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My MCD- Genetics > Lecture 4- Cancer > Flashcards

Lecture 4- Cancer Flashcards

1
Q

Why do genetic changes cause cancer?

A

The resulting protein changes activate signal transduction pathways which lead to a selective advantage for the cell

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2
Q

What are the commonly affected pathways in cancer?

A
  • cell cycle
  • proliferation
  • apoptosis
  • adhesion
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3
Q

What are the three different types of point mutations?

A

1) Silent mutations: change in base but the new triplet code, codes for the same aa and you don’t get a change in protein structure
2) Missense mutation: change in codon= different as= different protein structure
3) Nonsense mutation: change in codon which results in STOP codon= truncated protein

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4
Q

What are the functions of tumour suppressor genes?

A
  • regulate cell division
  • DNA damage checkpoints (damage= no division)
  • apoptosis if damaged
  • DNA repair
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5
Q

What are the functions of proto-oncogenes?

A

Promote growth and proliferation

  • growth factors
  • transcription factors
  • tyrosine kinases
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6
Q

Are TSG’s dominant, recessive or co-dominant?

A

Recessive

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7
Q

What are the consequences of a mutated tumour suppressor gene?

A
  • Defective growth-inhibiting protein

- uncontrolled cell division

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8
Q

What is the two hit hypothesis?

A

Need to have two mutated TSG alleles to give cells the selective advantage

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9
Q

What does Hit1 of the two hit hypothesis cause?

A
  • reduced transcript/ protein level

- insufficient to cause a phenotypic effect

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10
Q

What does hit 2 of the two hit hypothesis cause?

A
  • total loss of transcription

- malignant phenotype

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11
Q

What is haploinsufficiency?

A
  • when a single hit causes at least a 50% reduction in the level of transcript/ protein to give the cell a selective advantage
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12
Q

What is the difference between familial and sporadic retinoblastoma?

A

Familial:

  • born with one RB mutation (hit 1)
  • acquire second somatic mutation (hit 2)

Sporadic:

  • Acquire one somatic mutation (hit 1)
  • then have second somatic mutation in the same cell (hit 2)
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13
Q

In a loss of heterozygosity what sort of mutations are the two hits?

A

Hit 1= point mutation on the gene in one of the alleles

Hit 2= large deletion removing the TSG in the other chromosome

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14
Q

What causes inherited cancers?

A

Inheritance of mutation in germline tissue, usually in TSG

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15
Q

In inherited cancer syndromes, the risk of cancer is high but not always 100%. Why?

A

Two hit hypothesis
- hit 1 is inherited
- hit 2 in the second allele has to be acquired to cause a phenotypic change
But people who have the one mutated allele have a higher risk of acquiring the second hit

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16
Q

Germline mutation in Which genes cause an inherited predisposition to breast cancer?
- what is the risk of developing breast cancer and what other type of cancer might it cause?

A

BRCA1 and BRCA2

  • 60% risk developing breast cancer by the age of 90
  • earlier average age of onset
  • increased risk ovarian cancer and breast cancer in men (BRCA2)
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17
Q

What is the function of the BCRA1/2 genes?

A

Involved in DNA repair by a process called homologous recombination

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18
Q 
Name two causes inherited predispositions of cancer.
State their:
- name
- gene they affect
- % risk of cancer
A

FAMILIAL ADENOMATOUS POLYPOSIS (FAM)

  • APC gene (cell division)
  • 100% lifetime risk of cancer

LYNCH SYNDROME (HNPCC)

  • MLH1/2 (DNA repair)
  • 80% risk of colorectal cancer
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19
Q

How would you manage a patient for inherited cancer syndromes?

A

1) check family history
2) If FH is positive- offer genetic screening/ counselling
3) If mutation is positive- surveillance, prophylactic surgery, chemoprevention

20
Q

How can you explore the causes of polygenic cancers?

A

GWAS studies (genome wide association studies)

21
Q

What are cryogenic changes?

A
  • changes in chromosome structure and number
  • can be causal or accumulate
  • translocation, deletion and duplication
22
Q

How can translocations cause cancer?

A
  • two genes fuse

- new chromosome could code for oncogenic proteins

23
Q

What are cytogenetic analyses?

A

The observation of the morphology and number of chromosomes

24
Q

Why are cytogenic analyses mainly used for haematological malignancies?

A

1) Leukaemia genomes are more stable than those of solid tumours- easier to pinpoint pathogenetic change
2) Easier to perform cytogenetics on haematopoeic circulating cells

25
Q

What causes myeloid leukaemias?

A

Malignancy of monocytes and neutrophils

26
Q

What happens in Chronic Myeloid Leukaemia?

A

Overproduction of mature granulocytes

27
Q

What causes Chronic Myeloid Leukaemia?

A

Translocation between Chr 9 and Chr 22 –> BCR -ABL1 gene fusion in the changed Chr 22 which is oncogenic.

28
Q

What is another name for the newly formed Chr 22 in CML?

A

A philadelphia chromosome

29
Q

What is the BCR-ABL1 gene translate to produce?

A

BCR-ABL1 groin tyrosine kinase which causes CML

30
Q

What drugs is administered to people with CML as part of targeted molecular therapy?

A

Imantinib

31
Q

How does Imantinib work?

A
  • Blocks the ATP binding site of tyrosine BCR-ABL1 molecule –> cell death
  • kills CML cells
32
Q

What might be offered to patients who become resistant to Imantinib?

A

Second line Tyrosine Kinase Inhibitor

33
Q

Why is cytogenetics insufficient for monitoring the progress of CML?

A
  • only used in the first 6-12 months
  • low resolution
  • laborious
34
Q

What are the alternate methods of monitoring CML?

A
  • FISH (Fluorescence in situ Hybridisation)

- RT-qPCR ( Reverse Transcriptase quantitative PCR)

35
Q

How does FISH work?

A
  • apply fluorescently labelled probes to the genes at break point
  • coloured probe for BCR and another colour for ABL1
  • look for fusion of colours= CML
36
Q

How does RT- qPCR work?

A
  • measures the amount of gene transcript of BCR-ABL1 in the blood
  • shouldn’t detect any transcript at all
37
Q

When might you need to swap therapy for CML?

A
  • absence of cryogenic response by 12 months
  • > 10% RT-qPCR at 3 months
  • loss of RT-qPCR negativity = relapse imminent= change therapy
38
Q

What is APML?

A

Acute Promyelocytic Leukaemia= abnormal accumulation of immature granulocytes called promyelocytes

39
Q

What causes APML?

A
  • balanced chromosome translocation

- Retinoic Acid Receptor Alpha (RARA gene) on Chr 17 and Promyelocytic Leukaemia (PML) gene on Chr 15 (t(15;17)(q22;q12)

40
Q

What is the normal function of the RARa gene?

A
  • a nuclear receptor which binds to vitamin A and then to DNA and regulates the transcription of multiple genes
41
Q

What happens to the RARa gene when it fuses with the PML gene?

A
  • Change in shape of receptor
  • binds to strongly to DNA
  • Gene is silenced- blocks transcription
  • Cell proliferates
42
Q

What is the treatment for APML?

A

All Trans Retinoic Acid (ATRA) which is a vitamin A derivative

  • doesn’t kill cells
  • APML patients have to take ATRA for the whole of their lives
43
Q

How does ATRA prevent APML?

A
  • ATRA binds to DNA with higher affinity than abnormal RARa
  • RARa dissociates from DNA
  • DNA no longer silenced
44
Q

Name the four cancers caused by translocations

A
  • Burkitt’s Lymphoma
  • Philadelphia, CML (BCR- ABL1)
  • APML (RARa- PML)
  • Ewlings sarcoma
45
Q

What is pharmacogenomics

A

A branch of pharmacology which deals with the influence of genetic variation on drug response

46
Q

Give three examples of pharmacogenomics in use. State the test, drug and type of cancer

A

1) KRAS- etuximab- colorectal cancer (response less likely )
2) EGFR- gefitnib- non-small cell lung cancer (response more likely)
3) BCR-ABL1 T315I - dasatinib- CML (response less likely)

My MCD- Genetics (6 decks)

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