Cancer Genetics Flashcards
What is a cancer?
An abnormal growth of cels which tend to proliferate in an uncontrolled manner, and in some cases, to metastasize
What causes cancer cells to behave abnormally?
Changes in the DNA sequence of key genes which are known as cancer genes
What are the two causes for mutations in DNA?
Tumour supressor genes being silenced or oncogenes being over-expressed
What are the 14 hallmarks of cancer?
PAIN GUARDS TEES
Polymorphic microbiomes
Activating invasion and metastasis
Inducing or accessing vasculature
Non Mutational epigenetic reprogramming
Genome instability and mutation
Unlocking phenotypic plasticity
Avoiding immune destruction
Resisting cell death
Deregulating cellular metabolism
Senescent cells
Tumor-promoting inflammation
Evading growth suppressors
Enabling replicative immortality
Sustaining proliferative signalling
What is deregulating cellular metabolism?
Involves a metabolic reprogramming that leads to a high production of lactate.
What is phenotypic plasticity?
Describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion.
What is sustaining proliferative signalling?
Cancer cells are able to divide even without receiving these signals which leads to an uncontrolled proliferation of these abnormal cells.
What is a benign tumour?
A mass of well-differentiated cells that grows slowly, is capsulated and lacks the ability to invade neighbouring tissue or metastasise
How do you get to subclones with individual genotypes?
Normal cell-> founder cell-> subclones with individual genotypes
What is a malignant tumour?
A tumour which is not self limited in growth, cells are poorly differentiated and capable of invading into adjacent tissues = metastasis
What is late cancer?
1-10 more driver mutations
What four things can cause cancer?
- Radiation
- Chemicals
- Viruses
- Hereditary alteration in genes which make a person more susceptible to cancer
What is the difference between benign and malignant tumours? (4)
benign grow slow, malignant fast
benign is well differentiated, malignant is not
benign is capsulated, malignant is not
benign cannot metastasize or invade neighbouring tissue, malignant can
What type of cancers have epithelial tissue origin?
Carcinomas
What are common types of carcinomas?
Lung, breast and colon cancer
What is the name given to cancers which arise from cells found in the connective tissues of the body? What are examples of connective tissue?
Sarcomas
bone, cartilage, fat, vascular, or hematopoietic tissues
What are cancers that arise in lymph nodes and tissues of the body’s immune system called?
Lymphomas
What are cancers that arise from immature blood cells that grow in the bone marrow called?
Leukaemia
What is the most common cancer in children?
Acute lymphoblastic leukaemia
What type of mutation can be passed on to off-spring?
Germline mutations can be passed on
What type of mutations can’t be passed onto offspring?
Somatic mutations
A gene change in which cells cause germline mutations?
Reproductive cells
What are somatic mutations also known as?
Acquired or sporadic mutations
What are the seven types of mutations?
deletions
insertions
aneuploidy
inversions
translocations
single base mutations
chromosome instability
What is a deletion mutation?
When one or more nucleotide is removed from the DNA
what is a duplication mutation?
When one or more copies of a gene or region of a chromosome are made
What is an inversion?
Reversing the orientation of a chromosomal segment
What is a driver mutation?
A mutation which contributes to cancer growth
When does a passenger mutation occur?
A mutation which occurs during cancer growth
What type of studies can help identify cancer germline mutations?
Positional cloning linkage studies through gene mapping and gene indentification
What are the three types of point mutations?
Silent, non-sense and mis-sense
What affect does UV radiation have on the DNA?
forms covalent bonds between two adjacent pyrimidines (C and T) in the DNA molecule which causes cross linking, resulting in the formation of a dimer
What happens in the dimer formed due to UV radiation is not repaired?
Most DNA polymerases will insert 2 adenine opposite the dimer, resulting in a mutation
What does oncogene issues generally result in?
An increase in some form of protein activity, or a loss of regulation
Describe the process multistep carcinogenesis?
- begins with mutation in tumour supressor gene which therefore allows excessive cell proliferation
- proliferating cells tend to acquire additional mutations
- overtime the accumulated damage can yield a malignant, metastatic tumour
what type of protein is RAS?
A GTPase
What state is RAS in when GDP is bound?
It is inactive
Does Ras bind GDP or GTP with a higher affinity?
GTP
When Ras binds GTP, what state is Ras then in?
Active state
How does GAP ensure that Ras is not always active?
GTPase Activating protein hydrolyses the GTP into GDP so Ras is turned off
What happens when RAS is constantly stuck in the active form?
the cell extensively proliferates causing cancer as RAS controls a lot of cellular signalling pathways
What is the two hit hypothesis? and how does it relate to mutations to tumour supressor genes?
The two hit hypothesis states that both alleles that code for a particular protein must be affected before an affect is manifested.
Most mutations to tumour supressor genes are recessive, meaning in order for a particular cell to become cancerous, both of the alleles for the cells tumour supressor genes must be mutated
What do mutations in tumour supressor genes result in?
A loss of function, as they can no longer stop the cell from proliferating uncontrollably
what is the first event in the two hit hypothesis?
AN inherited mutation - however inheriting one germ line copy of the damaged gene is not sufficient
What is the second hit in the two hit hypothesis?
When the second (good) copy in the gene pair is mutated - causing cancer
What is p53?
a tumour supressor protein that is encoded by the TP53 gene
What does p53 do?
Unwinds DNA region from histone
RNA polymerase then does its thing
Loss of the TP52 gene gene due to mutation or deletion occurs in what percentage of human cancers?
> 50%
What is Li-Fraumeni syndrome?
an inherited condition which is characterised by an increased risk for certain types of cancers
What mutagens can cause damage to the TP53 gene?
Chemicals, radiation or viruses
What is a retinoblastoma?
Cancer of the retina
What does Rb protein do?
Prevents excessive cell growth by inhibiting cell cycle progression until a cell has made all the necessary checks in the G1 phase
What transcription factor does retinoblastoma protein bind?
E2F
What has to happen to the Rb for the E2F to be released?
Rb has to be phosphorylated - this leads to transcription
How do cancer cells evade the immune response?
activation of the checkpoint pathways such as PD-1 send negative signals to the cell to stop if from attacking the tumour cell
how does nivolumab work?
binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2,so the negative signals cannot be sent anymore
What is positional cloning?
A lab technique used to locate the position of a disease associated gene along a chromosome
Which type of mutation tends to cause clonal expansions?
Driver mutations
What is the life-time risk of developoing cancer in a particular tissues correlated with?
How often the stem cells in that tissue divide
How are most cancer causing mutations involving oncogenes acquired?
Chromosome rearrangements and gene duplications
What does the translocation between chromosome 9 and 22 result in?
The formation of the ABL-BCR1 gene which makes elevated tyrosine kinase activity - leads to more cell proliferation
(abnormal chromosome 22)
What do proto-oncogenes turn on?
Genes that cause oncogenes to be turned on
What condition is caused by a mutation in the RET gene?
Multiple Endocrine Neoplasia Type 2 (MEN2)
What type of cancer do people with multiple endocrine neoplasia type 2 develop?
a form of thyroid cancer called medullary cancer of the thyroid
What is the nature of most loss-of-function mutations that occur in tumour suppresor genes?
Recessive
What three things make cancer cells genetically unstable?
Unable to stop the cell cycle to allow time for repair
Unable to carry out efficient repair
Unable to undergo apoptosis
What do DNA repair genes do?
Code for proteins whose normal function is to correct errors which arise when cells duplicate prior to cell division
What factors is the rate of DNA repair dependant on? (3)
Cell type, age of cell and extracellular environment
After a cell has accumulated alot of DNA damage, what are the three states it can enter into
Dormancy
Apoptosis / programmed cell death
Unregulated cell division = cancer
What can mutations in DNA repair genes lead to?
Failure to repair which in turn allows mutations to accumulate
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How do viruses cause DNA damage?
Insert their genomes into the DNA of the host cell, which can disrupt important regulatory genes
What does the E7 protein from HPV do to promote cancer?
Binds to Rb to promote its degradation which allows cells to divide faster and
What are three viruses associated with cancer?
Papillomavirus
Hepatitis Virus
Epstein-Barr Virus
What has lead to the discovery of many common low risk variants for different cancers in recent years?
Genome wide association studies
What does the two-hit hypothesis predict?
That the chances for a cell with a germ-line mutation to get a second hit ie a somatic mutation is much higher than the chances of a non-carrier to get two hits in the same cell
What is tumour heterogeneity?
Describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.
This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity)
What are driver mutations?
Those that drive cancer initiation and progression
They can result in the acquisition of 1 or more of the hallmarks of cancer
What are passenger mutations?
Those that don’t drive cancer initiation and progression
What are proto-oncogenes?
Type of normal gene that produces a protein that promotes cell growth and proliferation
Driver mutations in a proto-oncogene could lead to cancer
A proto-oncogene with driver mutations is called an oncogene (Genes which stimulate the cell cycle)
What are tumour suppressor genes?
Type of normal gene that produces a protein that helps limit cell growth and proliferation
Driver mutations in tumour suppressor gene could lead to cancer
Genes which halt the cell cycle
What is Knudson hypothesis?
aka the 2 hit hypothesis
It is the hypothesis that most tumour suppressor genes require both alleles to be inactivated to cause a phenotypic change
What is a germline mutation?
Mutation in the reproductive cells (egg or sperm). Germline mutations are passed on from parents to offspring.
Entire organism carries the mutation
What are somatic mutations?
Mutation in any cell fo the body except the germ cells. They are not passed on from parents to offspring.
Path of the affected area carries the mutation
What is the cancer gene census?
Ongoing effort to catalogue those genes which contain mutations that have been causally implicated in cancer.
What are cancer-risk genes?
We all carry certain genes that are normally protective against cancer. These genes correct any DNA damage that naturally happen when cells divide.
Inheriting faulty versions or “variants” of these genes significantly raises your risk of developing cancer, because the altered genes cannot repair the damaged cells, which can build up and form a tumour. E.g., BRCA1 and BRCA2
Why is melanoma of the skin mostly C–>T mutations?
Because radiation causes this mutation
What are the most common mutated genes in pancreatic cancer?
KRAS & TP53
What are the ways to treat cancer? (5)
Surgery
Chemotherapy
Radiotherapy
Targeted therapy
Immunotherapy
