肿瘤学（Oncology).ppt

Mechanisms of Oncogene Activation ORF RS Proto-oncogene ORF RS ORF RS ORF RS mutation amplification ORF RS RS Re-arrangement deletion Point mutation Ras 15-20% K-ras N-ras H-ras carcinomas 30%:lung adenocarcinomas 50% colon carcinomas 90%:pancreatic carcinomas Blood malignancies Exon 12 insersion Partial karyotypes of trypsin-Giemsa-banded metaphase cells depicting nonrandom chromosomal rearrangements observed in lymphoid malignant diseases. t(4;11)(q21;q23) in ALL t(1;19)(q21;p13) in pre-B cell ALL t(8;14)(q24;q32) in B-cell ALL and Burkitts lymphoma inv(14)9q11q32) in T-cell leukemia/lymphoma t(8;14)(q24;q11) in T-cell leukemia/lymphoma t(14;18)(q32;q21) in B-cell NHL 8q24 :MYC gene 18q21: BCL2 14q32 : IGH q32 q32 q32 14 14 14 q32 q32 q32 14 14 14 ras Family. The ras family of oncogenes (homologous to the rat sarcoma virus) has three primary members (H-ras, K-ras, and N-ras) which are among the most common activated oncogenes found in human cancer. The ras genes code for a protein (p21) that is located on the inner surface of the plasma membrane, has GTPase activity, and may participate in signal transduction. ras oncogenes are activated by point nucleotide mutations that alter the amino acid sequence of p21. ras in Carcinogen-Induced Tumors Mice harboring the mutated H-ras transgene developed tumors exclusively in the lungs within weeks following birth. Ninety percent of these tumors had transforming genes in the (NIH) 3T3 assay; the gene was K-ras in all lung tumors. Studies in mice with carcinogen-induced lung cancers implicate genes of the ras family in the carcinogenesis process. Mouse lung tumors induced by tetranitromethane contained mutated K-ras genes. In most studies, K-ras mutations were confined to adenocarcinomas of the lung and occurred in 30% of tumors. Mutations were not observed in adenocarcinomas from nonsmokers. K-ras mutation appears to be an independent prognostic factor that indicates a poor prognosis and is unrelated to conventi