neoplastic mutations
Mutation of proto-oncogenes may convert them to oncogenes, while mutation of tumor suppressor genes may cause a loss of anti-proliferative functions.
Based on computational analysis of mutations affecting CAN-genes (candidate cancer genes) in breast and colorectal carcinomas, it has been estimated that cancers average 17 mutations (mostly SNPs) occurring within at least 90 genes [↓]. Cancers originating in the same tissue display mutation of different genes, and mutated genes contributing to breast cancer are different from genes mutated in colorectal cancers. Many of the mutated genes are involved in pathways involved in cell adhesion, cell movement, and cell signaling. Because each of the affected pathways incorporates multiple genes, mutations in different genes within a pathway could have similar consequences.
G-T mismatch in the Ras proto-oncogene can cause an alteration of the amino acid at position 12 from glycine to valine, causing the Ras oncogene-encoded G-protein to remain continuously activated when it cannot release GTP. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, RasD. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.
The Consensus Coding Sequences of Human Breast and Colorectal Cancers.
The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we have determined the sequence of well-annotated human protein coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J,
Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 2006 Sep 7; [Epub ahead of print] HHMI news.
[Analysis, identification and correction of some errors of model refseqs appeared in NCBI Human Gene Database by in silico cloning and experimental verification of novel human genes] [Yi Chuan Xue Bao. 2004] PMID: 15478601
Genetic alterations in the adenoma--carcinoma sequence. [Cancer. 1992] PMID: 1516027
Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. [Int J Cancer. 2001] PMID: 11391615
Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. [Am J Hum Genet. 2006] PMID: 16685647
Causes and consequences of microsatellite instability in endometrial carcinoma. [Cancer Res. 1999]
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