RESUMO
Analysis of genetic alterations in tumor cells represent a first step to understand the molecular mechanism of cancer etiology and development. Due to the progress in genome research, it is feasible to assess the complexity of genomic changes on a large scale. Protocols for gene expression profiling using cDNA arrays have been developed allowing to test the activity of almost all human genes in tumor cells. Another important approach is matrix-CGH which was recently developed to assess gains and losses on the genomic level with high resolution. This method not only allows to narrow down the position of novel oncogenes or tumor suppressor-genes but also contributes to a refinement of tumor classifications. Since matrix-CGH can be performed under highly standardized conditions in a fully automatized way, it is suited for diagnostics in clinical laboratories.
Assuntos
DNA de Neoplasias/genética , Perfilação da Expressão Gênica , Neoplasias/genética , Aberrações Cromossômicas , Mapeamento de Sequências Contíguas , Genoma Humano , Humanos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Supernumerary rings in the context of a simple karyotype characterize several low-grade malignant tumors of soft tissue and bone. Low-grade fibromyxoid sarcoma is an uncommon low-grade sarcoma, the cytogenetics of which has not yet been reported. Here we describe the first molecular-cytogenetic characterization of a pulmonary metastasis of low-grade fibromyxoid sarcoma. The histology of the primary and recurrent tumors was consistent with the diagnosis of low-grade fibromyxoid sarcoma of the usual type, whereas the pulmonary metastasis was of the "giant rosettes" variant. Cytogenetic analysis revealed a ring chromosome. Because gain of material of chromosomes 7 and 16 was detected by CGH, the ring chromosome is assumed to be composed of material from these respective chromosomes.
Assuntos
Fibrossarcoma/genética , Cromossomos em Anel , Neoplasias de Tecidos Moles/genética , Adulto , Southern Blotting , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 7/genética , DNA de Neoplasias/genética , Feminino , Fibrossarcoma/patologia , Humanos , Cariotipagem , Hibridização de Ácido Nucleico , Neoplasias de Tecidos Moles/patologiaRESUMO
The reason why human malignant melanomas respond poorly to chemotherapy is not known. In an attempt to identify genes responsible for such resistance or sensitivity to therapeutic drugs, we studied the parental human melanoma cell line MeWo, as well as eight drug-resistant sublines of MeWo. These have low and high levels of resistance to four chemotherapeutic drugs with different modes of action: Vindesine, cisplatin, fotemustine and etoposide. Comparative genomic hybridizations with genomic DNA from these cell lines as probes revealed a number of chromosome gains and losses which occurred upon selective pressure during development of the sublines. The MeWo subline with high resistance to the topoisomerase II inhibitor, etoposide, exhibited the highest number of acquired chromosome imbalances. Interestingly, the two lines with high resistance to cisplatin and fotemustine, respectively, shared three additional imbalances, loss of 9p, loss of distal 12p and gain on distal 15q. The importance of these coincident imbalances is discussed.
Assuntos
Aneuploidia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 9/genética , Cisplatino/farmacologia , Análise Mutacional de DNA , Sondas de DNA/genética , DNA Topoisomerases Tipo I/metabolismo , Etoposídeo/farmacologia , Genoma Humano , Humanos , Melanoma/enzimologia , Melanoma/patologia , Compostos de Nitrosoureia/farmacologia , Hibridização de Ácido Nucleico , Compostos Organofosforados/farmacologia , Seleção Genética , Inibidores da Topoisomerase I , Células Tumorais Cultivadas , Vindesina/farmacologiaRESUMO
Gastric adenocarcinoma is a malignant tumor with a high incidence and a low survival rate. In order to identify genetic alterations associated with this tumor, we screened 23 gastric adenocarcinomas for recurrent chromosomal imbalances by using comparative genomic hybridization (CGH). The most common gains of chromosomal material were found on chromosome arms 20q (10 cases), 16p (7 cases), and 1q (4 cases) and on chromosome 11 (4 cases). Losses were observed on chromosome arms 4q, 5q, 9p, and 21q (3 cases each). Four tumors exhibited high-level amplifications localized on chromosome regions 2p23-p24, 7q31-q32, 8p21-p22, 10q25-q26, 11q13, 17q11-q21, and 20q. Based on the position of these amplifications, candidate (onco)genes were selected and subsequently tested by Southern blot analysis of the respective tumors. Of the seven tested candidates, MYCN, MET, WNT2, and ERBB2 were found to participate in the amplicons of the respective tumor samples. Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer. Among the other regions of imbalance, gain of 20q seems particularly interesting, because it is found in almost half of the analyzed cases and is highly amplified. Our data allowed us to narrow the relevant region down to the commonly gained bands 20q12-q13.1. This and other imbalanced regions provide a basis for searching new putative oncogenes and tumor suppressor genes involved in the development or progression of gastric adenocarcinoma.
