Cancer Flashcards
What does dysplastic mean?
Abnormal cells
What fact demonstrates that cancer is not just a genetic disease?
That there are varying frequencies of different types of cancer across locations
e.g Australia has highest rate of melanoma
Describe the natural experiment on cancer in Hawaii
Context: 2 mass migration events of Japanese pop.s to Hawaii
Results: Hawaiian Japanese people acquire a profile of cancer incidents that resembles the location they live in, and not their ethnic origin
= environment is so important in determining type of cancer
What are the 3 environmental influences in causing cancer?
Infection
Diet
Noxious agents e.g smoking, sunlight
Describe Peyton Roux 1910 experiment on sarcoma in chickens
- He removed sarcoma tissue and broke it up, then injected filtrate into young chicken = eventually developed sarcoma
- We know know the material filtered out of the tumours was a Sarcoma virus
Describe what was found based on Roux’s 1910 experiment on Sarcoma virus.
Sarcoma virus works by expressing a SRC gene = product regulates this pathway
Cancer arises because the virus encodes a hyperactive form of a human tyrosine kinase gene
Give an example of a cancer caused by a viral infection
- Nasopharyngeal carcinoma, caused by Epstein-Barr virus
- Cervical carcinoma, caused by human papillomavirus (HPV)
- Kaposi’s sarcoma, caused by human herpesvirus 8 /HIV
Give an example of how diet can cause cancer + explain why it does
Aspergillus oryzae (koji mould: rice, peanuts) → hepatocellular carcinoma
- This mould generates an aflatoxin = modified by liver and activates it into aflatoxin-2,3-epoxide, this targets guanine in DNA = mutations
Give some examples of noxious substances that cause cancer
Smoking
Asbestos
UV light
Give some examples of cancers caused by genetics
- Retinoblastoma
- Gorlin’s syndrome
- Breast cancer syndrome
- Familial adenomatous polyposis coli (FAP)
Describe the chromosomal change that causes Chronic Myeloid leukemia (CML)
A chromosomal translocation:
Chromosomes 22 and 9 have swapped regions (can be identified using FISH)
Why does the chromosome translocation in CML have such devastating effects?
Causes the fusion of 2 genes:
ABL (9q34) → protein kinase, + regulator of cell growth
+
BCR (22q11)
When ABL is fused to BCR it cannot switch itself off = constant proliferation
Give an example of the emergence of an oncogene
The fusion of ABL and BCR in CM leukemia
What is an oncogene?
a gene that causes cancer by transforming cellular behaviour
What is a proto-onogene?
a ‘normal’ gene with the potential to cause cancer (they become oncogenes)
What is a protein kinase?
Kinases use ATP hydrolysis to introduce a phosphate group to amino group of the target = making it activated/inactivated (depending on the nature of the kinase)
(there are 500 different types!)
How do oncogenes come about?
Arise from genes involved in regulated proliferation (proto-oncogenes)
What happens if there’s a deletion/point mutation in the coding sequence of a proto-oncogene?
Hyperactive protein made in normal amounts
What happens if there’s a regulatory mutation in the proto-ongo gene?
Normal protein greatley overproduced
What happens if there’s a gene amplification of a proto-oncogene?
Normal protein greatly overproduced
What happens if there’s a chromosome rearrangement next to a proto-oncogene?
Nearby regulatory DNA sequence causes normal protein to be overproduced
What happens if there’s chromosomal rearrangement into a proto-oncogene?
Fusion to actively transcribed gene produced hyperactive fusion protein
Which gene was identified as the first human oncogene?
Ras
Describe Ras and its function
Ras is a small GTPase
- When Ras is bound to GTP = On
- When Ras is bound to GDP = Off
(Changes shape depending on which is bound)
When active Ras drives cell growth and proliferation
Describe how Ras is important in normal cell growth and proliferation
- When cells grow and proliferate they secrete growth factors to other cells in the vicinity
- Growth factors bind to tyrosine kinase
- TK phosphorylates itself = active
- That phosphorylation allows Grb2 and Sos to bind
- Sos (exchange factor), scoops out GDP from Ras
= Ras now switched on!
What are the 3 main targets of Ras?
PI3K = lipid kinase
Raf = protein kinase
Ral- GEF = exchange factor
What is the function of Sos
Sos = exchange factor that activates Ras by taking its GDP
Why does mutated Ras cause cancer?
Mutations tend to be in the 12 and 61 residues of the protein
= no longer a GTPase, therefore always on and cannot switch itself off, leading to uncontrolled cell proliferation
What did the cell fusion experiments show about oncogenes?
- When Hybrid of cancer cell and normal cell = normal is dominant
= Suggests that normal cells express tumour suppressor genes that are lost during oncogenesis
What type of cancer does our understanding of tumour suppressor genes come from?
Retinoblastoma tumours
Describe what Knudsen noticed about patients with retinoblastomas
Knudsen noticed in 1600 patients (1914-1984):
- Sporadic retinoblastoma tends to occur in 1 eye
- Familial almost always affects both eyes
- Familial type also prone to getting other types of cancers
Describe Knudsen’s one/two hit hypothesis
Familial retinoblastomas: already inherit one mutant gene, so only need one more ‘hit; to develop a tumour
Sporadic retinoblastomas: do not inherit a mutant gene, so two mutations must occur
Why do familial retinoblastomas form in both eyes, but sporadic in only one?
Familial : all cells have 1 mutant Rb gene = tumours in both eyes
Sporadic: because it’s so rare for 2 events to happen in a sporadic cell = tumour in one eye
What did Knudsen’s findings provide evidence for?
Provides evidence for tumour suppressor gene hypothesis
Evidence for inherited basis of cancer
Give some examples of tumour supressor genes identified in familial cancers
Retinoblastoma → Rb
Li-Fraumeni syndrome → P53
Wilm’s tumour → WT-1
Gorlin’s syndrome → Ptc
Breast cancer syndrome → BRCA-1
Familial adenomatous polyposis coli (FAP) → APC
Compare oncogenes and tumour suppressor genes
Oncogenes:
- Activating
- Gain of function
- Dominant
- 1 mutated allele to effect
- Enhanced function of the protein product
Tumour supressor genes:
- Inactivating
- Loss of function
- Recessive
- 2 alleles needed to effect
- Reduced function of the protein product
Describe the concept of ‘driver’ and ‘passenger’ mutations in causing cancer
Driver mutations predispose you to acquiring additional ‘passenger’ mutations (through various mechanisms)
Need 5-8 driver mutations to cause cancer (just 1 innsufficent)
Describe clonal expansion
→ Successive rounds of random inherited change and natural selection underpins tumour progression
- Demonstrates evolutionary nature of cancer cells = form ‘nastiest’ version
How are cancer cells are genetically unstable?
Analysis using FISH and circus plots show they have many translocations
Why are cancer cells genetically unstable?
Because they have defects in:
- DNA repair pathways (cancer cells accumulate damage instead of repairing / apoptosis if unable to repair)
- Correct mechanisms for DNA replication errors
- Correction mechanisms for DNA segregation errors
Which gene is essential in responding to cell stresses?
p53 - a tumour supressor gene
Describe how p53 is critical in responding to cell stress e.g DNA damage, hypoxia
- Cell cycle arrest: proliferation stops to allow cell to deal with stress = checkpoint. If dealt with proliferation continues
- If stress not dealt with cell will senesce (not proliferate ever again, but not die)
- If stressor very persistent/ strong = apoptosis
Which gene mutation is associated with almost all types of cancer?
p53
What is p53 an example of?
tumour supressor gene: cell cycle checkpoint gene
Describe cell cycle checkpoints
Key periods where cells will enact a program to check whether the genome has replicated properly / in mitosis that chromosome segregation is correct
If these are not correct the cell cycle is stopped
Which gene is key to the ‘restriction point’?
Rb
operates in G1 of the cell cycle, it allows the cell to not proceed into the next phase unless the conditions are favourable
