Lecture 26: Cancer Genetics Flashcards
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 metastasize.
What is a malignant tumour?
Not self-limited in its growth (escapes apoptosis, able to produce new blood vessels), cells are poorly differentiated and capable of invading into adjacent tissues, and may be capable of metastasizing
How may cancer begin in terms of genetics?
Because of accumulation of mutations involving oncogenes, tumour suppressor genes and DNA repair genes
What is carcinogenesis?
the initiation of cancer formation
What are the 3 stages of carcinogenesis?
1) initiation - irreversible genetic alteration
2) promotion
3) progression
What is the microscopic appearance of cancer cells?
- large no. of dividing cells
- large, variably shaped nuclei
- large nucleus to cytoplasm ratio
- variation in size and shape
- loss of normal cell features
- disorganised arrangement
- poorly defined tumour boundary
What are carcinomas?
- most common types of cancer arise from cells that cover external and internal body surfaces e.g. lung, breast and colon most frequent of this type (epithelial)
What are sarcomas?
- cancers arising from cells found in supporting tissues of body such as bone, cartilage, fat, connective tissue and muscle
What are lymphomas?
- cancers that arise in the lymph nodes and tissues of the body’s immune system
What are leukaemias?
- cancers of immature blood cells that grow in bone marrow and tend to accumulate in large numbers in bloodstream
What factors can cause cancer?
- ENVIRONMENT: chemicals e.g. from smoking and radiation
- EXOGENOUS: viruses introduce own genes into cells
- GENETICS: rare and common, heredity, alterations in genes that make person more susceptible to cancer
What are the 6 hallmarks of cancer?
1) self-sufficiency in growth signals
2) insensitivity to anti-growth signals
3) tissue invasion and metastasis
4) Limitless replicative potential
5) Sustained angiogenesis
6) Evading apoptosis
What is meant by the hallmarks of cancer?
anti-cancer defense mechanisms that are hardwired into our cells, that must be breached by a cell on the path towards cancer
What are the 4 new hallmarks of cancer?
- deregulating cellular energetics
- avoiding immune destruction
- tumour-promoting inflammation
- genome instability and mutation
What is a germline mutation?
a mutation occurring in gametes and can be passed onto offspring (every cell in entire organism will be affected)
What is a somatic mutation?
occur in a single body cell and cannot be inherited (only tissues derived from mutated cell are affected)
Which type of mutation is more common - germline or somatic?
Somatic (90% of cancers) - germline is only 10% of cancers
Variations in which gene can lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome?
BRCA1 gene
What percentage risk do females with an abnormal BRCA1 or BRCA2 gene have of developing breast cancer by age 90?
80%
Name some different types of mutation.
- deletions
- duplications
- inversions
- translocations
- single base substitutions
- chromosome instability
- aneuploidy
What is a passenger mutation?
a mutation that doesn’t provide a selective advantage - - - defined as mutations that do not directly drive cancer initiation and progression, neutral, have no effect on fitness of a clone
What is a driver mutation?
few mutations can confer a selective advantage and are recurrently found (in homozygote state) - drive cancer progression, cause clonal expansions
What is the lifetime risk of developing cancer in a particular tissue correlated with?
How often stem cells in that tissue divide
What is an oncogene?
A gene that has the potential to cause cancer - often mutated or expressed at high levels in tumour cells
Most cancer-causing mutations involving oncogenes are…?
acquired, not inherited
How can acquired mutations activate oncogenes?
By chromosome rearrangements, gene duplication, or mutation
A chromosome rearrangement can lead to the formation of the gene BCR-ABL. What type of cancer can this lead to?
Chronic myeloid leukaemia (CML)
What are RAS proteins?
Proteins belonging to the family of small GTPases which are activated in response to various extracellular stimuli
What do RAS proteins control?
- cellular signalling pathways responsible for growth
- migration
- adhesion
- cytoskeletal integrity
- survival and differentiation
How do RAS proteins function?
As binary molecular switches that control intracellular signalling networks
What is KRAS?
a gene that acts as an on/off switch in cell signalling. normally controls cell proliferation
What happens when KRAS is mutated?
negative signalling is disrupted, cell proliferation no longer controlled
What is a constitutive gene?
A gene that is transcribed continuously
What can a constitutive Ras signal lead to?
Cancer
Can mutations be inherited in proto-oncogenes?
Yes but it’s very rare
What is a proto-oncogene?
A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer.
What is a tumour suppressor gene?
A gene that regulates cell during cell division and replication
What can happen when a tumour suppressor gene is mutated?
It results in a loss or reduction in function which in combination with other genetic mutations could allow a cell to grow abnormally
What was the first tumour-suppressor protein to be discovered?
retinoblastoma protein (pRb) in human retinoblastoma
What is the two-hit hypothesis?
The hypothesis that most genes require two mutations to cause a phenotypic change. Inheriting one germline copy of a mutated gene is not enough to cause cancer but a second somatic mutation (2nd hit) to the good copy in the gene pair could produce cancer.
What gene encodes the p53 tumour-suppressor protein?
TP53
What functions does p53 have?
- DNA repair
- inducing apoptosis
- transcription
- regulating cell cycle
What percentage of cancer diagnoses each year involved p53 mutations?
37%
Loss of the TP53 gene occurs in what percentage of human cancers?
> 50%
How are cancer cells without the TP53 gene genetically unstable?
They are unable to:
- stop cell cycling to allow time for DNA repair
- carry out efficient DNA repair
- undergo apoptosis
What do 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 factors affect the rate of DNA repair?
- cell type
- cell age
- extracellular environment
What 3 states can a cell that has accumulated a large amount of DNA damage or one that no longer effectively repairs it DNA enters?
- an irreversible state of dormancy
- cell suicide (apoptosis)
- unregulated cell division –> lead to cancerous tumour
How can viral infections lead to cancer?
DNA in virus can mix with cell’s DNA which can trigger changes in cell to make it grow and multiply
What is an example of a cancer caused by a virus?
Cervical cancer caused by human papilloma virus (HPV) - responsible for 99.7% of cervical cancer
Give an example of how bacteria is linked with cancer.
Helicobacter pylori has been associated with development of stomach cancer
