Genetics of Cancer

Genetics of Cancer Cancer is caused by accumulations of mutations that cause cells to divide inappropriately

Genetics of Cancer Cancer results from genetic changes that affect cell cycle control

Oncogenes and Proto-Oncogenes Are normal cellular genes that code for proteins that stimulate normal cell growth and division Oncogenes Are cancer-causing genes cells have hyperactive growth and division, immortality

Mutations make proto-oncogenes excessively active Converts them to oncogenes, which may promote excessive cell division and cancer Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene Point mutation within a control element within the gene Oncogene Normal growth-stimulating protein in excess Hyperactive or degradation- resistant protein New promoter Figure 19.11

The ras gene is a proto-oncogene When mutated, it produces the Ras protein in excess, which causes the cell to grow and divide without the proper signals 1 Growth factor Figure 19.12a (a) Cell cycle–stimulating pathway. This pathway is triggered by a growth factor that binds to its receptor in the plasma membrane. The signal is relayed to a G protein called Ras. Like all G proteins, Ras is active when GTP is bound to it. Ras passes the signal to a series of protein kinases. The last kinase activates a transcription activator that turns on one or more genes for proteins that stimulate the cell cycle. If a mutation makes Ras or any other pathway component abnormally active, excessive cell division and cancer may result. 1 2 4 3 5 GTP Ras Hyperactive Ras protein (product of oncogene) issues signals on its own NUCLEUS Gene expression Protein that stimulates the cell cycle P MUTATION DNA G protein 3 Protein kinases (phosphorylation cascade) 4 2 Receptor Transcription factor (activator) 5

Tumor-Suppressor Genes Encode proteins that inhibit abnormal cell division When inactive, cells cannot control the cell cycle or accurately replicate DNA

(b) Cell cycle–inhibiting pathway. In this The p53 gene encodes a tumor-suppressor protein That is a specific transcription factor that promotes the synthesis of cell cycle–inhibiting proteins UV light DNA Defective or missing transcription factor, such as p53, cannot activate MUTATION Protein that inhibits the cell cycle pathway, DNA damage is an intracellular signal that is passed via protein kinases and leads to activation of p53. Activated p53 promotes transcription of the gene for a protein that inhibits the cell cycle. The resulting suppression of cell division ensures that the damaged DNA is not replicated. Mutations causing deficiencies in any pathway component can contribute to the development of cancer. (b) Cell cycle–inhibiting pathway. In this 1 3 2 Protein kinases 2 3 Active form of p53 DNA damage in genome 1 Figure 19.12b

Mutations that knock out the p53 gene Can lead to excessive cell growth and cancer (c) Effects of mutations. Increased cell division, possibly leading to cancer, can result if the cell cycle is overstimulated, as in (a), or not inhibited when it normally would be, as in (b). EFFECTS OF MUTATIONS Protein overexpressed Protein absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Figure 19.12c

Results of Oncogene and Tumor Suppressor Mutations Many oncogenes and tumor suppressor genes Cause cells to divide when they should not They are mutated They are already surrounded by cells

Cancer cells lose contact inhibition Allows them to form tumors

The Multistep Model of Cancer Development Normal cells are converted to cancer cells By the accumulation of multiple mutations affecting proto-oncogenes and tumor-suppressor genes

A multistep model for the development of colorectal cancer Colon Colon wall Normal colon epithelial cells Small benign growth (polyp) Larger benign growth (adenoma) Malignant tumor (carcinoma) 1 Loss of tumor- suppressor gene APC (or other) 4 Loss of tumor-suppressor gene p53 2 Activation of ras oncogene 3 Loss of tumor- suppressor gene DCC 5 Additional mutations Figure 19.13

When cells “metastasize” they will spread throughout the body, becoming more difficult to treat

Certain viruses Promote cancer by integration of viral DNA into a cell’s genome

Inherited Predisposition to Cancer Individuals who inherit a mutant oncogene or tumor-suppressor allele Have an increased risk of developing certain types of cancer