Cancer

Question 1

What does dysplastic mean?

Answer 1

Abnormal cells

Question 2

What fact demonstrates that cancer is not just a genetic disease?

Answer 2

That there are varying frequencies of different types of cancer across locations

e.g Australia has highest rate of melanoma

Question 3

Describe the natural experiment on cancer in Hawaii

Answer 3

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

Question 4

What are the 3 environmental influences in causing cancer?

Answer 4

Infection
Diet
Noxious agents e.g smoking, sunlight

Question 5

Describe Peyton Roux 1910 experiment on sarcoma in chickens

Answer 5

• 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

Question 6

Describe what was found based on Roux’s 1910 experiment on Sarcoma virus.

Answer 6

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

Question 7

Give an example of a cancer caused by a viral infection

Answer 7

• Nasopharyngeal carcinoma, caused by Epstein-Barr virus
• Cervical carcinoma, caused by human papillomavirus (HPV)
• Kaposi’s sarcoma, caused by human herpesvirus 8 /HIV

Question 8

Give an example of how diet can cause cancer + explain why it does

Answer 8

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

Question 9

Give some examples of noxious substances that cause cancer

Answer 9

Smoking
Asbestos
UV light

Question 10

Give some examples of cancers caused by genetics

Answer 10

• Retinoblastoma
• Gorlin’s syndrome
• Breast cancer syndrome
• Familial adenomatous polyposis coli (FAP)

Question 11

Describe the chromosomal change that causes Chronic Myeloid leukemia (CML)

Answer 11

A chromosomal translocation:
Chromosomes 22 and 9 have swapped regions (can be identified using FISH)

Question 12

Why does the chromosome translocation in CML have such devastating effects?

Answer 12

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

Question 13

Give an example of the emergence of an oncogene

Answer 13

The fusion of ABL and BCR in CM leukemia

Question 14

What is an oncogene?

Answer 14

a gene that causes cancer by transforming cellular behaviour

Question 15

What is a proto-onogene?

Answer 15

a ‘normal’ gene with the potential to cause cancer (they become oncogenes)

Question 16

What is a protein kinase?

Answer 16

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!)

Question 17

How do oncogenes come about?

Answer 17

Arise from genes involved in regulated proliferation (proto-oncogenes)

Question 18

What happens if there’s a deletion/point mutation in the coding sequence of a proto-oncogene?

Answer 18

Hyperactive protein made in normal amounts

Question 19

What happens if there’s a regulatory mutation in the proto-ongo gene?

Answer 19

Normal protein greatley overproduced

Question 20

What happens if there’s a gene amplification of a proto-oncogene?

Answer 20

Normal protein greatly overproduced

Question 21

What happens if there’s a chromosome rearrangement next to a proto-oncogene?

Answer 21

Nearby regulatory DNA sequence causes normal protein to be overproduced

Question 22

What happens if there’s chromosomal rearrangement into a proto-oncogene?

Answer 22

Fusion to actively transcribed gene produced hyperactive fusion protein

Question 23

Which gene was identified as the first human oncogene?

Answer 23

Ras

Question 24

Describe Ras and its function

Answer 24

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

Question 25

Describe how Ras is important in normal cell growth and proliferation

Answer 25

- 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!

Question 26

What are the 3 main targets of Ras?

Answer 26

PI3K = lipid kinase Raf = protein kinase Ral- GEF = exchange factor

Question 27

What is the function of Sos

Answer 27

Sos = exchange factor that activates Ras by taking its GDP

Question 28

Why does mutated Ras cause cancer?

Answer 28

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

Question 29

What did the cell fusion experiments show about oncogenes?

Answer 29

- When Hybrid of cancer cell and normal cell = normal is dominant = Suggests that normal cells express tumour suppressor genes that are lost during oncogenesis

Question 30

What type of cancer does our understanding of tumour suppressor genes come from?

Answer 30

Retinoblastoma tumours

Question 31

Describe what Knudsen noticed about patients with retinoblastomas

Answer 31

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

Question 32

Describe Knudsen's one/two hit hypothesis

Answer 32

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

Question 33

Why do familial retinoblastomas form in both eyes, but sporadic in only one?

Answer 33

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

Question 34

What did Knudsen's findings provide evidence for?

Answer 34

Provides evidence for tumour suppressor gene hypothesis Evidence for inherited basis of cancer

Question 35

Give some examples of tumour supressor genes identified in familial cancers

Answer 35

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

Question 36

Compare oncogenes and tumour suppressor genes

Answer 36

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

Question 37

Describe the concept of 'driver' and 'passenger' mutations in causing cancer

Answer 37

Driver mutations predispose you to acquiring additional 'passenger' mutations (through various mechanisms) Need 5-8 driver mutations to cause cancer (just 1 innsufficent)

Question 38

Describe clonal expansion

Answer 38

→ Successive rounds of random inherited change and natural selection underpins tumour progression - Demonstrates evolutionary nature of cancer cells = form ‘nastiest’ version

Question 39

How are cancer cells are genetically unstable?

Answer 39

Analysis using FISH and circus plots show they have many translocations

Question 40

Why are cancer cells genetically unstable?

Answer 40

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

Question 41

Which gene is essential in responding to cell stresses?

Answer 41

p53 - a tumour supressor gene

Question 42

Describe how p53 is critical in responding to cell stress e.g DNA damage, hypoxia

Answer 42

1. Cell cycle arrest: proliferation stops to allow cell to deal with stress = checkpoint. If dealt with proliferation continues 2. If stress not dealt with cell will senesce (not proliferate ever again, but not die) 3. If stressor very persistent/ strong = apoptosis

Question 43

Which gene mutation is associated with almost all types of cancer?

Answer 43

p53

Question 44

What is p53 an example of?

Answer 44

tumour supressor gene: cell cycle checkpoint gene

Question 45

Describe cell cycle checkpoints

Answer 45

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

Question 46

Which gene is key to the 'restriction point'?

Answer 46

Rb operates in G1 of the cell cycle, it allows the cell to not proceed into the next phase unless the conditions are favourable