Clinical Cancer Genetics Flashcards
What are polymorphisms
Changes in the DNA sequence that occur commonly in the population
What are germ line mutations
Different from polymorphisms and are rare inherited mutations that increase the risk of cancer significantly
How does genetic and environmental factors affect cancer risk
Different for different cancers
Lung cancer is very environmental
Retinoblastoma is mostly inherited
Give examples of inherited cancers
- Retinoblastoma
- Multiple endocrine tumours
- Breast cancer
- Colon cancer
How many mutations are usually required to form a human tumour cell
Evidence suggest at least 4 pathways must be mutated and that there are 3-6 rate limiting steps in the development of most cancers
What types of cancer gene are there
Oncogenes
Tumour suppressor gene
How do onco and tumour suppressor genes associated with cancer
Oncogene - gain of function or increased function associated with cancer
Tumour Suppressor gene - Loss of function or reduced function associated with cancer
What is a proton-oncogene
A normal gene that can become an oncogene due to mutations or increased expression
What proteins do proton-oncogenes code for
Proteins that help to regulate cell growth and differentiation
What processes are proton-oncogenes often involved in
Signal transduction
Mitogenic signals
What is oncogene activation
This is the conversion of a proton-oncogene to an oncogene
What is the restriction point of the cell cycle
This is the point near the end of the G1 phase of the cell cycle where beyond this point the cells will absolutely complete the cell cycle
What do Kinases do
These add phosphate to amino acids like serine (threonine kinases) or tyrosine (tyrosine kinases)
What do phosphatases do
Removes phosphate from amino acids
What do cyclins and cyclin dependent kinases (CDKs) do
These form complexes and the cyclins are regulatory and activate the CDKs
What is a major target of the cyclins
The retinoblastoma tumour suppressor gene that it phosphorylates at multiple points throughout the cell cycle
How do growth factors work
- Growth factors bind to receptors
- G-protein switch
- Kinase cascade
- Activates transcription factors
- Changes in gene expression
- Cells instructed to synthesis DNA
How do Epidermal growth factors work
- Binds to EGF receptor
- “Ras” g protein is activated
- Activates series of kinases called Raf/MEK/ERK kinases - part of the mitogen activated protein kinase complex
- ERK kinase activates transcription factors AP1 (fos/jun proteins)
- Cyclin D1 transcribed
- Cells instructed to synthesis DNA
How does the MYC proton-oncogene contribute to cancer
- Starts when a chromosomal translocation moves an enhancer sequence within the vicinity of the MYC gene
- The MYC gene codes for widely used transcription factors
- When the enhancer sequence is wrongly placed, these transcription factors are produced at much higher rates
How does the philadephia chromosome associate with choleric myelogenous leukaemia
The BCR (breakpoint cluster region) is moved next to a kinase called ABL
This chromosome is caused is caused by the translocation of pieces from chromosomes 9 and 22
BCR-ABL codes for a receptor tyrosine kinase that is constitutively active leading to uncontrolled cell proliferation
What proton-oncogenes are activated by increased gene copy number
- ERB1 - epidermal growth factor receptor
- CCND1 - cyclin D1
- MYC
Name a few tumour suppressors genes and what cancers they are associated with then the fail
- RB1 - retinoblastoma
- APC - colon cancer
- TP53 - Breast cancer
- BRCA1 and BRCA2 - Breast and Ovarian cancer
- MSH1 - colon cancer
Explain the two-hit hypothesis
If you inherited a mutated tumour suppressor gene then you were more likely to get the cancer as you might only need one more mutation for the tumour cells to be formed
What are the 2 types of tumour suppressor genes
Gatekeeper
Caretaker
Describe the function of gatekeeper tumour suppressor genes
These regulate tumour growth by controlling proliferation or promoting cell death
Describe the function of caretaker tumour suppressor genes
These are generally DNA repair genes or genes that otherwise protect the genome from acquiring or retaining DNA damage
How much risk is associated with gatekeeper gene inactivation
Very large more than 1000 fold because only one further mutation is required to initiate neoplasia
How much risk is associated with the inactivation of a caretaker gene
Smaller increase about 5-50 fold as there are up to 3 further mutations required to initiate neoplasia
How can the type of inheritance of some tumour suppressor genes affect the risk of cancer
Recessive = less likely as either 2 come to make a baby with it or needs an extra germ line mutation along with the 2 somatic gatekeeper mutations e.g. ATM gene
Describe the function and risk of failure of the pRB gatekeeper gene
Control of the restriction point and can lead to retinoblastoma and osteosarcoma
Describe the function and risk of failure of the CDKN2A (p16^INK4A protein) gatekeeper gene
Control of restriction point by inhibiting cyclin D1 and can lead to melanoma
Describe the function and risk of failure of the TP53 gatekeeper gene
Control of cell cycle and apoptosis and metabolism and can lead to breast cancer and many others
Describe the function and risk of failure of the APC gatekeeper gene
Controls the cell cycle, apoptosis and differentiation and can lead to colon cancer
Name some types of caretaker gene and their function
- Nucleotide excision repair genes
- Mismatch repair genes - repair of mismatched DNA
- BRCA1 and 2 - recombinational repair
What cancers can result from nucleotide excision repair genes
Skin cancers
What cancers can result from mismatch repair genes
Colon cancer
What cancers can result from BRCA1 and 2 genes
Breast and Ovarian cancer
What can viruses do to create viral oncogenes
They can recruit and modify versions of proton-oncogenes to activate them OR activate them by inserting powerful viral enhancer sequences next to them as in human Burkitt’s lymphoma with EBV and MYC
What is the most important human virus that can lead to cancer and how does it work
Human Papillomavirus that encodes proteins E6 that inhibits and destroys p53 and E7 destroys RB1 proteins, causes cervical cancer
What does the p16^INK4A protein do
It restrains the cyclin D1 and CDK4 complex that normally takes you through the cell cycle restriction point
