant mesothelioma risk, OR 1.73 (95% CI 1.02–2.96). Although there was no independent association between either CAT rs1001179 or hOGG1 rs1052133 polymorphism and malignant mesothelioma, interaction between both polymorphisms showed a protective effect, ORint 0.27 (95% CI 0.10–0.77).

Conclusions

Our findings suggest a role of both genetic variability in antioxidative defence and repair as well as the impact of gene-gene interactions in the development of malignant mesothelioma. The results of this study could add to our understanding of pathogenesis of malignant mesothelioma and contribute to prevention and earlier diagnosis of this aggressive cancer.