Cancer Biology

Classes of mutations

Chromosome mutations
- Chromosome losses/gains

- Translocation

- Multi-locus deletion

Gene mutations

- Deletions/ insertions

- Base pair substititions

- Frameshifts

Gene mutations effect

I. Intron: most often no effect

II. Promoter: may affect transcription efficiency

III. Splice site: mat affect spliving e.g. exon skipping

IV. Exon; may affect protein composition

Oncogens can be

- Secreted growth factors

- Cell surface receptors

- Intracellular signal molecules

- Transcription factors

- Components of the cell cycle control network

(Activation of oncogene results in "gain of function" and is domninant phenotype)

Examples 

Chromosomal translocation: Burkitt Lymphoma -> MYC protein overproduction

Chromosomal translocation (fusion gene): Philadelphia chromosome (CML) -> active tyrosine kinase

Types of Tumor suppressor genes

- Gate keepers: cell cycle control

- Caretakers: DNA repair genes

DNA integrity checkpoints

G1-S checkpoint (DNA damage? -> increased p53 -> repair/apoptosis)

S-phase checkpoint

G2-M checkpoint

Spindle checkpoint

Mutations resulting in loss of function  

1. Point mutation

2. Deletion/chromosomal rearrangement

3. Promoted hypermethylations

4. Loss of heterozygosity

Genomic instability

1. Chromosomal instability (CIN)

- Loss of spindle checkpoint -> aneuploidy

- Loss of DNA damage checkpoints -> chromosomal abnormalities

- Shorterining of terlomeres -> joining of chromosomes

2. Microsatellite instability (MIN)

- Loss of mismatch repair -> replcation errors are not repaired.

Clinical consequences of tumorcells heterogeneity
- Long interval between primary tumor and metastasis
- Differences between sensitivity of treament
- Selection of resistane clones during treatment
- Accelereated growth rate during treatment after initial good response