Chapter 23 - Cancer Genetics Flashcards
How is cancer classified as a disease?
Not a single disease
Varied group of disorders characterized by the presence of cells that do not respond to normal control on division
Signals are disrupted in cancer cells that cause them to proliferate at an abnormally high rate and eventually form tumors
- Cells lose their regular shape to form masses
- Divide rapidly and continuously to form tumors
What are metastases?
Cells that have broken off from primary tumor, traveled through the body, and establish secondary tumors
How is cancer classified as a genetic disease?
Cancer arises as a result of fundamental defects in the regulation of cell division
Knudson’s “two-hit” hypothesis
Clonal evolution
Any genetic defect that allows mutation to arise accelerate cancer progression
- Mutation in genes that regulate gene repair – often associated with cancers
- Different inherited disorders of DNA repair usually accompanied by increased incidence of cancer
- Mutations in genes that affect chromosomal segregation can contribute to clonal evolution - Duplicated or eliminated genes
What is Knudson’s “two-hit” hypothesis?
When cancer arises in a single eye, a single cell undergoes successive mutations
- A chance of those mutations happening in the same cell is very low, so retinoblastoma tends to be rare
When it arises in both eyes, the inheritance of one of those two mutations is required for that cancer
- When there is inheritance of one of these mutations, every cell will have one mutation, so in the future, it only has to undergo one more mutation, which makes its incidence higher
What is clonal evolution?
Single somatic cells undergo mutations that allow them to divide more rapidly and proliferate more than regular cells
First cell that has the mutation will give rise to clones that have that same mutation
- Further mutations can occur in already mutated cells to allow for division and proliferation to occur even more quickly
- Mutated cells are going to outcompete the unmutated cells
How is cancer classified as an environmental disease?
Most cancers are not inherited but are influenced by environmental factors
Seen when organisms/people migrate to a different place where incidence of cancer is higher but their personal incidence is low, their incidence tends to increase
The most common cancer-causing environmental agents are tobacco use, diet, obesity, alcohol, and UV radiation
- Cause somatic mutations that stimulate cell division and progression of cancer
Environmental factors can interact with genetic predispositions to cancer
What are cancer genes at the 2 types?
Signals that regulate cell division – molecules that can stimulate cell division and molecules that inhibit cell division
Types:
- Oncogenes
- Tumor suppressor genes
What are oncogenes?
Dominant acting genes that stimulate cell division
- Mutation in stimulatory genes usually act in a dominant manner because even the amount of gene product produced by a single allele is sufficient enough to produce a stimulatory effect
Tend to arise from a mutated copy of a normal cellular gene (a proto-oncogene – the normal cellular gene that when mutated becomes an oncogene)
What are tumor suppressor genes?
Regulatory gene is inhibitory
Typically they inhibit growth, but when they mutate to become inactive, they cannot slow down growth/division
Tend to act in a recessive manner
- Both alleles have to be mutated to remove all inhibitory effect – one nonmutated allele can still produce enough of an inhibitory effect to stop division
Genes stop excessive cell proliferation
Mutations in both oncogenes and tumor suppressor genes can lead to cancer
- Mutations are correlated with mutations in DNA repair genes
What are the 2 processes that control the rate at which mutations occur in a cell?
Rate at which errors arise during and after a course of DNA replication
- Controlled by the fidelity of DNA polymerase, who plays a large role in proofreading and lessening error rate
- Defects in genes that encode DNA polymerase or other proteins can lead to cancer
The efficiency at which errors are corrected (DNA repair itself)
- Mutations in genes that encode the mechanisms of DNA repair are associated with cancers
How can telomerase influence cancer occurrence?
Inappropriate activation of telomerase can contribute to cancer
In somatic cells, telomeres are shortened after every cell division, which eventually leads to cell death
- If genes that regulate the expression of telomerase in somatic cells, the cells no longer have the ability to program their cell death through telomere shortening because their telomeres are not shortening after each replication, allowing them to survive and replicate indefinitely
How does angiogenesis affect cancer occurrence and how does it occur?
Tumors need both oxygen and nutrients to survive - Occurs through blood vessels
Angiogenesis stimulated by growth factors and proteins
- In normal cells, genes that encode these factors/proteins are highly regulated
- In tumor cells, genes tend to be overexpressed
- Inhibitors of angiogenesis-promoting factors may be inactivated to allow for constant vascularization/angiogenesis to occur
How does metastasis occur?
Cancer cells have to escape through primary tumor site, have to evade immune system, travel to a new site in the body, adhere to cells in the new site, and have to receive oxygen and nutrients to sustain themselves in the new site
Many cellular changes are required to allow metastasis to occur
- Mostly all induced by different somatic mutations
What are microRNAs and how do they affect cancer?
Small RNA molecules that pair with complementary mRNA sequences and degrade the mRNA/inhibit the translation of mRNA
- Huge role in controlling gene expression
Tumor cells tend to exhibit widespread reduction of microRNA expression
- Seems to only affect later-stage tumor progression (after cancer cells are already initiated)
Lower levels of microRNAs can also allow for the expression of oncogenes that they would typically inhibit
Overexpression of microRNAs is also associated with cancer
- Associated during metastasis
How are epigenetics related to cancer?
Overall lower level of DNA methylation seen in cancer cells – called hypomethylation
- Makes sense because DNA methylation is associated with decrease in gene expression, so low methylation would stimulate expression and cancer
Hypermethylation has been observed in some CPG islands that are associated with some cancers
Some evidence of histone modification influencing cancer
Alteration in chromatin structure that effect gene expression are often implicated in cancers
Genes encoding proteins that are important regulators of epigenetic changes are often mutated in some types of cancer
Differences in chromatin structure between cancer cells and normal cells
How can chromosomal rearrangements cause cancer?
Deletions – result in the loss of one or more tumor suppressor genes
Inversions and translocations – chromosome breaks that accompany both inversions and translocations can lie within tumor suppressor genes, which disrupts their function, leading to cell proliferation
- Can bring together genes to generate a fusion protein, which stimulates some aspect of the cancer process
- Transfer of potential cancer causing genes to a new location, where it ends up being activated by different regulatory sequences
What are the characteristics of viruses and their genomes?
Viruses are simple, replicating structures that are made up of nucleic acids and surrounded by a protein coat
Vary in structure and size
Nucleic acids can be RNA or DNA and can be single-stranded or double-stranded and can be linear or circular
Tend to have very small genomes
What are the 2 cycles of viral reproduction and their steps?
Lytic cycle
- Phage attaches to a receptor on bacterial cell wall
- Injects DNA into host cell
- Host DNA degrades slightly
- Phage DNA is replicated, transcribed, and translated, producing more phage DNA and associated proteins
- Phage particles reassemble inside the cell
- Particles produce and enzyme that bursts open the cell, allowing the phages to escape (Kills host cell)
Lysogenic cycle (essentially phage DNA lying dormant in host)
- Phage attaches to a receptor on bacterial cell wall
- Injects DNA into host cell
- Inside host cell, host DNA doesn’t degrade
- Instead, phage DNA integrates itself into host’s DNA
- Replicates with the rest of the bacterial DNA
- Passed on when bacterial cell divides
- When there is certain stimuli, it can cause the prophage to dissociate from the bacterial chromosome, causing it to enter into the lytic cycle
What is transduction and its 2 types?
Type of gene exchange that takes place when viruses carry DNA from one bacterium to another
Once viral DNA is in host DNA, it can undergo recombination with bacterial chromosome
Types:
- Generalized transduction – any bacterial gene can be transferred
- Specialized transduction – genes only near specific sites on bacterial chromosome end up getting transferred (Requires lysogenic phages)
What is the mechanism of transduction?
Bacteria infected with phage
Bacterial chromosome is fragmented
Bacterial genes are incorporated into some of the phages – called transducing phages (phages that take up bacteria genes)
Cell lyses to release transducing phages
Transducing phages transfer bacterial genes to a new bacterium when they go and infect a new bacterium
What are retroviruses?
An RNA virus that integrates into the host genome (DNA) by using reverse transcriptase
What is the mechanism of retroviruses?
Injects RNA into a host
Reverse transcriptase, which is encoded by virus, reverse transcribed the RNA back into DNA
Second strand of cDNA will be synthesized by transcription
Viral DNA enters host nucleus and is integrated into the host chromosome – formation of a provirus
Under stress or other environmental factors, the viral RNA ends up being transcribed from the provirus and is translated in the cytoplasm
Viral RNA, proteins, and envelopes are assembled
Newly assembled virus buds out from the cell membrane
What are the 3 genes that are common across neraly all retroviruses?
gag – encodes for viral coat proteins
pol – encodes reverse transcriptase and integrase (allows viral DNA to integrate into host chromosome)
env – encodes glycoproteins on surface of viral envelope
How can viruses cause cancer?
Animals - primarily retroviruses
Humans - primarily DNA viruses
Can convert proto-oncogenes into oncogenes
- Add a provirus before proto-oncogene, which causes repeated rounds of viral infections in cells
- Proto-oncogenes can eventually become rearranged and mutated, turning into oncogenes and causing cancer
Can also cause alterations in host gene expression
- Provirus DNA is inserted, which can contain a strong promoter to ensure that their own genetic material is transcribed in host cell
- If viral promoter is near proto-oncogene, it will stimulate high expression of the proto-oncogenes, which can lead to increased cell proliferation
