What is caused by genetic changes in normal cells
Cancer (can be either somatic [acquired] or germ line [inherited])
What are the two main types of genes that are frequently mutated in cancer? What do each type do?
Oncogenes: promote cell growth and division (mutation/over expression causes uncontrolled growth)
Tumor suppressor genes (TS): suppress cell growth and division (inactivated causes uncontrolled growth)
Properties of oncogenes and TS genes
1. Number of mutational events required to contribute to cancer
2. Function of the mutant
3. Origin of the mutation
4. Mechanism of action
1. One (dominant: need only one mutant allele) / two (recessive: need two mutant alleles)
2. Gain of function / loss of function
3. Somatic / inherited or somatic
4. Stimulate cell division /to restrain cell division
5. Protein kinases / transcription factor
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Many cancer cells contain multiple copies of structurally normal oncogenes that can be seen in what two forms. These are types of amplification
Double minutes: small separate chromosomes (Leukemia; C-MYC oncogene)
Insertions within the normal chromosome: Homogeneously staining regions (HSR). Ex; neuroblastoma and others
What is a molecular-cytogenic technique that allows identification of the nature of all regions of amplification in a single experiment
CGH: comparative genome hybridization
What type of mutation is it called in which the RAS gene is affected. What is the mechanism
mutant RAS has reduced GTPase activity, thus GTP-RAS is inactivated more slowly, leading to excessive cellular response to the signal from the receptor
Chromosomal translocations and transpositions are also a mechanism of cancer mutation
What is an example of a translocation
Burkitt lymphoma: Myc normally found on chromosome 8 is transferred to chromosome 14, next to Ig Locus which is actively transcribed in antibody producing cells (this is see in malarial regions of central Africa and Papua New Guinea). This is different from the t(9; 22) translocation we saw because in there this was leading to the translation of a whole new protein, this on the other hand is leading to an increase an a protein that was already being made.
What does Knudson's two hit-hypothesis state? What is an example involving a TSG?
Two successive mutations are required to turn a normal cell line into a tumor cell.
Retinoblastoma (Mendelian: germline mutation and then somatic mutation leading to multiple tumors and bilateral early-onset) (Sporadic: normal gene with two somatic mutations leads to single tumors, and unilateral later onset)
What are the three ways in which an oncogene can become mutated?
1. Gene amplification
2. Point mutations
3. Chromosomal translocations
What is an important translocation seen in oncogene mutations?
t(9;22) found in CML: chronic myeloid leukemia (have large spleen, lots of granulocytes)
What are two ways in which tumor suppressor genes are inactivated?
Knudson's two hit hypothesis
Loss of heterozygosity
What is the function of TP53
It is a transcription factor that prevents cells with potential oncogenic changes or with DNA damage from progressing to S phase. When it is mutated, damaged cells will progress to S phase yielding proliferation of damaged cells.
Mutations in what genes lead to inefficient replication or repair of DNA? WHat are two examples of this?
Mismatch repair genes
Familial adenomatous polyposis and Hereditary nonpolyposis colon cancer
What are the six specific capabilities for a successful tumor
1. Become independent of external growth signals
2. Become insensitive to external anti-growth signals
3. Become able to avoid apoptosis
4. Become capable of indefinite replication
5. Become capable of sustained angiogenesis
6. Become capable of tissue invasion and metastasis