Cancer genetics Flashcards
Why can solid tumors be considered as organs?
As they consist of a variety of cell types and are thought to be maintained by a small population of stem cells
How many mutation events are needed to drive a normal cell to a cancer cell?
6
Oncogenes
Promote cell proliferation. A single mutant allele may affect the behaviour of a cell. The nonmutant version are called proto-oncogenes
Tumor suppressor genes
Inhibit cell proliferation. Loss of function. Both alleles must be inactivated to change the behaviour of the cell
How do DNA viruses cause tumours?
By rare anomalous integrations
Acute transforming retroviruses
Retrovirus particles which transform the host cell rapidly and with high efficiencies: their genome contains the oncogene
Retroviral life cycle
- Invasion of host cell. Reverse transcriptase provides a dsDNA copy of viral genome
- The viral genome is integrated into host DNA which is then transcribed into viral mRNA
- The viral mRNA is translated into viral proteins
- VIral proteins leads to the assembly of virus particles that bud off from cell membranes
What do oncogenes require?
A gain of function mutation
4 ways of activating oncogenes
- Amplification
- Point Mutations
- Translocation creating a novel chimeric gene
- Translocation into a transcriptionally active chromatin region
Amplification
Oncogene expressed at high levels in a cell
Point mutations
overactivation of protein: HRAS is a small GTPase and when we point mutations on specific residues on the catalytic site of the GTPase it results in oncogenic activation of the RAS signal
Translocation creating a novel chimeric gene
most famous example: philadelphia chromosome: translocation between chromosomes 9 and 22: breaks 2 genes: ABL1 gene and BCR gene
What do we get from Philadelphia chromosome?
Leukemia because we have a new protein that contains exons on both of the 2 genes
Translocation into a transcriptionally active chromatin region
Burkitt lymphoma
MYC oncogene is activated as it is placed close to IGH—> transforms B cells to lymphomas
When are tumor suppressor genes common?
If one of the mutations is present in all cells as it has been inherited
Retinoblastoma
If you acquire the allele at the heterozygous state sooner or later, you will develop a tumor in the retina
Inheritance and molecular level of retinoblastoma
Inheritance: dominant
Molecular level: recessive
What has been used as a marker to locate tumor suppressor genes?
Loss of heterozygosity
What are most tumor suppressors?
Proteins controlling cell-cycle pregression
Which is the most relevant checkpoint in the cell cycle?
G1-S checkpoint controlled by Cdk2 and cyclin E
Proteins that stop cell cycle progression
pRB: retinoblastomal cell tumor suppressor
p53: tumor suppressor that increases when there is DNA damage
p14 and p16
pRB function
acts as an inhibitor of the E2F protein that is a kinase activating CDK complex
p53 function
promotes p21 that will block cell cycle progression
Li-Fraumani Syndrome
mutation of one copy of p53 characterises this syndrome
2 types of instability of the genome
- Chromosomal instability
- Microsatellite instability
methods used to survey cancer cells for chromosomal changes
- Array- comparative genomic hybridisation of tumor DNA compared with normal DNA
- Hybridisation of tumor DNA to a high resolution SNP chip
- Multiolour FISH using a cocktail of different coloured chromosome paints
What is the primary detector of damage?
ATM protein
Describe the function of the ATM protein
The protein is activated by DNA double strand breaks: ATM kinase phosphorylates numerous substrates such as p53, CHEK2, BRCA1, NBS1
What does a loss of ATM function cause?
ataxia telaniectasia
Which forms of repair can suffer defects which are associated with types of cancer?
- nucleotide excision repair
- base excision repair
- double-stranded break repair
- replication error repair
2 categories of colon cancer
- Familial adenomatous polyposis
- Hereditary non-polyposis colon cancer
Cause of Familial adenomatous polyposis
Inherited mutation in the APC tumor suppressor gene
What are replication errors associated by?
hMUtSa, a dimer of M2H2 and M2H6 proteins. The proteins translocate along the DNA, bind the MLH1-PMS2 dimer hMutLa, then assemble the full repairosome, which strips back and resynthesizes the newly synthesised strand
What is used to distinguish tumors from healthy tissues?
Microarray expression
Sequence coverage
represents the number of sequenced reads that cover the site; affects the ability to detect point mutations
Physical coverage
Measures the number of fragments that span the site; affects the ability to detect the rearrangement, based on paired reads that map to different chromosomes
