16.1 Cancer Flashcards
Genetics of Cancer
- Cancers are often monoclonal (arise from a single cell)
- Malignancies require more than a single genetic alteration (mutation)
- Inheritance of mutated genes is not the leading cause of cancer (e.g. twins)
- Stem cells may be source of tumours
- Natural selection for cells that have advantages e.g. telomere length
Genetic Alterations
- Expression of telomerase
- Epigenetic changes
- Promoter alteration
- Methylation patterns
- Mutations of tumour suppressor genes
Detection of abnormal cells.
- Precancerous cells often exhibit histological changes
- Normal cervical epithelial cells. Small nuclei, homogeneous shape.
- Abnormal cells from cervical carcinoma. Large nuclei, heterogeneous in shape
Tumour Suppressor Gene vs. Oncogene
Both copies of tumour suppressor gene must be knocked out to cause a cell to lose growth control.
Mutation in one of two copies of oncogene sufficient (Dominant)
Activation of a photo-oncogene to an oncogene
1) mutating in gene alters structure and function of protein
2) gene amplification results in over expression of gene
3) rearragment of dan bring a new DNA segment into the victim. altering either its expression or the structure pf the encoded protein.
Mutations in Rb Gene Lead to Cancer
Sportatic- begins w 2 normal copies of RB, retnioblasta only occurs if rare mutations to both
Familial-individual has one abnormal RB (deletion for example) if the other becomes inactive (by point mutation for example) then retinal tumour
Sporadic
Individual begins with two normal alleles
Familial
Individual inherits one mutated gene
Role of pRb in Cell Cycle
- pRb bound to E2F protein
- Transcriptional repressor for genes involved in G1 to S progression
- Cdk phosphorylates pRb
- Dissociates from E2F
- E2F activates transcription
- leads to expression of gene being regulated
- mRNA into proteins that are required for progressopm of cells from G1–>S
Role of p53
•Tumor suppressor gene
•p53 levels rise in response to DNA damage
>50% of human cancers linked to mutation in p53 gene
•Activates p21 gene whose product inhibits progression from G1 to S
•Cell repairs damage
•p53 can promote cell to enter apoptotic pathway
•Activates Bax gene
•Most frequent mutations correlated with regions interacting with DNA
A model for the Function of p53
If DNA of cell becomes damaged due to mutagens, the level of p52 acts to
•Arrests cell in G1
•directs cell to apoptotic pathway
If both copies of TP523 inactive, cell loses ability to arrest the cell cycle or commit apoptosis after DNA damage. P53 mutation consequences
•Dies from Mitotic failure
•Continues to proliferate with genetic abnormalities. Division with damage—> Tumour
Experimental Evidence of Role of p53
1 has 2 working p53, the other only 1 working p53 and the last no working p53.
Double p53 (-/-) mutants less susceptible to chemical treatment Continue to divide in presence of chemotherapy (do not become apoptotic)
Senescence
- Cells remain alive and metabolically active (non-dividing)
- Senescence can be triggered by Ras oncogene
- Inactivation of p53 leads to malignancy (tumour progression)
Posttranslational modifications of p53
Phosphorylation, acetylation, methylation
Alternative splice variants
Familial adenomatous polyposis coli (FAP)
- Inherited disorder that leads to polyp formation on colon
- Deletion of APC gene on chromosome 5
- One allele mutated-premalignant
- Two alleles mutated-malignant
- Loss of APC function leads to-
- Abnormal chromosome segregation
