Role of genetic changes in carcinogenesis Flashcards
What is carcinogenesis?
Process of how a normal cell evolves into an invasive cancer cell
How much of carcinogenesis is a genetic process?
It is mostly a genetic process
Why is carcinogenesis mostly a genetic process?
It results from accumulation of multiple genetic changes
What 2 types of genes undergo genetic changes in carcinogenesis?
Oncogenes
Tumour suppressor genes
In the normal cell phenotype, how can cell regulation be described?
Highly regulated cell growth and division
What 2 kinds of signals control different stages of the cell-cycle in a normal cell phenotype?
Intracellular and extracellular signals
In the normal cell phenotype, how can an extracellular signal from a cell produce a response in another cell?
The extracellular signal molecule binds to the complementary receptor on the other cell, producing a response in the other cell
In the normal cell phenotype, does every cell type has the same set of receptors?
No, each cell type has a characteristic set of receptors
How do signalling molecules interact in the normal cell phenotype to regulate the cell?
Different combinations of extracellular signalling molecules needed to regulate division, differentiation, survival
If appropriate extracellular signals are missing, how does the normal cell phenotype typically respond?
Undergoes apoptosis
How is cell growth regulated in the cancer cell phenotype compared to the normal cell phenotype?
In cancer cell phenotype there is loss of control of cell growth, but in the normal cell phenotype cell growth is highly regulated
What are the 3 main cancer hallmarks that cause a normal cell to become tumourigenic?
Cell immortalisation
Cell fails to follow normal growth constraints
Cell invasion of normal tissues
How does cell immortalisation develop in the cancer cell phenotype?
Cell undergoes indefinite growth
How does cancer cell phenotype evade normal growth constraints?
Becomes independent of growth factors
How does cancer cell phenotype invade normal tissues?
The cancer cell invades basement membrane of origin tissue and spreads to other organs to establish colonies in
What is the name of the process of cancer cell invasion of normal tissues in other organs?
Metastasis
What 3 factors occur in carcinogenesis that make it a micro-evolutionary process?
Genetic change
Competition between aggressive clones
Natural selection
What is the effect of heritable changes in a cancer cell?
Changes function of cell operation
Give 3 examples of functional changes that occur in cellular operation due to heritable changes?
Protein underexpressed or overexpressed
Protein changes function
Regulatory pathway changed
What are the 3 main heritable changes that occur in a cancer cell?
Dominant driver mutation of oncogenes
Recessive driver mutation of tumour suppressor genes
Epigenetic changes
When dominant driver mutation of an oncogene occurs, how many alleles of the oncogene need to mutate to express the phenotype?
One allele of the oncogene, as it is a dominant mutation
What is the effect of the dominant driver mutation of oncogenes?
Oncogene products have been altered so have different function
What is the effect of recessive drive mutation of both tumour suppressor genes in the cancer cell phenotype?
Tumour suppressor genes undergo loss of function
Does epigenetic change alter the gene sequence of cancer cells?
No, it modifies the sequence eg. methylation
What is a driver mutation?
Alteration that gives cancer cell a survival advantage for its neoplastic transformation
What is a passenger mutation?
Alteration that has no effect on cancer cell fitness but is detected in cells that also have a driver mutation
How do passenger mutations demonstrate the hitch-hiker effect?
When cancer cells undergo clonal expansion, passenger mutations are also replicated
What are the 4 types of DNA mutations?
Substitution, deletion, insertion, copy number changes
How does DNA substitution occur?
A base in the genome is exchanged for another base
How does DNA deletion occur?
One base/multiple bases are removed from genome
How does DNA insertion occur?
One base/multiple bases are added to genome
How do DNA copy number changes occur?
Large section of genome is deleted, duplicated or has many copies
How do translations/chromosomal rearrangements occur?
Genome is cut in 2 places and joined, which can also lead to gene fusions
How do genetic changes cause different functional proteins to be synthesised?
Transcribed mRNA sequence is different, so codons will be complementary to different amino acids, so a different amino acid sequence is formed in translation
What 3 factors cause genetic change to occur in a cell’s lifetime?
Environmental factors
Lifestyle factors
Cell replication
Do all genetic changes that occur in a cell lifetime cause cancer development?
No, most changes are repaired but a few persist and develop into cancer
Why do more mutations occur with every stage of cancer development?
More mutations make the cancer more aggressive so that it can survive
How does a proto-oncogene mutate into an oncogene?
One allele of the proto-oncogene undergoes dominant driver mutation, which forms the oncogene
What are the 2 features of a protein expressed by an oncogene?
Increased activity
No regulation
What type of mutation forms the philadelphia chromosome?
Translocation
What genes are involved in formation of the philadelphia chromosome?
ABL proto-oncogene of chromosome 9 and BCR proto-oncogene of chromosome 22
What fusion gene in formed in the philadelphia chromosome?
ABL-BCR oncogene
What is the cancerous effect of the philadelphia chromosome?
Uncontrollable division, as ABL-BCR fusion gene is always switched on
How does the MYC proto-oncogene mutate in cancer?
Amplifies to form multiple copies of the MYC oncogene
What is amplification of genes?
Same gene has 10-100 copies in the genome
What is the cancerous effect of the MYC oncogene being amplified?
Increases expression of protein
How does the RAS proto-oncogene mutate in cancer?
Point mutation (affects single base)
What is the effect of the RAS oncogene on the expressed protein?
It has different amino acid sequence, so has different functionality
How is leukaemia subclassified in terms of disease course?
Acute or chronic
How is Leukaemia subclassified in terms of predominant abnormal cell type?
Lymphoid or myeloid
How is Leukaemia subclassified in terms of genetic changes?
eg. Translocation, DNA mutation
What is the normal role of TS genes?
Restrain uncontrollable cell division by activating DNA repair mechanisms or apoptosis in response to DNA damage
What kind of cancers can TS gene mutations be associated with?
Rare familial cancers
What mutation occurs in each TS allele in cancer cell phenotype?
One allele undergoes germline mutation or deletion
One allele undergoes deletion or inactivation
What chromosome is the RB gene on?
Chromosome 13
What cancer is caused by loss of both copies of the RB gene?
Retinoblastoma, retina tumour in children
What are the 2 forms of retinoblastoma?
Sporadic and inherited
In the sporadic form of retinoblastoma, what mutations occur?
Both RB genes undergo somatic (not passed on) mutations
In the inherited form of retinoblastoma, what mutations occur?
One RB gene undergoes germline (passed on in sperm/ovum) deletion
Other RB gene undergoes somatic mutation
What is the function of the TP53 gene?
Instructs how to synthesise p53 protein
Why is p53 called the ‘guardian of the genome’?
Regulates cell-cycle and division to prevent tumour development
In what percentage of all cancers is TP53 inactivated?
40%
What is Li-Fraumeni syndrome?
Rare autosomal disorder caused by inherited TP53 mutation
How does familial clustering occur in Li-Fraumeni syndrome?
Familial clustering of early onset tumour (before age 45)
Give 4 types of tumour that are predominant in Li-Fraumeni syndrome?
Sarcomas
Breast cancers
Brain cancers
Adrenocortical carcinomas
What is the approximate ratio of individuals with Li-Fraumeni syndrome worldwide?
1 in 5000 to 1 in 20,000
What percentage of people with Li-Fraumeni syndrome develop cancer by age 40?
50%
What percentage of people with Li-Fraumeni syndrome develop cancer by age 60?
90%
What is the percentage risk of females with Li-Fraumeni syndrome developing cancer in their lifetime and why?
Nearly 100% risk due to increased risk of developing breast cancer
How many cancers do many individuals with Li-Fraumeni syndrome develop during their lifetime?
2 or more primary cancers
What percentage of all UK deaths does cancer cause?
28%
What percentage of people are diagnosed with cancer in their lifetime in the UK?
50%
What is a germline mutation?
Detectable variation in genome of germ cell (reproductive cell in foetus), that is passed onto offspring when the mutated oocyte/sperm forms a zygote
Can germline mutations increase familial risk of cancer?
Yes, this is seen when there is a family history of cancer
What 2 procedures can patients with potential germline mutations have?
Additional screening
Preemptive treatment
What 2 genes can have germline mutations that develop ovarian and breast cancer?
BRCA1, BRCA2
What 2 preemptive treatments can women with BRCA1 and BCRA2 have?
Mastectomy (surgical removal of one/both breasts)
Oophorectomy (surgical removal of one/both ovaries
What is a somatic mutation?
Random genetic change in cell after fertilisation, so can’t be passed onto offspring as it doesn’t involve germline
What is the difference between initiator carcinogens and promoter carcinogens?
Initiator carcinogens predispose cells to cancer development, but promoter carcinogens stimulate cancer development
What are the 3 most preventable causes of cancer from most preventable to least preventable?
Smoking (19% preventable cases)
Obesity (7.8% preventable cases)
Alcohol (5.6% preventable cases)
What kind of carcinogen is tobacco smoke?
Chemical
Give 4 examples of cancers that are associated with tobacco smoke?
Lung, mouth, throat, bladder
Give 3 examples of cancers that are associated with ionising radiation?
Leukaemia, skin, bone
Give 2 examples of cancers that are associated with sunlight?
Skin, lymphomas
How does age affect the likelihood of developing cancer?
Incidence of cancer increases with age
Give 1 example of cancer whose likelihood doesn’t increase with age?
Testicular cancer
How can driver mutations explain why cancer incidence increases with age?
Several driver mutations need to occur over cell lifetime to develop into a cancer
How can oncogenes and TS genes explain why cancer incidence increases with age?
Up to 11 key changes in oncogenes or TS genes before cancer manifests
Why can cancers with familial risk take years to develop?
More genetic changes are needed for full expression to develop cancer
How many types of cancer is obesity associated with?
Up to 13
How does obesity lead to cancer development?
Fat cells synthesise extra hormones and growth factors, which signal to cell to divide more frequently, which increases chances of mutations occurring
