Flashcards in Molecular cell biology of cancer Deck (18)
8 hallmarks of cancer:
Apoptosis: ability to evade growth suppressors
Cellular deregulation: ability to deregulate normal cell metabolism
Immune evasion: ability to overcome immune attacks
Genes that has the potential to cause cancer when mutated or expressed at high levels.
Increased expression of oncogene can:
- Deregulate an expression of another gene
- Alter the protein product of a gene
- Increase expression of pro-malignant pathways
- Inhibits anti-malignant pathways
Oncogenes are dominant- mutation present on one allele causes the phenotype to be present.
Oncogene that codes for epidermal growth factor receptor.
Mutation in this gene activates EGFR and can cause increased proliferation of cells.
erbB2 (HER2) is overexpressed/amplified in 30% of breast cancers
Gene that could become oncogenes due to mutations or overexpression.
An oncogene that codes for the Ras protein.
Ras protein is a small GTPase, that activates other proteins in a cascade.
When RAS gene is mutated, it can permanently switch the Ras protein on, allowing continuous cell proliferation.
Ras losses its GTPase function as is unable to hydrolyse GTP to GDP, which inactivates it.
Tumour suppressor genes
Genes that code systems that control cell growth:
- Cell cycle checkpoint proteins.
- Growth inhibitors
- DNA repair
Loss of function in these genes results in a neoplasm.
These genes are recessive, mutation has to be present on both alleles to be expressed.
Example of these genes:
BRCA, RB, P53, APC, PTEN
BRCA1 and BRCA2 gene
(Breast cancer gene)
Tumour suppressor genes located on chromosome 17 that produce BRCA1 and 2 proteins in the breast.
These proteins help to repair double breaks in DNA damage and trigger apoptosis in cells with irreversible DNA damage.
Mutation in these genes increases the risk of developing breast cancer.
Tumour suppressor gene that codes for the retinoblastoma protein.
RB protein inhibits excessive cell growth by halting the cell cycle progression until the cell is ready to divide.
Mutation in this gene increases the likelihood of developing many cancers.
Tumour suppressor gene that codes for P53 protein.
P53 protein halts the cell cycle by activating p21, which inhibits G1/CDK2 cyclins.
If there is DNA damage, P53 either stimulates the cell to undergo apoptosis, preventing it from progressing to G2.
P53 can also halt the cycle to allow DNA damage to be fixed.
Mutation in P53 accounts for 50% of cancers.
Most cancers are caused by multiple mutations in oncogenes or tumour suppressor genes.
Most cancers are not monogenic. The mutation of one gene leads to another.
Seen in colorectal cancer
Colorectal cancer progression.
1. Loss of tumour-suppressor protein, such as APC causes a polyp.
2. Activation of Ras oncogene and loss of tumour suppressor gene DCC causes an adenoma.
3. Loss of P53 and more mutations causes a carcinoma.
Genetic basis of chronic myeloid leukaemia (CML)
9:22 chromosomal translocation (Philadelphia chromosome)
ABL1 gene of chromosome 9 fuses with BCR gene of chromosome 22
Causes haematopoietic progenitor to become a malignant clone.
Tyrosine-kinase inhibitor, chemotherapeutic drug used especially in chronic myeloid leukaemia.
Since tyrosine-kinase requires ATP to function, imatinib prevents ATP from binding.
Reasons for resistance to Imatinib
ABL kinase domain mutations: imatinib, no longer able to bind.
Increased amplification of BRC-ABL-1: outcompetes imatinib
Clonal evolution: Less reliance on BCR-ABL
Drug that targets BCL2 mutations
Chronic lymphocytic leukaemia
Cancer that results from clonal disorder of CD5+/CD19+ B cells. Overexpression of these receptors are used to diagnose CLL.
Causes tumour in the bone marrow, blood and secondary lymphoid tissue.
- Leads to decreased immunity and bone marrow dysfunction.
What is the median age of CLL