Escola Multicampi de Ciências Médicas do Rio Grande do Norte

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ATM, BCL2, and TGFb gene polymorphisms as radiotherapy outcome biomarkers in head and neck squamous cell carcinoma patients
(Mary Ann Liebert, 2017-12) Agostini, Lidiane Pignaton; Stur, Elaine; Garcia, Fernanda M.; Ventorim, Diego P.; Reis, Raquel S. dos; Dettogni, Raquel S.; Santos, Eldamária V. W. dos; Peterle, Gabriela T.; Maia, Lucas L.; Mendes, Suzanny O.; Carvalho, Marcos B. de; Tajara, Eloiza H.; Paula, Flavia de; Santos, Marcelo dos; Silva, Adriana M. A. da; Louro, Iúri Drumond
Aims: Polymorphisms in cell cycle genes are considered prognostic as radiosensitivity markers in patients with head and neck squamous cell carcinoma. Therefore, we aimed to investigate the relationship of ATM 5557G>A, ATM IVS62 + 60G>A, TP53 215G>C, BCL2-938C>A, TGFb-509C>T, and TGFb 29C>T with radiotherapy response. Materials and Methods: Genotyping was performed by polymerase chain reaction followed by restriction fragment length polymorphism in 210 patients with oral cavity/oropharyngeal carcinoma and 101 patients with laryngeal tumors. Results: In irradiated oral cavity/oropharyngeal tumors, the ATM IVS62 + 60G>A AA genotype significantly increased local recurrence risk (odds ratio [OR] = 4.43; confidence interval [CI] = 1.22–16.13) and the BCL2- 938C>A C allele and the TGFb-509C>T T allele were associated with worse disease-specific survival (hazar dratio [HR] = 0.46; CI = 0.24–0.90 and HR = 2.20; CI = 1.12–4.29, respectively). In irradiated laryngeal carcinoma, the TGFb 29C>T C allele was associated with increased local recurrence risk (OR = 0.09; CI = 0.02–0.53), death rate (OR = 0.18; CI = 0.04–0.86), and worse local disease-free and disease-specific survival rates (HR = 0.13; CI = 0.03–0.59 and HR = 0.21; CI = 0.07–0.60, respectively), while the BCL2-938C>A C allele was related to a worse disease-specific survival (HR = 0.32; CI = 0.12–0.83). Discussion: These results can help individualize treatment according to a patient’s genetic markers. We demonstrated that ATM IVS62 + 60G>A, TGFb 29C>T, TGFb-509C>T, and BCL2-938C>A can function as biomarkers of tumor radiosensitivity, being candidates for a predictive genetic profile of radiotherapy response
FAS ligand expression in inflammatory infiltrate lymphoid cells as a prognostic marker in oral squamous cell carcinoma
(Fundação de Pesquisas de Ribeirão Preto, 2015-09-22) Peterle, G. T.; Santos, Marcelo dos; Mendes, S. O.; Carvalho-Neto, P. B.; Maia, L. L.; Stur, E.; Agostini, Lidiane Pignaton; Silva, C. V. M.; Trivilin, L. O.; Nunes, F. D.; Carvalho, M. B.; Tajara, E. H.; Louro, I. D.; Silva-Conforti, A. M. A.
Currently, the most important prognostic factor in oral squamous cell carcinoma (OSCC) is the presence of regional lymph node metastases, which correlates with a 50% reduction in life expectancy. We have previously observed that expression of hypoxia genes in the tumor inflammatory infiltrate is statistically related to prognosis in OSCC. FAS and FASL expression levels in OSCC have previously been related to patient survival. The present study analyzed the relationship between FASL expression in the inflammatory infiltrate lymphoid cells and clinical variables, tumor histology, and prognosis of OSCC. Strong FASL expression was significantly associated with lymph node metastases (P = 0.035) and disease-specific death (P = 0.014), but multivariate analysis did not confirm FASL expression as an independent death risk factor (OR = 2.78, 95%CI = 0.81-9.55). Diseasefree and disease-specific survival were significantly correlated with FASL expression (P = 0.016 and P = 0.005, respectively). Multivariate analysis revealed that strong FASL expression is an independent marker for earlier disease relapse and disease-specific death, with approximately 2.5-fold increased risk compared with weak expression (HR = 2.24, 95%CI = 1.08-4.65 and HR = 2.49, 95%CI = 1.04-5.99, respectively). Our results suggest a potential role for this expression profile as a tumor prognostic marker in OSCC patients
HIF-1alpha expression profile in intratumoral and peritumoral inflammatory cells as a prognostic marker for squamous cell carcinoma of the oral cavity
(Public Library of Science, 2014-01-09) Mendes, Suzanny Oliveira; Santos, Marcelo dos; Peterle, Gabriela Tonini; Maia, Lucas de Lima; Stur, Elaine; Agostini, Lidiane Pignaton; Carvalho, Marcos Brasilino de; Tajara, Eloiza Helena; Louro, Iúri Drumond; Trivilin, Leonardo Oliveira; Silva-Conforti, Adriana Madeira Álvares da
The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. The present work investigated the relationship between HIF-1alpha expression in lymphocytes populating the intratumoral and peritumoral region of 56 patients with oral cancer. Our data indicates a prognostic value for this expression. High HIF-1alpha expression in peritumoral inflammatory cells is significantly related to worse patient outcome, whereas high expression in the intratumoral lymphoid cells correlates with a better prognosis. A risk profile indicating the chance of disease relapse and death was designed based on HIF-1alpha expression in tumoral inflammatory cells, defining low, intermediate and high risks. This risk profile was able to determine that high HIF-1alpha expression in peritumoral cells correlates with worse prognosis, independently of intratumoral expression. Low HIF-1alpha in tumor margins and high expression in the tumor was considered a low risk profile, showing no cases of disease relapse and disease related death. Intermediate risk was associated with low expression in tumor and tumor margins. Our results suggest that HIF-1alpha expression in tumor and peritumoral inflammatory cells may play an important role as prognostic tumor marker
JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma
(Public Library of Science, 2018-03-28) Maia, Lucas de Lima; Peterle, Gabriela Tonini; Santos, Marcelo dos; Trivilin, Leonardo Oliveira; Mendes, Suzanny Oliveira; Oliveira, Mayara Mota de; Santos, Joaquim Gasparini dos; Stur, Elaine; Agostini, Lidiane Pignaton; Couto, Cinthia Vidal Monteiro da Silva; Dalbo, Juliana; Assis, Arícia Leone Evangelista Monteiro de; Archanjo, Anderson Barros; Mercante, Ana Maria Da Cunha; Lopez, Rossana Veronica Mendoza; Nunes, Fábio Daumas; Carvalho, Marcos Brasilino de; Tajara, Eloiza Helena; Louro, Iúri Drumond; Álvares-da-Silva, Adriana Madeira
Aims: Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. JMJD1A gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types. Methods and results: We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffinembedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk. Conclusion: JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets
Keratins 17 and 19 expression as prognostic markers in oral squamous cell carcinoma
(Fundação de Pesquisas de Ribeirão Preto, 2015-11-24) Coelho, B. A.; Peterle, G. T.; Santos, Marcelo dos; Agostini, Lidiane Pignaton; Maia, L. L.; Stur, E.; Silva, C. V. M.; Mendes, Suzanny Oliveira; Almança, Carlos Cesar Jorden; Freitas, Flávia Vitorino; Borçoi, Aline Ribeiro; Archanjo, Anderson Barros; Mercante, A. M. C.; Nunes, Fabio Daumas; Carvalho, M. B.; Silva, Eloiza Helena Tajara da; Louro, Iuri Drummond; Silva-Conforti, A. M. A
Five-year survival rates for oral squamous cell carcinoma (OSCC) are 30% and the mortality rate is 50%. Immunohistochemistry panels are used to evaluate proliferation, vascularization, apoptosis, HPV infection, and keratin expression, which are important markers of malignant progression. Keratins are a family of intermediate filaments predominantly expressed in epithelial cells and have an essential role in mechanical support and cytoskeleton formation, which is essential for the structural integrity and stability of the cell. In this study, we analyzed the expressions of keratins 17 and 19 (K17 and K19) by immunohistochemistry in tumoral and non-tumoral tissues from patients with OSCC. The results show that expression of these keratins is higher in tumor tissues compared to non-tumor tissues. Positive K17 expression correlates with lymph node metastasis and multivariate analysis confirmed this relationship, revealing a 6-fold increase in lymph node metastasis when K17 is expressed. We observed a correlation between K17 expression with disease-free survival and disease-specific death in patients who received surgery and radiotherapy. Multivariate analysis revealed that low expression of K17 was an independent marker for early disease relapse and disease-specific death in patients treated with surgery and radiotherapy, with an approximately 4-fold increased risk when compared to high K17 expression. Our results suggest a potential role for K17 and K19 expression profiles as tumor prognostic markers in OSCC patients
MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma
(Fundação de Pesquisas de Ribeirão Preto, 2015-10-26) Anders, Q. S.; Stur, E.; Agostini, Lidiane Pignaton; Garcia, F. M.; Reis, R. S.; Santos, J. A.; Mendes, S. O.; Maia, L. L.; Peterle, G. T.; Stange, V.; Carvalho, M. B.; Tajara, E. H.; Santos, Marcelo dos; Silva-Conforti, A. M. A.; Louro, I. D.
The C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymorphisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the KaplanMeier model, and significant differences were analyzed by the Wilcoxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in laryngeal SCC patients
PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma
(John Wiley and Sons, 2018-05) Peterle, Gabriela Tonini; Maia, Lucas Lima; Trivilin, Leonardo Oliveira; Oliveira, Mayara Mota de; Santos, Joaquim Gasparini dos; Mendes, Suzanny Oliveira; Stur, Elaine; Agostini, Lidiane Pignaton; Rocha, Lília Alves; Moysés, Raquel Ajub; Cury, Patrícia Maluf; Nunes, Fábio Daumas; Louro, Iúri Drumond; Santos, Marcelo dos; Silva, Adriana Madeira Alvares da
Background: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. Materials and Methods: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. Results: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). Conclusion: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients
Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism
(Fundação de Pesquisas de Ribeirão Preto, 2015-10-16) Stur, E.; Agostini, Lidiane Pignaton; Garcia, F. M.; Peterle, G. T.; Maia, L. L.; Mendes, S. O.; Anders, Q. S.; Reis, R. S.; Santos, J. A.; Ventorim, D. P.; Carvalho, M. B.; Tajara, E. H.; Santos, Marcelo dos; Paula, F.; Silva-Conforti, A. M. A.; Louro, I. D.
The aims of this study were to analyze the polymorphisms XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPC Lys939Gln, ERCC1 Asn118Asn, and RAD51 -98G>C and to verify their influence on radiotherapy response and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Peripheral blood DNA was extracted from 311 patients and analyzed by PCR-RFLP. Our results showed that in irradiated oral and oropharyngeal patients, the 939Gln allele increased 6-fold local disease relapse risk (OR = 6.04; CI = 1.47-24.88) and over 2-fold the earliness of relapse (HR = 2.63; CI = 1.04-6.70). As for the XRCC3 polymorphism, multivariate analysis showed that the 241Met allele increases over 33-fold local relapse risk (OR = 33.64; CI = 3.23-350.85), over 12-fold earliness of relapse (HR = 12.55; CI = 2.47-63.73) and over 3-fold earliness of death (HR = 3.04; CI = 1.08-8.61). For polymorphism RAD51 -98, multivariate analysis showed that allele C increases over 3-fold the risk of relapse (OR = 3.13; CI = 1.12-8.78) and over 2-fold the earliness of relapse (HR = 2.84; CI = 1.25-6.47). For polymorphism XRCC1 Arg399Gln, multivariate analysis showed that the 399Gln allele increased the risk of local disease relapse for irradiated oral and oropharyngeal patients (OR = 3.35; CI = 1.10-10.13) by over 3-fold. Based on these results, we suggest that these polymorphisms may be useful markers of prognosis in HNSCC

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