The Genetic Basis of Cancer
■ Dominant gain-of-function mutations in proto-oncogenes and recessive loss-of-function mutations in tumor-suppressor genes are oncogenic.
■ Among the proteins encoded by proto-oncogenes are growth-promoting signaling proteins and their receptors, signal-transduction proteins, transcription factors, and apoptotic proteins (see Figure 23-8).
■ An activating mutation of one of the two alleles of a proto-oncogene converts it to an oncogene. This can occur by point mutation, gene amplification, and gene translocation.
■ The first human oncogene to be identified encodes a con-stitutively active form of Ras, a signal-transduction protein. This oncogene was isolated from a human bladder carcinoma (see Figure 23-4).
■ Slow-acting retroviruses can cause cancer by integrating near a proto-oncogene in such a way that transcription of the cellular gene is activated continuously and inappropriately.
■ Tumor-suppressor genes encode proteins that directly or indirectly slow progression through the cell cycle, checkpoint-control proteins that arrest the cell cycle, components of growth-inhibiting signaling pathways, pro-apoptotic proteins, and DNA-repair enzymes.
■ The first tumor-suppressor gene to be recognized, RB, is mutated in retinoblastoma and some other tumors.
■ Inheritance of a single mutant allele of RB greatly increases the probability that a specific kind of cancer will develop, as is the case for many other tumor-suppressor genes (e.g., APC and BRCA1).
■ In individuals born heterozygous for a tumor-suppressor gene, a somatic cell can undergo loss of heterozygosity (LOH) by mitotic recombination, chromosome mis-segregation, mutation, or deletion (see Figure 23-11).
■ Many genes that regulate normal developmental processes encode proteins that function in various signaling pathways (see Figure 23-12). Their normal roles in regulating where and when growth occurs are reflected in the character of the tumors that arise when the genes are mutated.
■ DNA microarray analysis can identify differences in gene expression between types of tumor cells that are indistinguishable by traditional criteria. Some tumor cells appear to be related to specific types of normal cells at certain stages of development based on similarities in their expression patterns.
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