Genetics - Cancer Genetics Flashcards
When do we get a compromising of a cell function?
When a functional or regulating region of DNA is damaged/mutated
What are cancer genes?
Critical gene DNA sequence that will compromise cell function
What types of cancer genes do we have?
Tumour suppressor genes which are silenced
Proto oncogenes which are over expressed
What factors can lead to cancer?
Environment
Exogenous factors
Hereditary
What are benign tumours?
Well differentiated
Slow growth
Capsulated
Non invasive
What are malignant tumours?
Poorly differentiated
Fast growth
Invade local tissue
Integrated
What are the 6 hallmarks of cancer needed for successful cancer?
Self sufficiency in growth signals Insensitivity to anti growth signals Evading apoptosis Limitless replicative potential Sustained angiogenesis Tissue invasion/metastasis
What 2 hallmarks have recently been added to the classic 6
Genome instability
Evading immune destruction.
Give an example of evading immune destruction
PD1 protein found on normal cells and tumour cells
What does the lifetime risk of developing cancer correlate with?
How often stem cells in that tissue divide
What are germline cells?
Cells which produce our gametes - undergo meiosis and mitosis.
What do germline mutations lead to?
Heritable cancer
What are somatic cell mutations?
Mutations occurring in any non-germline cell
Are somatic cell mutations heritable?
no
How do we get cancer families?
Cancer predisposing mutation may occur in germline so is inherited
What increases the risk of breast cancer by 80%?
Abnormal BRCA-1/BRCA-2 gene
What increases the risk of ovarian cancer by 55%?
Abnormal BRCA-1 gene
How do germline mutations compare to somatic?
Smaller and indistinguishable
What is a silent mutation?
Mutations has no effect as same amino acid is produced
What is a mis sense mutation?
Codons code for a completely different amino acid
What is a non sense mutation?
Mutation leads to premature stop codon
How do somatic cell mutations compare in size?
Can be much larger
What is chromosome instability?
Higher rate of chromosome mis segregation can lead to alterations in chromosome number
How do we get chromosome instability?
Defective cell cycle control
What does the loss of a repair system lead to?
Loss of amplification and rearrangement of chromosome segments
What does the loss of a repair system cause in the long term?
loss in the cell’s ability to induce cell cycle apoptosis when there are defective or incorrect chromosome
What are the 3 stages of carcinogenesis?
initiation promotion and progression
What are passenger mutations?
many mutations can be tolerated by somatic cells (often in heterozygote state) - don’t confer growth advantage however are present in the ancestor of cancer cells when the cell acquires one of the driver mutations
What are drivers mutations?
few mutations can confer a selective growth advantage and are recurrently found (in homozygote state) - they confer clonal expansion
What are candidate driver genes?
genes mutated in a greater proportion of cancer samples than would be expected from the background mutation rate.
How do we identify candidate driver genes?
cell is more likely to become cancerous than they would have been without mutation of that gene, and thus that the gene is a candidate driver.
What happens once we identify a candidate driver gene?
somatic mutations in that gene that have a consistent predicted effect on the gene’s activity, can be considered as candidate driver mutations
How may we distinguish candidate driver genes from passenger genes?
Candidate driver mutations may also be distinguished from passengers by their tendency to have a greater impact on protein function than passenger mutations do.
How may we base the assessment of the functional impact of a mutation?
• evolutionary conservation (if the protein has close homologs)
• secondary and tertiary structural features
• biochemical similarity of the previously existing amino acid to its replacement
placement of side chains in the three-dimensional protein structure
What are oncogenes?
Oncogenes are genes which have to potential to cause cancer
How do oncogenes normally operate?
Normally operate via chromosome rearrangement, gene amplification or mutation
How many dominant oncogene mutations do we need for cancer?
1
What are RAS proteins?
RAS proteins belong to the large family of small GTPases, which are activated in response to various extracellular stimuli.
Ras proteins function as binary molecular switches that control intracellular signaling networks.
When RAS proteins function normally, what does it control?
RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation.
When it functions normally, it controls cell proliferation.
When RAS is mutated, what is disrupted?
When it is mutated, negative signalling is disrupted
What are the 3 methods of oncogene activation?
Mutation in proto-oncogene or regulatory protein
Increase protein expression
Increase mRNA stability
What is KRAS?
Gene that acts as an on/off switch for cell signalling
It is called KRAS because it was first identified as an oncogene in Kirsten RAt Sarcoma virus
How many recessive tumour suppressing mutations are needed for cancer development?
2
What are the functions of tumour suppressing genes?
gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer.
What is the significance of a bilateral retinoblastoma?
It’s always inherited
What is the significance of a unilateral retinoblastoma?
Not heritable
What was observed concerning the onset of retinoblastoma?
the age of onset distribution of bilateral cases (much earlier) was consistent with a the presence of a single mutation, whereas sporadic unilateral cases followed a two-hit kinetics (came later in life).
What was suggested about the inheritance of retinoblastoma?
all retinoblastoma derived from two mutations but that in the familial cases one hit is inherited.
Why is a second mutation required in familial retinoblastoma?
In the first event in the two-hit model is an inherited mutation, however inheriting one germline copy of a damaged gene present in every cell in the body is not sufficient to enable this cancer to develop.
A second hit (or loss) to the good copy in the gene pair could occur somatically, producing cancer.
Why are familial retinoblastoma cancers easier to get than a purely somatic retinoblastoma?
It is more likely for someone with the first hit to get the second somatic mutation than for someone to get two somatic mutations
What is p53?
tumor-suppressor protein encoded by the TP53 gene.
What are the functions of p53?
DNA repair, inducing apoptosis, transcription, and regulating the cell cycle.
When do we see abnormalities of p53?
Li-Fraumeni syndrome
How may we damage/lose the TP53 gene?
The TP53 gene can be damaged in cells by mutagens (chemicals, radiation, or viruses), increasing the likelihood that the cell will begin decontrolled division.
Loss of the TP53 gene (due to mutations or deletion) occurs in >50% of human cancers (almost 100% of high grade serous ovarian cancers)
What is the role of DNA repair genes?
DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division.
What does the rate of DNA repair depend on?
cell type, the age of the cell, and the extracellular environment.
With a cell with too much DNA damage, what are its 3 options?
- an irreversible state of dormancy
- cell suicide, also known as apoptosis or programmed cell death
- unregulated cell division, which can lead to the formation of a tumor that is cancerous
What can a mutation in DNA repair genes lead to?
failure in repair, which in turn allows subsequent mutations to accumulate.
What are the 2 types of cancer viruses?
DNA and RNA viruses
What is the principle of cancer viruses?
Several viruses have been linked to certain cancers in humans
How do some viruses cause cancer?
DNA of the virus mixed with the human cell DNA causing it to grow and multiply
What is an example of virus cancer?
Cervical cancer, 99,9% is caused by human papilloma virus
