RESUMO
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
Assuntos
Cromossomos Humanos Par 17 , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Assuntos
Cromossomos Humanos Par 8/genética , Ligação Genética , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Próstata/genética , Negro ou Afro-Americano , Europa (Continente) , Genômica/métodos , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estados Unidos , População BrancaRESUMO
PURPOSE OF REVIEW: In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. RECENT FINDINGS: The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. SUMMARY: Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.
Assuntos
Neoplasias do Sistema Digestório/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Neoplasias do Ânus/irrigação sanguínea , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/enzimologia , Neoplasias do Sistema Biliar/irrigação sanguínea , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/enzimologia , Neoplasias do Sistema Digestório/irrigação sanguínea , Neoplasias do Sistema Digestório/enzimologia , Sistemas de Liberação de Medicamentos , Receptores ErbB/antagonistas & inibidores , Neoplasias Esofágicas/irrigação sanguínea , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/enzimologia , Humanos , Neovascularização Patológica/tratamento farmacológicoRESUMO
Although the prognosis of cancer remains poor recent advances in the diagnostic methods, new approaches in surgical procedures and the development of new therapeutic agents have had a significant impact in the outcome of cancer patients. A better understanding of the molecular pathways that characterize cell growth, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. The epidermal growth factor receptor (EGFR) mediated signal transduction has been one of the most studied pathways in carcinogenesis. The phosphorylation of EGFR activates multiple biological processes including apoptosis, differentiation, cellular proliferation, motility, invasion, adhesion, DNA repair and survival. Several therapies have been developed to inactivate the EGFR pathway including monoclonal antibodies against the extracellular domain of EGFR. In this review, the authors examine the development of monoclonal antibodies against EGFR and the effects of this blockage in cell cycle, as well as the most important trials with these monoclonal antibodies in several tumor types.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cetuximab , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Sistemas de Liberação de Medicamentos , Receptores ErbB/imunologia , Receptores ErbB/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Estadiamento de Neoplasias , Neoplasias/imunologia , Neoplasias/mortalidade , Neovascularização Patológica/imunologia , Panitumumabe , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: The utility of many molecules as tumor markers in melanoma has been investigated with different results. The aims of this study was to compare the value of tyrosinase mRNA by reverse transcription polymerase chain reaction (RT-PCR) in peripheral blood and of serum S-100 protein in patients with melanoma at different stages of disease. METHODS: We have studied 90 peripheral blood samples corresponding to 90 patients that had been diagnosed with melanoma. The clinical staging at the time of blood sampling was performed according to the American Join Committee on Cancer guidelines. S-100 protein in serum was measured by enzyme-linked immunosorbent assay (normal range: 0-0.150 microg) and the presence of tyrosinase mRNA was assessed by RT-PCR. RESULTS: Median progression-free survival was 281 days for tyrosinase positive patients and it has not been reached for tyrosinase negative patients (P = 0.03). Median progression free survival was 213 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P < 0.001). Median overall survival (OS) was 396 days for tyrosinase positive patients and it has not been reached for negative patients (P = 0.0096). Median OS was 282 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P < 0.001). In a multivariate analysis, both markers have significant prognostic value for time to progression and for survival (chi(2) test). CONCLUSIONS: RT-PCR for tyrosinase mRNA and S-100 are significant prognostic factors for progression-free survival and OS in melanoma. S-100 has higher sensitivity and specificity than tyrosinase.
Assuntos
Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Proteínas S100/metabolismo , Neoplasias Cutâneas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/genética , Pessoa de Meia-Idade , Monofenol Mono-Oxigenase/genética , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Taxa de SobrevidaRESUMO
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.