Browsing by Author "Coucelo, Margarida"
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- Diagnosis and laboratory follow-up of patients with multiple myeloma: guidelines from the Portuguese multiple myeloma groupPublication . Pires, Ana Marta; Barreto, João Pedro; Caetano, Joana; Soares, Maria José; Geraldes, Catarina; Fernandes, Bruno; Coucelo, Margarida; Chacim, Sérgio; Coelho, Henrique; Correia, Cecília; Cruz, Ana Paula; Cunha, Manuel; Cunha, Maria Rosário; Cunha, Nuno; Ferraz, Patrícia; Freitas, José Guilherme; Henrique, Rui; Lisboa, Susana; Lúcio, Paulo; Paiva, Artur; Pedrosa, Cláudia; Ramos, Inês; Sarmento, Ana Bela; Seabra, Patrícia; Sevilha, Joana; Sousa, Maria José Rego de; Sousa, Sara; Sousa, Teresa; Tavares, Márcio; Trigo, Fernanda; Bergantim, Rui; Roque, Adriana; João, CristinaMultiple myeloma is a neoplasm of plasma cells that in most cases is associated with the secretion of monoclonal immunoglobulins and can involve multiple organs. Its timely diagnosis is essential to limit or avoid irreversible damage and dysfunction of target organs. Appropriate initial stratification of patients allows for optimization in the selection and sequence of therapy, as well as proper follow-up during treatment and monitoring, impacting survival. These laboratory guidelines from the Portuguese Multiple Myeloma Group provide recommendations for the diagnosis and laboratory follow-up of patients with multiple myeloma. The follow-up and diagnosis of patients with other clinically significant monoclonal gammopathies were not included in this text. This article was based on international guidelines, scientific publications, and the experience of a panel of specialists in clinical and laboratory fields dedicated to the study and treatment of multiple myeloma.
- Genetic variants in oxidative stress-related genes and their impact on prognosis and treatment response in chronic myeloid leukemia patientsPublication . Alves, Raquel; Ventura, Filipa; Jorge, Joana; Marques, Gilberto; Coucelo, Margarida; Diamond, Joana; Oliveiros, Bárbara; Pereira, Amélia; Freitas-Tavares, Paulo; Almeida, António M.; Gonçalves, Ana Cristina; Sarmento-Ribeiro, Ana BelaChronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR::ABL1 fusion gene, which codifies the BCR-ABL protein with increased tyrosine kinase activity. Despite the clinical results for the outstanding tyrosine kinase inhibitors (TKIs), drug resistance is a problem in CML management. Genetic variants that alter redox homeostasis by changing antioxidant enzyme expression or activity may influence patient responses and could enhance patient stratification. We aimed to assess the association of SOD2, CAT GPX1, NRF2, and KEAP1 genetic variants with TKI response and disease prognosis. For this purpose, we genotyped the variants rs4880 (SOD2), rs1050450 (GPX1), rs1001179 (CAT), rs6721961, rs4893819, rs35652124, rs6706649, rs13001694 (NFE2L2), and rs113540846 (KEAP1) via PCR in 187 CML patients. Our results show that variants in genes related to oxidative stress influence the development and degree of TKI resistance (allele G and GG genotypes of GPX1 and CT genotype of NFE2L2 rs4893819), the appearance of mutations in the BCR::ABL1 gene (AG genotype of NFE2L2 rs13001694 and genetic profile GGCTTCCCGG of the NFE2L2/KEAP1 axis), disease evolution (AG genotype of SOD2 and CT genotype of NFE2L2 rs4893819), and overall survival (CC genotype of CAT and GG genotype of NFE2L2 rs13001694) of CML patients. Our study found that variants in oxidative stress-related genes impact treatment response and outcomes in CML.
- Genetic variants of ABC and SLC transporter genes and chronic myeloid leukaemia: impact on susceptibility and prognosisPublication . Alves, Raquel; Goncalves, Ana Cristina; Jorge, Joana; Marques, Gilberto; Ribeiro, André B.; Tenreiro, Rita; Coucelo, Margarida; Diamond, Joana; Oliveiros, Bárbara; Pereira, Amélia; Freitas-Tavares, Paulo; Almeida, António M.; Sarmento-Ribeiro, Ana BelaSolute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.
- Influence of genetic variants of oxidative stress related genes on prognosis and therapy response in chronic myeloid leukemiaPublication . Alves, Raquel; Ventura, Filipa; Jorge, Joana; Ribeiro, Ilda P.; Marques, Gilberto; Coucelo, Margarida; Diamond, Joana; Freitas-Tavares, Paulo; Almeida, António; Goncalves, Ana Cristina; Sarmento-Ribeiro, Ana BelaChronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 oncogene. Oxidative stress conditions are crucial in tumor development and progression. The NRF2, codified by NFE2L2 gene, plays a central role in redox balance, promoting the transcription of cytoprotective and antioxidant genes such as SOD2, GPX1 and CAT. The action of this transcription factor is regulated by KEAP1. Alterations in these genes, either due to somatic mutations or genetic variants (SNV), have been associated with the development, prognosis, and therapeutic response in cancer. This work evaluated the influence of polymorphisms in genes associated with oxidative stress (NFE2L2, KEAP1, SOD2, GPX1, and CAT) in prognosis and treatment response with tyrosine kinase inhibitors (TKI) in CML patients. In 194 CML samples, nine genetic variants in NFE2L2 (rs6721961, rs4893819, rs35652124, rs6706649 and rs13001694), KEAP1 (rs113540846), SOD2 (rs4880), GPX1 (rs1050450) and CAT (rs1001179) were genotyped by PCR based assays. The association of these genetic variants with clinical-laboratory characteristics were assessed by Fisher’s test, logistic regression, and Kaplan-Meier curves, considering a p<0.05. The results obtained showed that patients with G allele on GPX1 rs1050450 and KEAP1 rs113540846 variants have an approximately 2-fold and 31-fold higher probability of being TKI resistant, respectively. In TKI-resistant group, patients with CT genotype in NFE2L2 rs4893819 variant were more likely to need three or more lines of treatment (OR=5.60, 95%CI 1.22-25.75, p=0.027). An important factor for TKI response is BCR-ABL1 mutational status, and we found that individuals with AG genotype in NFE2L2 rs13001694 present, approximately 9x more risk of mutation on this fusion gene. Moreover, patients heterozygous for the NFE2L2 rs4893819 (CT genotype) and SOD2 rs4880 (AG genotype) variants have faster disease progression [NFE2L2: hazard ratio (HR)=7.84, 95% CI 1.82-29.93, p=0.020; SOD2: HR=7.19, 95% CI 1.62-31.96, p=0.035] comparing with other genotypes. While the GG genotype of the NFE2L2 rs13001694 variant has a 2-fold lower overall survival than other patients (HR=11.86, 95% CI 1.39-1000.7, p=0.023). Additionally, we also observed an association between haplotypes and genotypic profile with CML prognosis. In conclusion, our results suggest that genetic variants in genes associated with the redox state might be important factors in the prognosis, survival, and therapy response in CML patients.