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Flashcards in Genetics 4 Deck (25)
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1
Q

What causes cancer?

A

Altered transcription levels or incorrect gene transcripts

2
Q

What do Tumour Suppressor genes do (TSGs)

A

They regulate cell division by having DNA damage checkpoints.

They may stimulate DNA repair, or apoptosis.

Mutations may cause cells to uncontrollably proliferate

3
Q

What is a proto-oncogene?

A

Opposite of TSG essentially.

Growth and proliferation by stimulating growth factors, transcription factors, tyrosine kinases.

4
Q

What are 2 genetic changes that can give rise to cancer in the cell

A
  1. Point mutations

2. Changes in structure or number of chromosome

5
Q

3 types of point mutation.

A

Silent mutation

Missense mutation

Nonsense mutation

6
Q

Usually (not always), both TSG alleles must be affected to give cells cancer. What is the 2 hit hypothesis?

A

Hit 1 - often point mutation (on Allele A)

Hit 2 - often a gross change (e.g. larger deletion)

Inactivation of both gives total loss of transcription for TSG.

7
Q

What is haploinsufficiency?

A

A single hit causes sufficient reduction in transcript/protein to have a biological effect, which will give the cell a selective advantage (mitosis)

8
Q

Explain loss of heterozygosity.

primitive way of locating cancer genes

A
  1. Hit 1 is a point mutation.
  2. Hit 2 is a large deletion, which removes the TSG part but also removes a lot of other material.
  3. This means that there will have been some originally heterozygous alleles that were removed.
  4. Therefore, only one allele of a previously heterozygous genes will remain and so appears to be homozygous.
9
Q

What can oncogenes do?

A

They can override apoptosis meaning damaged cells survive and proliferate.

They can signal cascades and mitogenic pathways.

10
Q

What percentage of cancers are inherited?

A

1%

11
Q

Why is it that people who have a inherited cancer syndrome their risk of cancer is not 100%

A

Because 1 hit has been done, but another is required.

Not a 100% chance of acquiring second hit.

12
Q

How are 2-4% of all Breast cancers caused?

A

By germline mutations of the BRCA1 and BRCA 2 genes

13
Q

In breast/ovarian cancer, how is the 2nd allele usually inactivated?

A

Somatic deletion

14
Q

Describe the pathogenetic mechanism of BRCA genes.

IMPAIRED DNA REPAIR IS A COMMON THEME IN CANCER

A
  1. BRCA1/2 is there for DNA repair through homologous recombination.
  2. Mutation = non functioning protein.
  3. Non functioning protein = impaired DNA repair, so mistakes go uncorrected.
15
Q

Explain how one can have inherited predisposition to colorectal cancer.

A

FAP (Familial Adenomatous Polyposis)

  • 1000s of intestinal polyps, one/more will become cancerous
  • Mutation of APC gene controlling cell division
  • virtually 100% lifetime risk of cancer

HNPCC (Hereditary Non-Polyposis Colorectal Cancer)

  • 3% of cases
  • Most common inherited form
  • Mutation of MLH1 or MSH2
  • 80% lifetime risk
16
Q

How are patients managed for inherited cancer syndromes?

A
  1. Check family history
  2. If positive family history, offer genetic screening/counselling
  3. If mutation positive, surveillance/prophylactic surgery/chemoprevention
17
Q

How can translocations cause cancer?

A

Translocation is when parts of different chromosomes undergo a reciprocal swap.

Can lead to new “fusion” gene around the breakpoint which could have oncogenic properties.

18
Q

Why is cytogenetic analysis used more in haematological malignancies?

A
  1. Leukaemias are more stable than solid tumours so easier to pinpoint pathogenetic changes
  2. Easier to perform cytogenetics on circulating haematopoietic cells.
19
Q

What is Chromic Myeloid Leukaemia?

A

Haematological stem cells disorder; overproduction of granulocytes (mature blood cells)

Characterised by TRANSLOCATION BETWEEN Chr 9 and Chr 22

20
Q

What does translocation t(9;22) give?

A

BCR-ABL1 gene fusion

ABL (Chr 9), BCR (Chr 22)

Half of both genes broken, and chromosome 22 is changed, which gives an oncogenic fusion (Philadelphia chromosome)

CAUSES Chronic Myeloid Leukaemia as mRNA translated which produces BCR-ABL1 protein tyrosine kinase.

21
Q

Why is imatinib given as targeted molecular therapy for CML?

A

It inhibits BCR-ABL1 tyrosine kinase.

It does this by blocking the ATP binding site of tyrosine BCR-ABL1 , which makes it inactive.

Inactive leads to cell death.

RESISTANCE MAY FORM TO IMATINIB which is why monitoring is key.

22
Q

How can you quantify residual disease in CML?

A
  1. Cytogenics (low resolution)
  2. FISH (Fluorescence in site Hybridisation) - coloured BCR probe and different colour for ABL1
  3. RT-qPCR (high sensitivity for early detection of disease relapse after treatment)
23
Q

Describe Acute Promyelotic Leukaemia.

A
  1. Caused by a balanced chromosome translocation.

Retinoic Acid Receptor Alpha (RARA) gene on Chromosome 17 and Promyelotic Leukaemia gene on Chromosome 15 are TRANSLOCATED.

  1. Abnormal accumulation of immature granulocytes called promyelocytes.
24
Q

Explain APML pathogenesis and treatment.

A
  1. RARA is a receptor which binds to Vit. A then DNA (and regulates transcription of many genes).
  2. When PML translocates. the protein binds to DNA too strongly and silences the genes - causes cell proliferation.

TREATMENT:

  1. Give All Trans Retinoic Acid (ATRA). Vit. A derivative which replaces the RARA-PML protein and binds to DNA (has greater affinity than RARA-PML).
  2. RARA-PML protein dissociates and so gene aint silenced.

IT IS NOT CHEMO, AND APML SUFFERERS HAVE TO TAKE ATRA LIFE LONG.

25
Q

Talk to me bout pharmacogenomics.

A

Branch of pharmacology dealing with influence of genetic variation and genetic change on drug response.

Useful for planning chemotherapy.