It is becoming evident that both environmental/lifestyle and genetic factors may influence the development of many diseases. This chapter highlights the importance of considering gene-environment interactions, which is shown on the example of our studies into asbestosis, one of the most frequent asbestos-related diseases. Asbestos fibres induce generation of reactive oxygen and nitric species (ROS and RNS), and it is generally accepted that ROS and RNS are involved in the pathogenesis of asbestosrelated diseases. Human tissues contain specific enzymes that metabolise ROS and RNS, such as superoxide dismutases (SODs), catalase (CAT), glutathione-S-transferases (GSTs) and inducible nitric oxide synthase (iNOS). As these enzymes are encoded by polymorphic genes, genetic variability in an individual's capacity to detoxify these reactive species may modify the risk for disease. Our previous studies into asbestosis showed that the associations between the risk of asbestosis and MnSOD Ala-9Val polymorphism and between asbestosis and iNOS genotypes were modified by CAT -262C)T polymorphism. A strong interaction was also found between smoking (lifestyle factor) and GSTM1-null polymorphism, between smoking and iNOS (CCTTT)n polymorphism and between cumulative asbestos exposure (environmental factor) and iNOS (CCTTT)n polymorphism. The findings of our studies and other studies indicate that in addition to environmental and/or occupational exposure to different hazards and lifestyle factors, genetic factors as well as the interactions between different genotypes, between genotypes and lifestyle factors and between genotypes and environmental/occupational exposure to hazards may also have an important role on the development of diseases and should be further investigated.
F.01 Acquisition of new practical knowledge, information and skills
COBISS.SI-ID: 33080537Occupational and environmental exposure to chemical substances, including asbestos, ecological and biological monitoring of exposure, adverse effects of chemical substances, including diseases related to exposure to asbestos, were presented during the Training for health promotion advisers, held on 29.9.2017 at the Clinical Institute for Occupational, traffic and sports Medicine, University Medical Centre Ljubljana. The participants were also alerted to the importance of interactions between genetic factors and environmental factors (such as asbestos).
F.18 Transfer of new know-how to direct users (seminars, fora, conferences)
COBISS.SI-ID: 4192940Immune checkpoints are crucial modulators of a balanced physiological immune response. Tumors can exploit these mechanisms to acquire immune resistance, which promotes survival of cancer cells and tumor progression. Recently, therapeutic approaches inhibiting immune checkpoints programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) have been successful in several tumors. Furthermore, platinum drugs were shown to affect immune response, and expression of PD-1 and PD-L1 was associated with resistance to cisplatin. Cisplatin-based chemotherapy is commonly used in malignant mesothelioma (MM), an aggressive cancer of pleura or peritoneum. Our aim was therefore to determine whether single nucleotide polymorphisms (SNPs) in PD-1 and PD-L1 genes influence the outcome of cisplatin based chemotherapy in MM patients. The study included 171 MM patients treated with gemcitabine/cisplatin or pemetrexed/cisplatin doublet chemotherapy. All were genotyped for six SNPs in genes coding for PD-1 (PDCD1) and PD-L1 (CD274). Cox and logistic regression were used to assess their influence on treatment outcome. CD274 rs4742098 (c.*2635A)G) was significantly associated with the outcome of gemcitabine/cisplatin chemotherapy: carriers of at least one polymorphic allele had significantly longer PFS compared to carriers of two wild-type alleles (9.1 vs 7.1 months, HR=0.64, 95% CI=0.43-0.94, P=0.025), as well as significantly longer OS (21.5 vs 14.0 months, HR=0.59, 95% CI=0.39-0.91, P=0.016). They were also more likely to achieve partial or complete response (OR=2.19, 95% CI=1.02-4.71, P=0.045). CD274 rs4742098 was also associated with increased risk of nausea or vomiting (P=0.024) and alopecia (P=0.036). CD274 rs4143815 and PDCD1 rs10204525 were also associated with increased risk of nausea or vomiting (P=0.023 and P=0.025, respectively). In conclusion, genetic variability of immune checkpoints may influence response to gemcitabine/cisplatin chemotherapy in MM and may potentially contribute to a more personalized treatment approach.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 33479897