Cancer Genetics Flashcards
What causes cancer?
Chemicals and radiation
Environment
Viruses- can introduce new genes into cells
Genetics
What are nucleorporins?
Form the structural basis of nucelopore
A class of proteins
Advanced cancer has over expression of nucleoporins
An increased number of nucleopores in the nuclear membrane causes an abnormal influx of beta-catenin (a growth factor thats normally mutated in colorectal cancer) in the nucleus
What is a carcinoma?
Malignant neoplasm of epithelial origin
What is the most common cause of cancer mortality in the UK?
Lung cancer is most common cancer death
Next is bowel, prostate and breast cancer
What are cancers with the highest 5 year survival rate in the UK?
Melanoma, Hodgkin lymphoma, breast, prostate, testicular, cervical cancer
What is the most common childhood cancer?
Leukaemia- most commonly ALL and AML
What are the 6 hallmarks of cancer?
Self- sufficient growth signals Insensitivity to anti-growth signals Sustained angiogenesis Limitless replicative potential Evading apoptosis Tissue invasion and metastasis
What are characteristics of germline mutations?
Germ cells produce gametes- the only cells that can undergo meiosis and mitosis
Germline mutations are gene changes which happen in reproductive cells that become incorporated into DNA of every cell in body
They’re passed on from parents to offspring- hereditary mutation
They are rare
What are characteristics of somatic mutations?
Occurs during mitosis anywhere in the body
Will not be passed on to offspring
Alterations can possibly cause cancer or other diseases
They’re common
How can we sequence germline mutations?
In linkage analysis all chromosomes are mapped with use of polymorphic markers until a specific region likely containing mutated gene is found
Once the region is identified you can sequence all the genes that are present and compare sequence of cancer family to normal
What are the different types of mutations?
Deletion
Duplication
Inversion
Translocation
Single base substitution (point mutations, silent, nonsense, missence)
Aneuploidy
Chromosome instability - higher than normal rate of missegregation of chromosomes or part of chromosomes
What is multi-step carcinogenesis?
A single mutation can’t cause cancer
E.g. for colon cancer, carcinogenesis can be shown in 3 steps:
1. Initiation: irreversible genetic alteration- simple mutation in tumour suppressor gene
2. Promotion: excessive cell proliferation- these cells tend to acquire more mutations
3. Progression: eventually tumour becomes carcinoma and progresses to metastasise
How do mutations vary between different cancers?
Mutations vary more than 1000 fold between lowest and highest across cancers
What are typical mutations caused by UV light?
UV light induced mutations leave a typical signature of C to T or G to A mutations
These specific mutations occur as DNA damage from UV radiation leads to formation of covalent bonds between 2 adjacent pyrimidines (C and T)
If DNA changes occur in critical genes this can lead to inappropriate and sometimes aggressive cell growth and therefor development of malignant tissue
How can smoking affect lung cancer?
In lung cancer P53 mutation patterns are different between smokers and non-smokers with an excess of G to T transversions in smoking associated cancers
What are passenger mutations?
Many mutations can be tolerated by somatic cell (often in heterozygous state)
These mutations have no effect to fitness of a clone but may be associated to clonal expansion because it occurs in the same genome with a driver mutation. This is known as hitchhiker in evolutionary biology
What are driver mutations?
Few mutations can cause a selective advantage (often in homozygous state)
These mutations tend to use clonal expansion and affect the phenotype
How do we identify a driver mutation?
A candidate driver is identified- these are cells which have greater mutation rate than background mutation rate and are most likely to become cancerous
Somatic mutations that have constant effect on genes activity may be considered as candidate driver mutations
Candidate driver mutations have greater impact on protein function than passenger mutation
What are oncogenes?
A gene that has the potential to cause cancer
In tumour cells these genes are often mutated or expressed at high levels
Activated oncogenes causes cells which would normally undergo apoptosis to survive and proliferate
How do most oncogenes begin?
Most begin as proto-oncogenes: these are normal genes involved in cell growth and proliferation and inhibition of apoptosis
If normal genes promoting cellular growth are unregulated they’ll predispose the cell to cancer
What kind of cancer causing mutations involve oncogenes?
Acquired mutations
These generally activate oncogenes by chromosome rearrangement, gene duplication or mutation
e.g. chromosome rearrangement can lead to formation of gene BCR-ABL- leads to chronic myeloid leukaemia
What are basic methods of oncogene activation?
- mutation in a proto-oncogene or in regulatory region can cause a change in protein structure causing:
a) an increase in protein activity
b) a loss of regulation - An increase in the amount of a certain protein caused by:
a) an increase in protein expression
b) an increase in protein (mRNA) stability, prolonging its existence and thus activating the cell
c) gene duplication resulting in increased amount of protein in cell
How does Philadelphia translocation arise?
Reciprocal translocation between chromosome 9 and 22 specifically t(9;22)(q34;q11)
This causes an elongated chromosome 9 and a truncated chromosome 22
Philadelphia translocation is associated with chronic myeloid leukaemia
What is the role of the ABL gene?
ABL1 gene encodes non-receptor tyrosine kinase ABL
In response to growth factors, cytokines, cell adhesion, DNA damage, oxidative stressed other signals, ABL is activated to stimulate cell proliferation or differentiation, survival or death, retraction or migration
The production of the oncogene has elevated ABL tyrosine kinase activity
What is the function of RAS proteins?
Control cellular signalling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation
RAS protein belongs to a large family of small GTPases which are activated in response to various extracellular stimuli
They function as binary molecular switches that control intracellular signalling networks
What is KRAS?
A gene that acts as an off/ on switch in cell signalling
When it functions normally it controls cell proliferation
When mutated negative signalling is disrupted
What is the most common mutation in RAS?
Mutation found at residue G12 in the P-loop and catalytic residue Q61
Gly to Val mutation at residue 12 makes GTPase domain of RAS insensitive to inactivation by GAP so its stuck in an “on state”
RAS needs GAP for inactivation as its a poor catalyst on its own
Residue 61 is responsible for stabilising the transitional state for GTP hydrolysis. Mutation of G61 to K reduces rate of intrinsic RAS GTP hydrolysis to low levels
What are examples of cancers caused by inherited mutations in oncogenes?
Few cancers are caused by inherited mutation of proto-oncogene that cause oncogene to be turned on
E.G
1. Multiple endocrine neoplasm type 2 (MEN2): inherited mutation in gene called RET- often causes development of medullary cancer of thyroid
2. Inherited mutation in KIT gene can lead to hereditary gastrointestinal stromal tumours (GISTs)
3. Inherited mutations in gene called MET leads to hereditary papillary renal cancer
4. Inherited mutation in CDK4 leads to malignant melanoma
What is a tumour suppressor gene?
Aka. an anti-oncogene
Gene regulates cell during division and replication
When a tumour suppressor gene is mutated it leads to a loss or reduction in its function- with other mutations it can cause cell to grow abnormally
Loss of function in these genes may be more significant than activation of oncogenes
What are the function of tumour suppressor proteins?
Repression of genes needed for continuing cell cycle
Coupling cell cycle to DNA damage
If damage can’t be repaired, cell undergoes apoptosis
DNA repair proteins are classified as tumour suppressors
What is the first tumour- suppressor protein discovered?
Retinoblastoma protein
Tumour can occur in 1 or both eyes
Bilateral cases are aways heritable. Unilateral are not heritable
Bilateral happen earlier in life and are often cause of single mutation
Unilateral cases come later in life and follow two-hit kinetics
What is the two hit model?
Most “loss of function” mutations in tumour suppressor genes are recessive- for cells to become cancerous both copies of the gene must be mutated
First event of two hit model is an inherited mutation (1 mutation is insufficient)
A second hit could occur somatically
This hypothesis predicts that chances of a germline mutation to get a second mutation is much greater than 2 non-carrier to get two hits in same cell
What is P53?
Encoded by TP53 gene- its a tumour suppressor
Has many functions in the cell: DNA repair, inducing apoptosis, transcription, regulating cell cycle
P53 mutation is common so is a popular target for cancer therapies
Homozygous loss of P53 found in 65% of colon cancers
Mutated P53 involved in pathophysiology of leukaemia, lymphoma, sarcomas and neurogenic tumours
Abnormalities in P53 can be inherited in Li- fraumeni syndrome (LFS)
What is an effect of a mutated TP53 gene?
Tumour suppressor function is severely reduced
People who inherit only 1 functional copy of TP53 gene will most likely develop tumour in early adulthood- Li Fraumeni syndrome
What are DNA repair genes?
DNA repair genes code for proteins which correct errors that arise when cells duplicate their DNA prior to division
Rate of DNA repair depends on many factors such as cell type, age of cell and extracellular environment
What happens to cells that undergo large amounts of DNA damage and cant be repaired?
Go into an irreversible state of dormancy
Undergo apoptosis
Undergo unregulated cell division - tumour formation
What is the role of BCRA1 and BCRA2 in DNA repair?
BCRA1 gene is phosphorylated by ATM and CHK2 in response to dsDNA breaks
BCRA1 bind to BCRA2 which interact with RAD51 to form a complex which is involved in DNA repair
How are viruses linked to cancer?
Some virus infections cause cancer
This occurs when DNA in viruses mixes with cell’s DNA which triggers a change in the cell causing it to grow and multiply
E.g. HPV leading to cervical cancer
