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Mol & Cell 1 > Cancer > Flashcards

Cancer Flashcards

1
Q

What does dysplastic mean?

A

Abnormal cells

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2
Q

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

A

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

e.g Australia has highest rate of melanoma

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3
Q

Describe the natural experiment on cancer in Hawaii

A

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

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4
Q

What are the 3 environmental influences in causing cancer?

A

Infection
Diet
Noxious agents e.g smoking, sunlight

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5
Q

Describe Peyton Roux 1910 experiment on sarcoma in chickens

A
  • 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
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6
Q

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

A

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

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7
Q

Give an example of a cancer caused by a viral infection

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

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

A

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

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9
Q

Give some examples of noxious substances that cause cancer

A

Smoking
Asbestos
UV light

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10
Q

Give some examples of cancers caused by genetics

A
  • Retinoblastoma
  • Gorlin’s syndrome
  • Breast cancer syndrome
  • Familial adenomatous polyposis coli (FAP)
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11
Q

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

A

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

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12
Q

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

A

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

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13
Q

Give an example of the emergence of an oncogene

A

The fusion of ABL and BCR in CM leukemia

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14
Q

What is an oncogene?

A

a gene that causes cancer by transforming cellular behaviour

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15
Q

What is a proto-onogene?

A

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

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16
Q

What is a protein kinase?

A

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!)

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17
Q

How do oncogenes come about?

A

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

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18
Q

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

A

Hyperactive protein made in normal amounts

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19
Q

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

A

Normal protein greatley overproduced

20
Q

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

A

Normal protein greatly overproduced

21
Q

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

A

Nearby regulatory DNA sequence causes normal protein to be overproduced

22
Q

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

A

Fusion to actively transcribed gene produced hyperactive fusion protein

23
Q

Which gene was identified as the first human oncogene?

A

Ras

24
Q

Describe Ras and its function

A

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

25
Q

Describe how Ras is important in normal cell growth and proliferation

A
  • 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!
26
Q

What are the 3 main targets of Ras?

A

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

27
Q

What is the function of Sos

A

Sos = exchange factor that activates Ras by taking its GDP

28
Q

Why does mutated Ras cause cancer?

A

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

29
Q

What did the cell fusion experiments show about oncogenes?

A
  • When Hybrid of cancer cell and normal cell = normal is dominant
    = Suggests that normal cells express tumour suppressor genes that are lost during oncogenesis
30
Q

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

A

Retinoblastoma tumours

31
Q

Describe what Knudsen noticed about patients with retinoblastomas

A

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

32
Q

Describe Knudsen’s one/two hit hypothesis

A

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

33
Q

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

A

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

34
Q

What did Knudsen’s findings provide evidence for?

A

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

35
Q

Give some examples of tumour supressor genes identified in familial cancers

A

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

36
Q

Compare oncogenes and tumour suppressor genes

A

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

37
Q

Describe the concept of ‘driver’ and ‘passenger’ mutations in causing cancer

A

Driver mutations predispose you to acquiring additional ‘passenger’ mutations (through various mechanisms)

Need 5-8 driver mutations to cause cancer (just 1 innsufficent)

38
Q

Describe clonal expansion

A

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

39
Q

How are cancer cells are genetically unstable?

A

Analysis using FISH and circus plots show they have many translocations

40
Q

Why are cancer cells genetically unstable?

A

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

41
Q

Which gene is essential in responding to cell stresses?

A

p53 - a tumour supressor gene

42
Q

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

A
  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
43
Q

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

A

p53

44
Q

What is p53 an example of?

A

tumour supressor gene: cell cycle checkpoint gene

45
Q

Describe cell cycle checkpoints

A

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

46
Q

Which gene is key to the ‘restriction point’?

A

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

Mol & Cell 1 (27 decks)

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