Molecular Basis of Cancer Flashcards
What are the five properties of malignant cancer cells?
Unresponsive to normal signals for proliferation control,
De-differentiated, that is, lack many of the specialized structures and functions of the tissue in which they grow,
Invasive, that is capable of outgrowth into neighboring normal tissues to extend the boundaries of the tumor,
Metastatic, that is capable of shedding cells that can drift through the circulatory system and proliferate at other sites in the body,
Clonal in origin, that is, they are derived from a single cell.
What is the multi-step process for carcinogenesis? You should be able to discuss the relative importance of heredity environment and why early events may include mutations in DNA repair genes.
General process: when you inherit a mutation, or accumulate many somatically from the environment, or a combination of these two steps, cells become cancerous. Tumor initiation, promotion, conversion and progression are the four steps. An early event may be a mutation in a DNA repair gene that increases the rate of obtaining further mutations; examples are p53, BRCA1 and BRCA2.
What types of genes are usually mutated in tumor initiation? Describe the effect on cellular proliferation that the product of these genes has.
Tumor initiation occurs by mutations in at least two types of genes: a. Oncogenes, which normally stimulate cellular proliferation (analogous to the “gas pedal” of your car), are activated. b. Anti-oncogenes or tumor suppressors, which normally inhibit cellular proliferation (analogous to the “brake pedal” of your car), are inactivated. When this happens, cells start dividing uncontrollably.
What type of cytogenetic abnormalities are associated with malignancy? You should be able to give at least two different examples.
Cytogenetic analysis to study cancer gave first clues to genetic abnormalities in cancer cells and is used in clinical diagnosis. Translocations and gene deletions may activate oncogenes or inactivate tumor suppressors. For example, chronic myelocytic leukemia (CML) is associated with the Philadelphia chromosome. Inactivation of tumor suppressors may occur by loss of heterozygosity. Some examples are retinoblastoma (RB) and APC gene in FAP (Familial Adenomatous Polyposis).
What events can produce loss of heterozygosity (LOH)? Give at least two examples and state how they support Knudson’s theory.
LOH can occur by several different ways, but the end result is the same-loss of a tumor suppressor. LOH can occur through: Mutations, mitotic recombination, chromosome loss and/or environmental factors. “Knudson theory” said that two hits or events were needed to produce retinoblastoma (or other cancers).
Are cancers associated with both dominant and recessive syndromes? You should be able to give a different example of each type.
Susceptibility to cancer can be inherited either in dominant or recessive fashion. Examples of cancers that are inherited as autosomal dominant disorders are: Familial Adenomatous Polyposis (FAP-APC gene), Familial Retinoblastoma (RB gene), familial Breast and Ovarian Cancer (BRCA1 and BRCA2 genes) and Wilms tumor syndromes. Examples of cancers that are inherited as autosomal recessive disorders are Xeroderma pigmentosa (XP genes), Ataxia-telangiectasia (AT gene), Bloom’s syndrome and Fanconi’s congenital aplastic anemia (FA genes).
How was the RB retinoblastoma gene first identified? What was the important cytogenetic and molecular evidence?
Cytogenetic analysis of cells from retinoblastomas showed that the region around chromosome 13q14 often had an abnormal structure. Retinoblastoma cells from some patients lack RB completely. Both copies of RB have been deleted as detected by genomic DNA analysis (PCR or Southern hybridization). Some patients have partial deletions or other rearrangements of RB.
What are three properties of the protein product of the RB gene?
It is a tumor suppressor gene. It has two phosphorylation states: The hypophosphorylated form of the RB protein normally functions to repress the entry of cells into the S phase of the cell division cycle. When RB becomes hyperphosphorylated, it no longer inhibits this transition and the cells begin a cell division cycle. Thus, when there is no RB protein or it is all nonfunctional, cells cannot down regulate their cell division and grow out of control. It is a target for many animal tumor viruses.
Describe how the RB protein functions during the cell cycle and why it is important in cancer. You should be able to give an explanation of how the loss of RB may produce a malignancy.
The Rb protein is hyperphosphorylated in rapidly proliferating cells at S or G2 of the cell cycle, but is hypophosphorylated in non-proliferating cells in G0 of G1 of the cell cycle. Thus, when there is no RB protein or both are nonfunctional, cells cannot down regulate their cell division and grow out of control. Hello cancer. Hello moto.
What is the hallmark of a tumor suppressor gene or anti-oncogene (using RB as an example)?
In cases of inherited retinoblastoma (i.e. when there was a parent and other family members who also had the disease), the DNA from normal tissue of the patient or from other unaffected family members often shows a defect in the retinoblastoma gene, but has one normal copy of the gene per cell. In these patients it appears that normal, nonmalignant retinal cells, are heterozygous for the retinoblastoma gene, but the tumor cells have descended as a clone from a single cell that has acquired homozygosity for the retinoblastoma susceptibility gene.
Explain why APC BRCA1 and BRCA2 genes are tumor suppressors.
The APC gene encodes a cytoplasmic protein that regulates the localization of the Beta-catenin protein. Beta-catenin is kept at the plasma membrane by being bound to E- cadherin in normal cells. The APC protein causes the degradation of any unbound and free Beta-catenin in the cytoplasm. When the APC is lost in FAP patients, Beta-catenin goes to the nucleus to produce transcription of oncogenes like c-myc. Thus, loss of APC tumor suppressor causes an overexpression of the c-myc oncogene, resulting in cancer!Both BRCA1 and BRCA2 function in DNA repair and their loss may give rise to the many mutations needed for full-blown malignancy.
Why was p53 originally incorrectly thought to be an oncogene?
The explanation was found by showing that the oncogenic p53 mutations produce a mutant p53 protein that can bind the wild-type p53 protein and inactivate it. These “dominant-negative” p53 mutations can be viewed as “spoilers” or “monkey wrenches”.
Why is p53 is the “guardian of the genome”?
Cells missing p53 accumulate mutations at a much higher rate and thereby, have a greater chance of becoming malignant. p53 acts as a “guardian of the genome” by preventing potentially deleterious mutations through the replication of damaged DNA, and inducing apoptosis in cells with too much damage.
What is the cellular function of the p53 protein?
p53 protein acts as a transcription factor important for the expression of genes, which prevent cells from replicating damaged or foreign DNA. p53 is also required for apoptosis, in which cells commit suicide if their DNA is damaged beyond repair. In p53 defective cells, damaged DNA is replicated, thereby producing additional mutations including chromosomal rearrangements, which can lead to cancer.
What kinds of proteins do oncogenic viruses make? What is their purpose?
p53 interferes with the life cycle of many human viruses including Adenovirus and HPV (human papilloma virus). The viruses have oncogenes that act by inactivating p53, for example, Adenovirus E1B and HPV E6 proteins. Remember that these viruses also inactivate RB protein. In fact, destruction of both RB and p53 either by cellular mutations or viruses is a major route to cancer.
