Cancer as a genetic disorder Flashcards
How does a cell become cancerous?
- Change in transcription levels
- Activate signal transduction pathways to give selective advantage to cell
What are the 7 hallmarks of cancer?
- Dysregulated growth
- Evasion of apoptosis
- Limitless replication
- Sustained angiogenesis
- Genome instability
- Invasion/metastasis
Define polyclonal, somatic, germline, driver, passenger
Polyclonal: one tumour may have different genomes
Somatic: sporadic, non inherited 99%
Germline: 1% inherited germline component - risk will be high not always 100% because inherits hit 1 but not 100% sure will acquire hit 2
Driver: turns it from normal to malignant cell
Passenger: mutation that does not provide growth advantages
Explain the two- hit Hypothesis:
Both TSG alleles must be mutated to have a selective advantage
Hit 1: mutation (reduces level but still have 50% of functional gene)
Hit 2: gross change removing other allele (often a larger deletion causing total transcriptional loss)
- Some TSG only require 1 allele inactivation - Mutations in other genes accumulate as disease progresses
Define loss of heterozygosity (LOH)
- Alleles originally heterozygous will be removed so only 1 allele remains and appears homozygous
What is the function of a tumor suppressor?
- causes faulty cell division
- act as G1/S checkpoint, or mediate DNA replication themselves
- If cell damaged tells cell to die or go into DNA repair pathways
- promote cell growth and proliferation e.g GFs, TFs
- TSG inactivation causes uncontrolled cell division, mutations
What is the function a (Proto)Oncogene?
- Usually in signaling cascades or mitogenic pathways
- No gene inherently oncogene
- activated oncogenes over ride apoptosis and divide and proliferate when they shouldn’t
How do translocations cause cancer?
- parts of different Chr reciprocal swap causing 2 new Chr with abnormal morphology
- If genes at breakpoint then a new gene may be formed at a new junction made up of 2 halves of different Chr
- New protein may have oncogenic properties
How is Cytogenetic analysis used in cancer diagnosis?
observation morphology and number of Chr in metaphase
When is it used and why?
- Used more in Hematological malignancies (leukemia, lymphome) because
1. Leuk. Genomes more stable than those of solid tumours
2. Relatively easy to perform cytogenetics on hametopeic circulating cells
How are patients managed?
- Check family history (manchester criteria)
- If postitive offer screening
- If positive offer surveilance
- Prophylactic surgery
- Chemoprevention
What is the genetic cause of Chronic Myeloid Leukemia?
- Chr 9 and Chr 22 translocation
- Following splicing BCR-ABL1 mRNA formed –>BCR-ABL1 protein tyrosine kinase–>CML
What does this result in?
Genetic change in hematological stem cells causes overproduction of granulocytes
How is CML treated?
Imatinib (Glivec): targeted CML moleular therapy inhibiting defective protein
- Blocks ATP binding site of protein –>inactivates–>death
- Some (20-30%) develop imatinib resistance but a second TK inhibitor is there so you need to monitor disease
What are ways to monitor CML progression?
- Cytogenetics: look at Chr and count cells positive for abnormality
- Fluorescence in situ hybridisation (FISH) apply probes to genes at break point, look at colour fusion
- Higher resolution
- Reverse transcriptase quantative PCR: measure amout of gene transcript in peripheral blood and hope not to detect any
- Many patient achieve this after 18-24 months
Why is Acute Promyelocytic Leukemia caused?
- balanced Chr translocation causing PLMRARA –> abnormal accumulation of immature granulocytes (promyelocytes)
- Transfer of RARA (recpetor binding to Vit A then DNA), regulates transcription of many genes, if mutated binds DNA ist regulating too strongly and so silences genes so cells proliferate) on Chr 17 and PML on Chr 15
How is APL treated?
- all trans retinoic acid: Vit A derivitive,
- Greater DNA affinity so abnormal protein dissociates from DNA and no longer silenced
- Doesn’t kill cells, they have to take ATRA all their lives because the leukemia cells remain
What is pharmogenics and it’s role?
- Deals with influence of genetic variation and genetic change to drug response
- In cancer treatment identify patients which are likley to respond to which drug based on presnece or absence of a somatic muation
What type of gene is associated with BRCA and hereditary nonpolyposis colon cancer?
DNA repair
