RESUMO
OBJECTIVES: This study aimed to evaluate the potential role of the PTGS2 single nucleotide polymorphisms (SNPs) -1195 A>G and +8473 T>C in endometriosis' development, and characterizing their association with the prognostic features of the disease. STUDY DESIGN: DNA from 254 women with endometriosis and 267 controls, recruited from two reference hospitals from the Brazilian public health system, were genotyped using TaqMan allelic discrimination assays. The association between SNPs and endometriosis features was evaluated by multivariate logistic regression, using the adjusted odds ratios (OR) with their respective 95% confidence intervals (95% CI). RESULTS AND CONCLUSION: There were significant differences between cases and controls regarding age (P < 0.001), body mass index (BMI) (P = 0.001), educational level (P < 0.001), physical activity (P = 0.003), smoking status (P < 0.001), contraception use (P = 0.02), family history of endometriosis (P = 0.002) and all symptoms (P < 0.001). The distribution of -1195 A > G was statistically different between the groups, suggesting a lower risk of developing the disease for the carriers of the -1195 GG genotype (OR = 0.19; 95% CI = 0.04 - 0.93). No differences were found for the +8473 T>C between the two groups and neither in prognostic features of the disease for both PTGS2 SNPs. In conclusion, PTGS2 -1195A>G SNP was negatively associated with development of endometriosis and the two groups were statistically different regarding age, BMI, educational level, physical activity, smoking status, contraception use, history of endometriosis and all endometriosis symptoms.
Assuntos
Endometriose , Brasil , Estudos de Casos e Controles , Ciclo-Oxigenase 2 , Endometriose/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in ERCC1, ABCB1, CYP2C8, and CYP3A5 genes on the incidence of severe toxicities, including nephro- and hepatotoxicity. METHODS: A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin was recruited at the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consultations or from electronic medical records. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR. RESULTS: ABCB1 c.1236C>T was associated with moderate-to-severe (grades 2-4) nephrotoxicity (ORadjusted 2.40; 95% CI 1.39-4.15), even after adjustment for age (≥ 65) and diabetes. The risk association between ABCB1 c.1236C>T and moderate-to-severe nephrotoxicity following paclitaxel/carboplatin chemotherapy was also present among non-diabetic patients (ORadjusted 2.16; 95% CI 1.22-3.82). ERCC1 c.118C>T was the only individual variable associated with an increased risk for moderate-to-severe (grades 2-4) hepatotoxicity (OR 3.71; 95% CI 1.08-12.77), severe nausea (OR 4.18; 95% CI 1.59-10.95), and severe myalgia (OR 1.95; 95% CI 1.12-3.40). CONCLUSIONS: ABCB1 c.1236C>T and ERCC1 c.118C>T might serve as potential biomarkers for the risk of moderate-to-severe toxicities to carboplatin/paclitaxel chemotherapy of gynecological cancers.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Brasil , Carboplatina/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Estudos de Coortes , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Humanos , Nefropatias/induzido quimicamente , Nefropatias/genética , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Breast cancer is the leading cancer among women, and its increasing incidence is a challenge worldwide. Estrogen exposure is the main risk factor, but obesity among postmenopausal women has been shown to favor disease onset and progression. The link between obesity and mammary carcinogenesis involves elevated estrogen production and proinflammatory stimuli within the adipose tissue, with activation of the cyclooxygenase-2 pathway. Here, we evaluate the impact of the four most common cyclooxygenase-2 gene polymorphisms (rs689465, rs689466, rs20417 and rs20417), in combination with obesity, on the risk of breast cancer progression in a cohort of Brazilian breast cancer patients (N = 1038). Disease-free survival was evaluated using Kaplan-Meier curves, with multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadj). Obesity did not affect disease progression, whereas rs689466 variant genotypes increased the recurrence risk among obese patients (HRadj = 2.5; 95% CI = 1.4-4.3), either for luminal (HRadj = 2.2; 95% CI = 1.1-4.2) or HER2-like and triple-negative tumors (HRadj = 3.2; 95% CI = 1.2-8.5). Likewise, the haplotype *4, which contains variant rs689466, was associated with shorter disease-free survival among obese patients (HRadj = 3.3; 95% CI = 1.8-6.0), either in luminal (HRadj = 3.5; 95% CI = 1.6-7.3) or HER2-like and triple-negative (HRadj = 3.1; 95% CI = 1.1-8.9) tumors. Such deleterious impact of variant rs689466 on disease-free survival of obese breast cancer patients was restricted to postmenopausal women. In conclusion, cyclooxygenase-2 genotyping may add to the prognostic evaluation of obese breast cancer patients.
Assuntos
Neoplasias da Mama/genética , Ciclo-Oxigenase 2/genética , Recidiva Local de Neoplasia/genética , Obesidade/genética , Idoso , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N = 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 - 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HRadjusted = 1.82; 95% CI = 1.16 - 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 - 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 - 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 - 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.