Assuntos
Adenocarcinoma/cirurgia , Colectomia/métodos , Neoplasias do Colo/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Cirurgia Vídeoassistida/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Estudos de Coortes , Colo Transverso/cirurgia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Mesocolo/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab. PATIENTS AND METHODS: Experimental study: The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice. The effect of trastuzumab was determined in both experimental models. Clinical study: 61 patients with advanced breast cancers and treated by trastuzumab were genotyped for HER2 by PCR-RFLP. The influence of HER2 genotype on the trastuzumab treatment was examined. RESULTS: Experimental study: HER2-expressing cells acquired the characteristics of tumor cells. The Val isoform-expressing cells showed the highest growth capacity and developed aggressive tumors sensitive to trastuzumab. Clinical study: There was no link between tumor response or survival and HER2 genotype. All cases of treatment-related cardiotoxicity were found in the Ile/Val group and there was no cardiac toxicity in the Val/Val and Ile/Ile patients. CONCLUSIONS: This study establishes a clear-cut difference between the two HER2 isoforms regarding their tumorogenic potential with an advantage for the Val/HER2 isoform. In breast cancer patients treated with trastuzumab, the presence of a Val allele may constitute a risk factor for cardiac toxicity.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Coração/efeitos dos fármacos , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados , Sequência de Bases , Western Blotting , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Feminino , Cardiopatias/induzido quimicamente , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Isoformas de Proteínas/genética , Transfecção , TrastuzumabRESUMO
Supernumerary ring and large marker chromosomes are a characteristic of atypical lipomas and well-differentiated liposarcomas (ALP-WDLPS) and are composed of amplified 12q14-15 sequences in association with variable segments from other chromosomes. Although stably transmitted, these chromosomes contain centromeric alterations, showing no detectable alpha-satellite sequences. We performed C-banding, fluorescence in situ hybridization, and immunostaining with anti-centromere antibodies in 8 cases of liposarcomas with supernumerary rings and large markers, including 5 ALP-WDLPS and 3 dedifferentiated-LPS and high-grade LPS. Our results with alpha-satellite probes and anti-CENPB antibodies confirm the lack of detectable alpha-satellite sequences in the five ALP-WDLPS supernumerary chromosomes, whereas centromeric activity was proved by the detection of kinetochores by using anti-CENPC antibodies. In contrast, the high grade and dedifferentiated liposarcomas showed a different pattern. In 2 cases, amplified chromosome 12 sequences, including amplification of alpha-satellite 12 sequences in 1 case, were present on chromosomes with typical centromeres. In another case, the rings were similar to WDLPS-ALP rings, but a large marker contained a chromosome 5 centromere and amplified alpha-satellite sequences from chromosome 8. ALP-WDLPS is the first example of a tumor class for which the presence of stable analphoid chromosomes is a constant and specific abnormality. Formation of newly derived centromeres, so-called neocentromeres, could be an original and effective way to maintain a selective advantage in neoplastic cells by conferring stability to the supernumerary chromosomes of ALP-WDLPS. The activation of normally non-centromeric sequences might be obtained by an epigenetic mechanism due to the peculiar chromatin conformation of these highly complex chromosomes.