Genetics of cancer Flashcards
What are the Hallmarks of Cancer? (x10)
- Sustaining proliferative signalling 2. Evading growth suppressors 3. Activating invasion and metastasise 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death 7. Deregulating cellular energetics 8. Avoiding immune destruction 9. Tumour-promoting inflammation 10. Genome instability and mutation
What are proto-oncogenes?
Code for essential proteins involved in MAINTENANCE of CELL GROWTH, DIVISION and differentiation.
What are oncogenes?
When a mutation (can be a SINGLE mutation) converts a proto-oncogene to a protein which no longer responds to control influences. i.e. mutation changes activation of the protein, so protein cannot be turned off.
How can oncogenes be activated? (x4)
- MUTATION in the coding sequence leading to ABERRANT ACTIVATION of the proto-oncogene, which is now an oncogene.
- GENE AMPLIFICATION – where multiple gene copies are overproduced, so the protein is OVER EXPRESSED.
- CHROMOSOMAL TRANSLOCATION (Chimaeric genes), where a promoter of a gene is inserted in front of the proto-oncogene leading to OVER-EXPRESSION.
- INSERTIONAL MUTAGENESIS e.g. from viral infection, where there is fusion to an actively transcribed gene leading to OVER-EXPRESSION of the protein, or a protein which is ABERRANTLY ACTIVE.
What is the Philadelphia chromosome?
The end of the long arms of Chromosome 9 and Chromosome 22 are exchanged to form the BCR-ABL fusion protein. ABL is a very strong promoter region, so BCR is over-expressed (anti-apoptotic signal).
What if the effect of mutant Ras in relation to cancer?
• Ras is activated with GTP, and dephosphorylation to GDP inactivates it. • Ras is responsible for activation of RAF and its downstream pathway (–>MEK–>Erk) which promotes cell proliferation and survival. • Mutant Ras has ABERRANT ACTIVITY and fails to dephosphorylate GTP and remains active. There is removal of inhibition.
What example are there of oncogenes? How are they activated? What cancers are they associated with? (x8) !!
• HER2/EGFR is mutationally overexpressed and activated in many breast cancers. • Cyclin D1 is mutationally activated in many cancers. • B-Raf is mutationally activated in melanomas. • C-MYC is a transcription factor, activated by translocation. It is associated with Burkitt’s lymphoma. • Ha-RAS is a G-protein, activated by point mutation. It is associated with bladder cancer. • Ki-RAS is a G-protein, activated by point mutation. It is associated with colon and lung cancer. • SRC is a tyrosine kinase, activated by overexpression/C-terminal deletion. It is associated with breast, colon and lung cancers. • JUN is a transcription factor, activated by overexpression/deletion. It is associated with lung cancer.
What are tumour suppressor genes?
These are proteins whose function is to regulate cellular proliferation and maintain cell integrity e.g. Rb. Each cell has TWO COPIES of each tumour suppressor gene, so mutation or loss of both copies leads to LOSS OF CONTROL –> cancer. However, mutation or deletion of one gene copy is USUALLY insufficient to promote cancer (when it is sufficient, it’s called HAPLOINSUFFICIENCY).
What is Knudson’s two hit hypothesis in relation to tumour suppressor genes?
His observations indicated that some people have genetic predispositions to cancer because they have a mutation already in a tumour suppressor gene. He identified two types of cancer from tumour suppressor genes as a result: SPORADIC CANCER (two acquired mutations) and HEREDITARY CANCER (1 inherited and 1 acquired in lifetime).
What are the features of patients with inherited cancer susceptibility (in relation to tumour suppressor genes)? (x6)
• Family history of related cancers. • Unusually early age of onset. • Bilateral tumours in paired organs. • Synchronous or successive tumours. • Tumours in different organ systems in the same individual. • Mutation inherited through the germline.
Examples of tumour suppressor gene mutations? What cancers are they associated with? (x8)
• RB1 gene is a cell cycle regulator, associated with retinoblastomas. • P53 gene is a cell cycle regulator, associated with many cancers including colon, breast and bladder. • BRCA1 gene is a cell cycle regulator, associated with breast, ovarian and prostate cancer. • PTEN gene is involved in tyrosine and lipid phosphatase production, associated with prostate and glioblastoma. • APC is involved in cell signalling, associated with colon cancer. • P16-INK4A is a cell cycle regulator, associated with colon cancer. • MLH1 is involved in mismatch repair, associated with colon and gastric cancer. • P27^KIP1 encodes a protein belonging to KIP family which inhibits Cdks (cell cycle regulator), associated with breast and prostate cancer.
What is the mechanism of retinoblastoma? Difference between hereditary and sporadic form?
• Malignant cancer of the developing retinal cells. • Sporadic disease usually involving one eye. Hereditary disease can be unilateral or bilateral and multifocal (arising from more than one location). • Occurs due to mutation of the RB1 tumour suppressor gene on chromosome 13q14 (Chromosome 13, q, position 14). • RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle – involving Cdk 4 and 6 which moves cell into S phase.
What is the mechanism of APC mutation?
• Occurs due to deletion in Chromosome 5 (q, position 21). Mutation result in loss of APC gene. • The tumour suppressor gene APC participates in the WNT signalling pathway. In this pathway, it is a negative regulator of beta-catenin, which is involved in (adhesion and) promotion of cell proliferation by binding to LEF-1 complex which causes transcription. • Therefore, sufferers develop multiple benign adenomatous polyps of the colon. There is a 90% risk of developing colorectal carcinoma.
What is the mechanism of p53 mutation?
It is the GUARDIAN OF THE GENOME and involved in apoptosis, cell response to physiological stresses and DNA repair. It is an extremely important (tumour suppressor) gene. Therefore, mutants of p53 act in a dominant manner and MUTATION OF A SINGLE COPY is enough to get dysregulation of activity and cancer.
What are the functional classes of tumour suppressor genes? (x8) Don’t need to be able to list these; just to gain an idea of what the genes do.
• FUNCTIONS RELATE TO REGULATION AND CONTROL. • Regulate cell proliferation. • Maintain cell integrity. • Regulate cell growth. • Regulate the cell cycle. • Nuclear transcription factors. • DNA repair proteins. • Cell adhesion molecules. • Cell death regulators.
What are the stages in the development of colorectal cancer? This is a good model for demonstrating the step wise loss of genes in cancer development.
- Normal epithelium.
- APC (tumour suppressor gene) is the first mutation in the development of colon cancer, leading to hyperproliferative epithelium –> increased proliferation and cell turnover increases risk of further mutations.
- K-ras (protooncogene) is expressed aberrantly (oncogene) as a result DNA hypomethylation, leading to development of an adenoma.
- P53 (tumour suppressor gene) is lost and carcinoma is formed – can lead to metastasis.
- Therefore, the process = HYPERPLASIA –> METAPLASIA –> DYSPLASIA –> CARCINOGENESIS.
