RESUMO
BACKGROUND: Abnormalities in the intrinsic apoptosis pathway, associated with single nucleotide variants (SNVs) in caspase (CASP) genes, alter head and neck squamous cell carcinoma (HNSCC) proliferation and progression. This prospective study aimed to evaluate whether CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs influence the outcome of patients with HNSCC. Two hundred sixty-two HNSCC patients were enrolled in the study. METHODS: DNA and RNA of peripheral blood samples were analyzed using real-time polymerase chain reaction (PCR) for genotyping and quantitative PCR method for gene expression, respectively. Differences in CASP3 expressions were analyzed using the Mann-Whitney test. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier curves, log-rank test, and Cox analyses. RESULTS: CASP3 c.-1191AG or GG genotype was associated with higher CASP3 expression when compared with AA genotype (0.50 arbitrary units (AUs) ± 0.29 standard deviation (SD) vs 0.28 AUs ± 0.12 SD; P = .02). Patients with CASP9 c.-1339GG genotype had 1.54 more chance of presenting disease progression or relapse than patients with CASP9 c.-1339AA or AG genotype. Patients with CASP9 c.-1339GG and CASP3 c.-1191GG combined genotype had 2.64 more chance of presenting progression or relapse of the disease and 2.84 more chance of evolving to death than those with the remaining combined genotypes. CONCLUSIONS: Our findings provide, for the first time, preliminary evidence that inherited abnormalities in the intrinsic apoptosis pathway, related to CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs, act as predictors of HNSCC patients' survival.
Assuntos
Neoplasias de Cabeça e Pescoço , Polimorfismo de Nucleotídeo Único , Caspase 3/genética , Caspase 9/genética , Genótipo , Neoplasias de Cabeça e Pescoço/genética , Humanos , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
We aimed to evaluate whether variants in repair (XPD Asp312Asn, XPD Lys751Gln) and detoxification (GSTM1, GSTT1) genes alter risk, clinicopathological aspects and survival of cutaneous melanoma (CM). Genotyping was performed in 229 CM patients and 258 controls. Individuals with XPD 312Asp/Asn or Asn/Asn plus GSTT1 null genotype were under 2.00 (95% CI: 1.06-3.79), and XPD 312Asn/Gln haplotype was under 1.44-fold (95% CI: 0.99-2.08) increased risks to CM than others. Individuals with GSTM1 plus GSTT1 null genotype had 9.61-fold (95% CI: 2.28-40.38) increased risk of metastatic CM. At 60 months of follow-up, patients with XPD 751Gln/Gln plus GSTT1 null and GSTM1 null plus GSTT1 null genotype presented 7.36 and 3.05 more chances of evolving to death in multivariate Cox analysis, respectively. In conclusion, our data indicate, for the first time, that specific variant combinations of XPD, GSTM1 and GSTT1 may increase susceptibility to CM and influence patients' clinicopathological features and survival.
Assuntos
Glutationa Transferase/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/genética , Idoso , Asparagina/genética , Ácido Aspártico/genética , Sobrevivência Celular , Intervalo Livre de Doença , Predisposição Genética para Doença , Variação Genética , Genótipo , Glutamina/genética , Humanos , Lisina/genética , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
The objective of this research was to assess the association of genetic polymorphisms related to intrinsic apoptosis pathway CASP8 rs3834129 and CASP3 rs4647601 with the risk, clinical and pathological aspects, and survival of oropharynx squamous cell carcinoma (OPSCC) patients that received cisplatin and radiotherapy. The genotypes were identified in 198 patients with OPSCC and 200 controls using polymerase chain reaction methods. Chi square or Fisher's exact test and logistic regression were applied for the detection of differences between groups. Patients' genotypes were statistically evaluated considering the event-free survival and overall analysis using Kaplan-Meier estimate and Cox regression. CASP3 rs4647601 GG genotype (44.4% vs. 30.0%, p = 0.03) and G allele (63.9% vs. 55.5%, p = 0.04) were more common in patients with OPSCC than in controls. Carriers of GG genotype and G allele were under 1.78-fold and 1.40-fold increased risk of OPSCC than others, respectively. The frequency of CASP8 rs3834129 DD genotype was higher in patients with OPSCC with poorly differentiated or undifferentiated tumors when compared to others (34.5% vs. 16.1%, p = 0.02). No influence of CASP8 and CASP3 polymorphisms on OPSCC patients' survival was seen in this study. Our results indicate that inherited genetic variants in the intrinsic apoptosis pathway related to CASP3 rs4647601 and CASP8 rs3834129 polymorphisms may be an important determinant of OPSCC risk and tumor cell differentiation.
Assuntos
Carcinoma de Células Escamosas/genética , Caspase 3/genética , Caspase 8/genética , Neoplasias Orofaríngeas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Carcinoma de Células Escamosas/mortalidade , Estudos de Casos e Controles , Diferenciação Celular , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Prognóstico , Análise de SobrevidaRESUMO
This study aimed to evaluate whether XPC A2920C, XPF T30028C, TP53 Arg72Pro, and GSTP1 Ile105Val polymorphisms alter outcomes of cutaneous melanoma (CM) patients. DNA from 237 CM patients seen at the University of Campinas Teaching Hospital from April 2000 to February 2014 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival (PFS) and overall survival (OS) of CM patients were examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox regression analyses. At 60 months of follow-up, shorter PFS and OS were seen in patients with XPF CC genotype (48.9 vs. 66.7 %, P = 0.002; 77.9 vs. 83.5 %, P = 0.006, respectively) and XPF CC + TP53 ArgArg (43.6 vs. 65.9 %, P = 0.007; 71.6 vs. 84.8 %, P = 0.006, respectively) compared with those with remaining genotypes (Kaplan-Meier estimates). Patients with XPF CC (hazard ratio (HR) 2.45, P = 0.002; HR 3.77, P = 0.005) and XPF CC + TP53 ArgArg (HR 2.67, P = 0.009; HR 4.04, P = 0.03) genotypes had more chance to present tumor progression in univariate and multivariate analyses, whereas patients with XPF CC (HR 2.78, P = 0.009) and XPF CC + TP53 ArgArg (HR 3.84, P = 0.01) genotypes were under greater risk of progressing to death in univariate analysis, compared with those with the remaining genotypes. The data suggest, for the first time, that inherited abnormalities in DNA repair pathway related to XPF 30028C and TP53 Arg72Pro polymorphisms act as prognostic factors for PFS and OS of CM patients.
Assuntos
Proteínas de Ligação a DNA/genética , Glutationa S-Transferase pi/genética , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/mortalidadeRESUMO
We examined the influence of MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p = 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p = 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p = 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p = 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p = 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P = 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma de Células Escamosas/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Exodesoxirribonucleases/genética , Neoplasias de Cabeça e Pescoço/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Estudos de Associação Genética , Genótipo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 3 Homóloga a MutS , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , América Latina , Consenso , SunitinibeRESUMO
We examined the influence of the CYP1A1 A4889G and T6235C, GSTM1 and GSTT1 polymorphisms, involved in carcinogen metabolism, on the head and neck (HN) squamous cell carcinoma (SCC) risk. DNA from 142 HNSCC patients and 142 controls was analysed by polymerase chain reaction (PCR)-restriction fragment length polymorphism or multiplex-PCR for the polymorphisms analyses. Excesses of the CYP1A1 4889AG+GG and 4889AG+GG plus GSTT1 null genotype were seen in patients with heavy tobacco habit compared with controls (41.9% versus 26.8%, P = 0.03; 26.2% versus 10.3%, P = 0.04, respectively). Carriers of the referred genotypes and heavy tobacco consumption were under a 2.0-fold and 2.8-fold increased risks for HNSCC than others, respectively. The CYP1A1 6235TC+CC plus GSTM1 and GSTT1 null genotypes were more common in pharyngeal SCC patients than in controls (5.3% versus 0.7%, P = 0.04). Carriers of the combined genotype had 16.0-fold increased risk for the disease than others. The frequency of one null genotype of the GSTM1 or GSTT1 gene was higher in patients with pharyngeal SCC and heavy smoking status than in controls (76.3% versus 57.7%, P = 0.04). Carriers of the referred genotype and heavy tobacco status had a 2.4-fold increased risk for pharyngeal SCC than others. In contrast, the CYP1A1 6235TC+CC genotype was more common in controls than in laryngeal SCC patients (35.9% versus 21.6%, P = 0.01). Carriers of the genotype had a 0.2-fold decreased risk for the disease than others. Our data present preliminary evidence that inherited combined CYP1A1 A4889G and T6235C abnormalities and GSTM1 and GSTT1 pathways are important determinants of HNSCC, particularly pharyngeal SCC in heavy smoking individuals from south-eastern Brazil.
Assuntos
Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Glutationa Transferase/genética , Neoplasias de Cabeça e Pescoço/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Brasil , Carcinoma de Células Escamosas/enzimologia , Feminino , Frequência do Gene , Genótipo , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , FumarRESUMO
Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1ß (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients' survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher's exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan-Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III-V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10-8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Interleucina-1beta/genética , Melanoma/patologia , Polimorfismo de Nucleotídeo Único , Receptores Tipo II de Interleucina-1/genética , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/genética , Taxa de Sobrevida , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
We conducted a two-stage association study on patients with oropharynx (OP) squamous cell carcinoma (SCC) and healthy controls to identify single nucleotide variants (SNVs) located at the microRNA (miR)-binding sites of carcinogenesis genes associated with risk and prognosis of the disease. In stage 1, 49 patients and 49 controls were analyzed using Genome-Wide Human SNV Arrays to identify variants in the 3'-untranslated region (3'-UTR) of carcinogenesis-related genes, and one SNV was selected for data validation in stage 2 by TaqMan assays in 250 OPSCC patients and 250 controls. The ERP29 c.*293A > G (rs7114) SNV located at miR-4421 binding site was selected for data validation among 46 SNVs. The ERp29 and miR-4421 levels were evaluated by quantitative-PCR and Western blotting. Interaction between miR-4421 with 3'-UTR of ERP29 was evaluated by luciferase reporter assay. Event-free survival (EFS) was calculated by Kaplan-Meier and Cox methods. ERP29 GG variant genotype was more common in OPSCC patients than in controls (6.4% vs 3.6%, p = 0.02; odds ratio: 5.67; 95% confidence interval (CI) 1.27-25.26). Shorter EFS were seen in the base of tongue (BT) SCC patients with GG genotype (0.0% vs 36.2%, p = 0.01; hazard ratio: 2.31; 95% CI: 1.03-5.15). Individuals with ERP29 AG or GG genotypes featured lower levels of ERP29 mRNA (p = 0.005), ERp29 protein (p < 0.001) and higher levels of miR-4421 (p = 0.02). The miR-4421 showed more efficient binding with 3'-UTR of the variant G allele when compared with wild-type allele A (p = 0.001). Our data suggest that ERP29 rs7114 SNV may alter the risk and prognosis of OPSCC due to variation in the ERp29 production possibly modulated by miR-4421.
Assuntos
Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Proteínas de Choque Térmico/genética , MicroRNAs/genética , Neoplasias Orofaríngeas/genética , Adulto , Alelos , Sítios de Ligação , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Taxa de SobrevidaRESUMO
Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features.
Assuntos
Adenilil Ciclases/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/genética , Neoplasias Cutâneas/patologia , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Pigmentação da Pele/genética , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes that act in intrinsic apoptosis pathway may modulate cancer susceptibility. This study investigated the roles of CASP9 c.-1339A>G (rs4645978) and CASP3 c.-1191A>G (rs12108497) SNPs on risk and behavior of head and neck (HN) squamous cell carcinoma (SCC). METHODS: DNA of 350 patients with HNSCC and 350 controls was analyzed by polymerase chain reaction method for genotyping. RESULTS: CASP3 c.-1191AG or GG genotype was more common in patients with HNSCC and oral cavity or oropharynx SCC than in controls; carriers of this genotype were under 2.15 and 2.81-fold increased risks of the respective tumors. CASP9 c.-1339AG or GG plus CASP3 c.-1191AG or GG genotypes were associated with oral cavity or oropharynx SCC early onset. CONCLUSION: These findings present, for the first time, preliminary evidence that inherited abnormalities related to CASP9 c.-1339A>G and CASP3 c.-1191A>G SNPs are determinants of HNSCC risk and clinical aspects.
Assuntos
Caspase 3/genética , Caspase 9/genética , Predisposição Genética para Doença , Neoplasias Laríngeas/genética , Neoplasias Bucais/genética , Neoplasias Faríngeas/genética , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Cutaneous melanoma (CM) cells are resistant to apoptosis, and steroid hormones are involved in this process through regulation of TP53, MDM2, BAX, and BCL2 expression. We analyzed herein sex differences in outcomes of CM patients associated with TP53 c.215G>C, MDM2 c.309T>G, BAX c.-248G>A, and BCL2 c.-717C>A polymorphisms. DNA from 121 men and 116 women patients was analyzed by polymerase chain reaction and enzymatic digestion assays. At 60 months of follow-up, shorter progression-free survival (PFS) was seen in males with MDM2 GG + BCL2 AA (20.0 vs. 62.6%, P = 0.0008) genotype. Men carriers of the genotype had poor PFS (HR 3.78, 95% CI 1.30-11.0) than others. For women, shorter PFS was associated with TP53 GC or CC (61.4 vs. 80.8%, P = 0.01) and TP53 GC or CC + MDM2 TG or GG (59.1 vs. 85.4%, P = 0.01) genotypes at the same time. Women carriers of the genotypes had poor PFS (HR 2.46, 95% CI 1.19-5.09; HR 9.49, 95% CI 1.14-78.50) than others, respectively. Our data present, for the first time, preliminary evidence that inherited abnormalities on TP53, MDM2 and BCL2 genes, enrolled in apoptosis pathways, have a pivotal role in differences of outcomes in women and men with CM.
Assuntos
Apoptose/genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores SexuaisRESUMO
AIMS: To compare the efficacy and tolerability of taxane and nontaxane therapy in senior adults with chemonaïve metastatic castration-resistant prostate cancer (mCRPC), and examine the effect of patient health status on outcomes. PATIENTS AND METHODS: Between 2009 and 2011, 333 patients aged≥70 years with mCRPC were enrolled in a prospective international registry. Patients were categorized as having received taxane-based or nontaxane therapy, and classified as fit, vulnerable, frail, or terminal, according to investigator judgement or International Society of Geriatric Oncology guidelines. Efficacy measures included overall survival (OS) and progression-free survival. Grade 3/4 toxicities were recorded. Predictors of OS were identified using multivariate Cox regression. RESULTS: The proportions of fit/vulnerable/frail patients were 65%/14%/17% (International Society of Geriatric Oncology), and 39%/43%/17% (investigator). In single-factor analyses, taxane therapy improved OS (hazard ratio [95%CI] = 0.53 [0.30-0.93]; P = 0.027) and progression-free survival (hazard ratio [95% CI] = 0.55 [0.40-0.76]; P<0.001) vs. nontaxane therapy. Patients with frailty also benefited from taxane therapy (adapted regimen in 52%). In multivariate analysis, taxanes improved OS even with poor prognostic factors present (P = 0.017); age was unrelated to prognosis. Taxane therapy was well tolerated; most common grade 3/4 toxicities (taxane vs. nontaxane) were fatigue (17% vs. 4%), nausea/vomiting (14% vs. 5%) and neutropenia (10% vs. 1%). CONCLUSIONS: The results of this nonrandomized, observational study suggest that first-line taxane therapy may benefit senior adults with mCRPC more than alternative therapies. Treatment decisions should not be based on chronological age.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cooperação Internacional , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Fadiga/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Vômito/induzido quimicamenteRESUMO
PURPOSE: We examined the influence of OGG1 c.977C>G (rs1052133), APEX1 c.444T>G (rs1130409), XRCC1 c.-77T>C (rs3213245), c.580C>T (rs1799782), c.839G>A (rs25489) and c.1196G>A (rs25487) single-nucleotide polymorphisms (SNPs), involved in base-excision repair (BER) pathway, on oropharyngeal squamous cell carcinoma (OPSCC) risk and prognosis. METHODS: Aiming to identify the genotypes, DNA from 200 consecutive OPSCC patients and 200 controls was analyzed by PCR-RFLP. The prognostic impact of genotypes of SNPs on progression-free survival (PFS) and overall survival of OPSCC patients was examined using the Kaplan-Meier estimates and Cox regression analyses. RESULTS: XRCC1 c.580CT or TT genotypes (19.5 vs. 11.0 %, P = 0.04) and XRCC1 TTGG haplotype from c.-77T>C, c.580C>T, c.839G>A and c.1196G>A SNPs (17.5 vs. 10.0 %, P = 0.04) were more common in patients with OPSCC than in controls. Carriers of combined genotypes of c.580C>T and TTGG haplotype of XRCC1 gene were under 3.35- and 3.22-fold increased risk of OPSCC than others. For survival analysis, we selected only patients with tumor at stage IV. The median follow-up time was 24.5 months. At 24 months of follow-up, PFS was shorter in patients with OGG1 c.977CC genotype when compared with others genotypes (35.5 vs. 52.1 %, log-rank test, P = 0.03). After multivariate Cox analysis, patients with OGG1 c.977CC genotype had more chance to present tumor progression when compared with others (HR 1.68, P = 0.02). CONCLUSIONS: Our data present, for the first time, evidence that inherited OGG1 c.977C>G; XRCC1 c.-77T>C, c.580C>T, c.839G>A and c.1196G>A abnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , DNA Glicosilases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
INTRODUCTION: The role of neoadjuvant endocrine therapy for resectable breast cancer is not well established, despite encouraging results obtained in the metastatic and adjuvant settings. This systematic review aims to examine existing medical literature on neoadjuvant hormone therapy (HT). METHODS: Data from prospective, randomized trials was included if comparing neoadjuvant HT versus surgery alone without adjuvant treatment, or neoadjuvant HT versus chemotherapy (CT), or HT plus CT versus CT alone, or HT plus CT versus HT alone, or two distinct HT. Odds Ratios (OR) were calculated from pooled data. RESULTS: Five studies compared HT with tamoxifen versus HT with aromatase inhibitors (AI). A meta-analysis of their results demonstrated superiority of AIs in overall response rate (ORR) (OR 1.9; 95% CI 1.17-3.08). Two trials compared HT against CT, and pooled data from them demonstrated a trend favoring CT (OR for ORR 0.75; 95% CI 0.35-1.6). That trend disappeared when only postmenopausal women were considered (OR 1.01; 95% CI 0.62-1.63). One trial compared HT plus CT with no neoadjuvant treatment, and obtained an 83% ORR. One trial compared HT plus CT versus CT alone and found a non-significant increase in ORR for adding HT to CT (OR 1.48; 95% CI 0.58-3.77). No trial compared HT plus CT versus HT alone. CONCLUSIONS: Neoadjuvant HT is a safe and feasible option, but it cannot be considered equivalent to CT. If neoadjuvant HT is performed, AIs are preferable over tamoxifen due to higher response rates.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia Segmentar , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Angiogenesis (AG) is essential for epithelial ovarian cancer (EOC) development. Vascular endothelial growth factor (VEGF), encoded by the VEGF gene, and endostatin, the product of the COL18A1 gene, act as a potent promoter and an inhibitor of AG, respectively. In the present study, we tested whether VEGF C936T and COL18A1 D104N polymorphisms alter the risk of EOC. METHODS: Genomic DNA from 131 EOC patients and 137 controls were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. The differences between groups were analyzed by χ (2) or Fisher's exact test and logistic regression analysis. RESULTS: The frequency of the VEGF 936CC genotype was higher in patients than in controls (84.8% vs. 75.3%, P = 0.03). Individuals with respective genotypes had a 1.98 (95% CI 1.04-3.78)-fold increased risk of EOC than those with the remaining genotypes. An excess of VEGF 936CC plus COL18A1 DN genotype was seen in patients when compared to controls (48.6% vs. 30.5%); however, only a tendency toward a statistically significant difference in genotype frequencies was found in the study (P = 0.06), reflecting a trend toward an increased risk of 2.44 for EOC in carriers of the combined genotype. CONCLUSION: Our data present, for the first time, preliminary evidence that VEGF C936T alone or combined with the COL18A1 D104N polymorphism of AG constitutes an important inherited EOC determinant.
Assuntos
Biomarcadores Tumorais/genética , Colágenos Associados a Fibrilas/genética , Neoplasias Ovarianas/genética , Polimorfismo Genético/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prognóstico , Regiões Promotoras Genéticas , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The P53 Arg72Pro, MDM2 c.+309T>G, BAX c.-248G>A, and BCL2 c.-717C>A polymorphisms have variable roles in the apoptosis pathways. OBJECTIVE: To clarify the roles of these polymorphisms in the risk for cutaneous melanoma (CM). METHODS: Genomic DNA of 200 CM patients and 215 controls was analyzed by PCR-RFLP. RESULTS: In women, the frequencies of BAX GG (83.0% vs. 71.0%, P=0.04), BCL2 AA (32.0% vs. 15.0%, P=0.003), P53 ArgArg plus BAX GG (84.9% vs. 63.2%, P=0.01), P53 ArgArg plus BCL2 AA (37.0% vs. 13.1%, P=0.003), BAX GG plus BCL2 AA (70.3% vs. 33.3%, P=0.001), MDM2 GG plus BAX GG plus BCL2 AA (27.3% vs. 3.7%, P=0.03), and P53 ArgArg plus MDM2 GG plus BAX GG plus BCL2 AA (33.3% vs. 5.6%, P=0.04) genotypes were higher in patients than in controls. Female carriers of the respective genotypes were under 1.98 (95% CI: 1.01-3.91), 2.87 (95% CI: 1.43-5.77), 3.48 (95% CI: 1.34-9.04), 4.23 (95% CI: 1.63-10.96), 6.04 (95% CI: 2.10-17.37), 25.61 (95% CI: 1.29-507.24), and 25.69 (95% CI: 1.11-593.59)-fold increased risks for CM than others, respectively. In men, the frequencies of BCL2 CA+AA (83.0% vs. 67.6%, P=0.01) and MDM2 TG+GG plus BCL2 CA+AA (94.2% vs. 68.3%, P=0.003) genotypes were higher in patients than in controls. Male carriers of the respective genotypes were under 2.43 (95% CI: 1.23-4.82) and 9.22 (95% CI: 2.16-39.31)-fold increased CM risks than others, respectively. CONCLUSION: The data suggest for the first time that P53 Arg72Pro, MDM2 c.+309T>G, BAX c.-248G>A, and BCL2 c.-717C>A polymorphisms, enrolled in apoptosis pathways, constitute distinct determinants of CM in women and men.
Assuntos
Genes p53 , Melanoma/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Neoplasias Cutâneas/genética , Proteína X Associada a bcl-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Raios Ultravioleta/efeitos adversos , Adulto JovemRESUMO
PURPOSE: We examined the influence of XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1 Ile105Val polymorphisms in the risk of cutaneous melanoma (CM). METHODS: DNA from 146 CM patients and 146 controls was analysed by polymerase chain reaction (PCR)--restriction fragment length polymorphism (RFLP). RESULTS: The frequencies of XPC CC (15.1 vs. 6.9 %, P = 0.02), TP53 ArgArg (59.6 vs. 45.9 %, P = 0.02), XPC CC plus TP53 ArgArg (19.7 vs. 5.2 %, P = 0.01) and TP53 ArgArg plus GSTP1 IleIle (50.7 vs. 35.6 %, P = 0.03) genotypes were higher in patients than in controls. Carriers of the respective genotypes were under a 2.51 (95 % CI: 1.13-5.55), 1.76 (95 % CI: 1.09-2.83), 4.52 (95 % CI: 1.35-15.16), and 2.01 (95 % CI: 1.04-3.90)-fold increased risks for CM than others, respectively. An excess of TP53 ArgArg genotype was seen in patients with excessive sun exposure compared to patients with standard sun exposure (69.2 vs. 44.1 %, P = 0.02) and also compared to controls (69.2 vs. 45.9 %, P = 0.002). Individuals with TP53 ArgArg genotype and highly exposed to sunlight had 2.65 (95 % CI: 1.42-4.92)-fold increased risk for CM than others. XPC CC (27.8 vs. 10.4 %, P = 0.02) and the GSTP1 IleIle (58.3 vs. 36.8 %, P = 0.04) genotypes were more common in patients with advanced tumours than in patients with localized tumours and were also more common in these patients than in controls (27.8 vs. 6.9 %, P = 0.001; 58.3 vs. 37.0 %, P = 0.02, respectively). Individuals with the respective genotypes had 5.23 (95 % CI: 1.97-13.82)-fold and 2.38 (95 % CI: 1.13-5.01)-fold increased risks for advanced tumour than others, respectively. CONCLUSION: Our data suggest that inherited abnormalities of XPC, XPF, TP53 and GSTP1 pathways of the DNA repair, apoptosis and metabolism of reactive oxygen species are important determinants of CM in individuals from south-eastern Brazil.
Assuntos
Proteínas de Ligação a DNA/genética , Glutationa S-Transferase pi/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Apoptose , Estudos de Casos e Controles , Reparo do DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Análise de Sequência de DNA , Adulto JovemRESUMO
Dermatomyositis is an autoimmune disorder that affects mainly muscles and skin. In some cases it may be associated to neoplasms occurring before the diagnosis of cancer. Its relation to germ cell tumor is not well documented, so we describe a case of a patient with history of muscle weakness and cutaneous rash that preceded cancer for 6 months. Dermatomyositis must remind of a possible occult neoplasm and its remission may follow the treatment of the tumor.