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GTS 368 > Cancer Genetics And Genomics > Flashcards

Cancer Genetics And Genomics Flashcards

1
Q

What are the reasons for the emergence of a clone of cells:

A
  1. The cancer cells are Freed of programmed constraints. Meaning there is a disruption of orderly and regulated cycle of cell replication and division.
  2. The cancer cells are capable of inappropriate proliferation meaning that cancer cells duplicate and divide more frequently than neighbouring cells.
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2
Q

Major classes of cancer genes that are positive regulators.

A
  1. Activation of Classic oncogenes leads to cell proliferation
  2. Activation of telomerase leads to cell proliferation
  3. Inhibition of anti-apoptotic genes leads to the inhibition of cell death
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3
Q

Major classes of cancer genes that are negative regulators.

A
  1. Inhibition of classic tumour suppressor genes leads to cell proliferation.
  2. Inhibition of indirectly acting tumour suppressor genes leads to cell proliferation
  3. Activation of apoptotic genes leads to cell death
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4
Q

What are they ten hallmarks of cancer ?

A
  1. Self sufficiency in growth signaling
  2. Insensitivity to signal suppressing growth
  3. Ability to avoid apoptosis
  4. Replication immortality
  5. Genome instability
  6. Induction of angiogenesis
  7. Tissue invasion ant metastasis
  8. Ability to avoid immune destruction
    9 induction of tumour-promoting inflammation
    10 reprogramming energy metabolism
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5
Q

If the mutation rate in cells is so small how is cancer possible?

A
  1. Given typical mutation rates of 10^-6 per gene per cell, the chance of any cell subsequentially acquiring ten specific mutations = 10^-60 which is a very small probability.
    Only way is if mutations early in process greatly increase the probability of later mutations.
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6
Q

What are the two ways in which the cancer cells can overcome the bodies defence mechanisms.

A
  1. Mutations can enhance cell proliferation.
  2. Mutations can increase general mutation rate by destabilising the genome.
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7
Q

Explain how mutations can enhance cell proliferation.

A

If mutant cell can generate 1000 mutant daughter cells.
Chance that one mutant cell can acquire next mutation is increased 1000-fold

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8
Q

What are the two ways in which cancer cells show genomic instability:

A
  1. Chromosomal instability
    2 micro satellite instability
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9
Q

What role do driver mutations play in cancer.

A

They confer growth advantage and are positively selected, any mutation not a driver mutation is a passenger mutation.

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10
Q

Define driver mutation

A

Somatic mutation that arise de novo in cancer cells.

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11
Q

What are proto-oncogenes.

A

Are components of signalling pathways that regulate (drive) normal/ healthy proliferation and differentiation,

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12
Q

What are the six broad categories of proto-oncogene.

A
  1. Growth factors
  2. Cell surface receptors proteins
  3. Cytoplasmic signal transducer proteins
  4. Nuclear proteins (transcription factors)
  5. Components of the network that govern progress through cell cycle. (Cyclins, CDK, telomerase)
  6. Anti-apoptotic proteins
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13
Q

How is a proto-oncogene made oncogenic.

A
  1. Point mutations can cause hyperactive proteins that are transcribed in Normal cells. Example: RAS gene in bladder cancer.
  2. Amplification this causes the over production/ transcription of normally functioning proteins. Example: N-Myc in neuroblastoma
  3. Chromosome translocation
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14
Q

Explain what chromosome translocation that cause up regulation of expression result in?

A

There is a overproduction of normal proteins .
Example Burkitt lymphoma -cMYC at 8q24

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15
Q

How do cancer cells reduce adhesion.

A
  1. They weaken adhesion receptors
  2. They release reactive oxygen species to damage the blood vessels.
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16
Q

Explain what chromosome translocation that cause rearrangement of gene?

A
  1. Cause fusion of proteins that become hyperactive in the cell.
  2. common in haematological tumours and sarcomas
  3. rare in carcinomas
    Example is t(9,22) in CML gene
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17
Q

Passenger mutations

A

Mutations that occur after tumour has formed. They are named passenger mutations because although they did not cause the start of the tumour they are responsible for keeping the tumour growing.

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18
Q

How does heterogeneity within a tumour.

A
  1. Tumour is capable of recruiting surrounding cells, to help it grow.
  2. Passenger mutations.
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19
Q

Mutations are somatic - Four exceptions (do not under go gain of function but loss of function)

A
  1. MET – Hereditary papillary renal carcinoma
  2. RET – Multiple endocrine neoplasia
  3. KIT – Gastrointestinal stromal tumour syndrome
  4. CDK4 – Malignant melanoma
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20
Q

Inherited susceptibility to cancer is linked to what genes?

A

Some cancers clearly show a Mendelian mode of inheritance because they arise due to mutations in tumour suppressor genes. These are recessive cancer susceptibility genes.

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21
Q

Explain the difference between hereditary and sporadic retinoblastoma according to the two-hit model.

A

In both cases cancer is caused when there is a mutation in both alleles at a loci. One mutation is not enough to cause cancer.
1. Hereditary retinoblastoma : the first mutation is inherited, second mutation is a somatic mutation.
2. Sporadic retinoblastoma: the first and second mutation are both somatic.

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22
Q

Explain the Knudsons theory (two-hit model) in the light of retinoblastoma.

A

The are two types of retinoblastoma in Children.
Unilateral- tumour develops in one eye
Bilateral- tumour develops in both eye
Looking at age of diagnosis we see.
Unilateral disease that later develop bilateral disease at a younger age indicates a inherited mutation.
Unilateral disease that did not develop second cancer at older ages indicates random somatic mutation.

23
Q

Characterise Hereditary cancer ( inherited mutation)

A
  1. Multiple tumours
  2. Bilateral
  3. Early onset
24
Q

Sporadic cancer ( random somatic mutation)

A
  1. Single tumour
  2. Unilateral
  3. Later onset
25
Q

Why is retinoblastoma a recessive trait, but inheritance of retinoblastoma susceptibility is dominant.

A
  1. Because the risk of developing the second mutation is very high.
  2. probability that one will get the second mutation equals 90-95%.
  3. Thus the average age at diagnosis: newborn to 12 months
26
Q

Explain the mechanisms of the 2nd hit and loss of heterozygosity at chromosomal levels.

A
  1. Chromosomal loss: Chromosome containing the normal allele/gene is lost leaving only the mutated gene.
  2. Chromosome loss and republication: Chromosome containing the normal allele/gene is lost and in its place the chromosome containing the mutant allele/ gene is duplicated, resulting in 2 mutant genes(cancer)
  3. Mitotic recombination: normal allele/gene is recombined with a mutant allele/ gene resulting in 2 mutant genes (cancer)
27
Q

Explain the mechanisms of the 2nd hit and loss of heterozygosity at level of gene/gene region?

A
  1. Gene inactivation:
  2. Epigenetic silencing:The Normal allele/ gene is silenced Epigenetically (methylation, deacetylation)
28
Q

Function of tumour suppressor genes.

A

General property is to Block uncontrolled cellular proliferation.by…
1. Participating in pathway that regulate cell cycle
2. Regulating upstream growth signalling pathway
3. May induce apoptosis

29
Q

What are the two classes of tumour suppressor genes.

A
  1. Gatekeepers: They play a central role in regulation of cellular proliferation which means that mutations lead directly to development of tumours .
  2. Caretakers : play a more global role, maintaining genome integrity thus mutation does not lead directly to tumours. Instead tumours arise because of genome instability leading to mutations in other genes.
30
Q

What are some gatekeeper tumour suppressor genes and their associated autosomal dominant cancer syndrome .

A
  1. Rb-gene: retinoblastoma
  2. TP53: Li-Fraumeni syndrome
  3. APC -gene: Familial adenomatous polyposis.
31
Q

Characterise the Li-Fraumeni syndrome/SBLA syndrome.

A
  1. Rare “cancer families” striking history of:
  2. 1 Sarcomas
    1.2 Adrenocortical carcinoma
    1.3. Brest cancer
    1.4 Leukaemia
  3. Germ line mutations in TP53 gene that code for DNA binding protein which are important component of cellular response to DNA damage.
32
Q

Characterise Familial adenomatous polyposis. (FAP)

A
  1. Thousands of polyploids? From childhood.
  2. Inevitable progress to tumours - 100% penetrants
  3. Average age at diagnosis 40yrs
  4. Caused by mutations in APC.
33
Q

Function of APC gene

A

APC induces phosphorylation and degradation of unbound Beta-catenin = keeping free Beta-catenin levels low.

34
Q

What is p53

A

A TF that is induced under condition of cellular damage, that activates genes responsible for inhibiting cellular growth during repair and also as an inhibitor of cyclin dependent kinases.

35
Q

How does p53 regulate gene expression

A
  1. P53 stimulates the transcription of growth interfering genes (GIG) that inhibiting growth.
  2. Inhibit the expression of growth stimulating genes (GSG) whose protein products stimulating growth.
36
Q

How does p53 affect growth stimulating genes directly?

A
  1. Preventing an activator (A) to bind to its binding sites.
  2. Enhancing a tightly packed chromatin structure.
  3. Directly interacting with the activator preventing it to bind DNA.
37
Q

Example of caretaker tumour suppressor genes.

A
  1. Familial Brest cancer: BRACA1 and BRACA 2 genes
  2. Lynch syndrome (HNPPC : MLH1 and MSH2
38
Q

Function of BRACA proteins

A
  1. Nuclear proteins which form multi-protein complex
  2. Cellular response to DNA double strand break due to normal homologous recombination or as results of damage to DNA
39
Q

What are the two types of Lynch syndrome - two types

A
  1. Type 1- colon specific cancer
  2. Type 2 colorectal cancer and extra-colonic cancer
40
Q

Characterise Type 1, lynch syndrome

A
  1. Colon specific cancer
  2. Males - 90% lifetime risk
  3. Females - 70% lifetime risk
41
Q

Characterise type 2 lynch syndrome

A
  1. colorectal cancer and extra-colonic cancer
  2. Endometrial cancer (women -40% risk)
  3. Upper gastrointestinal system (10-20% risk) this includes biliary ducts and pancreas)
  4. Ovarian cancer [10% risk]
42
Q

What goes wrong in the DNA to cause Lynch syndrome (HNPCC)

A
  1. Caused by mutations in mismatch repair genes (MMR)
  2. MMR- genes maintain fidelity of DNA replication by correcting incorrectly paired bases, or insertion/ deletion loops in DNA because strand slippage is not repaired.
43
Q

Function of hMutS-alpha

A
  1. Recognises base-base mismatches and single nucleotide insertion/ deletion.
    Subunits: MSH2 and MSH6
44
Q

Function of hMutS-beta

A

Recognises short insertion /deletions caused by replication slippage.
Subunit: MSH2 and MSH3

45
Q

Function of hMutL-alpha

A
  1. Forms complex with hMutS and DNA, contributes sPSM2 Endonuclease to malate nick.
  2. Subunit: ,MLH1 and PMS2
46
Q

What happens when mismatch repair gene disrupted.

A
  1. Replication errors increase
  2. Results in instability of DNA repeat sequence which manifests as increase or decrease in number of repeats (micro satellites instability (MSI).
  3. Repeat sequences in coding regions also are vulnerable.
47
Q

Stages of colon cancer evolution.

A
  1. Normal colon cell APC muation leads to
  2. Increased proliferation leads to
  3. Adenoma 1 undergoes RAS gene mutation
  4. Adenoma 2 undergoes loss of chromosomal 18 which contains DCC tumour-suppressor gene, which leads to.
  5. Adenoma 3 which undergoes loss of chromosomal 17 which contains DCC tumour-suppressor gene, which leads to.
  6. Carcinoma which can undergo loss of other chromosomes and other mutations leading to metastasis
48
Q

Genetic alterations and progression of colorectal cancer. Progression with age.

A
  1. 30-50 years - APC mutation
  2. 40-60 years - RAS mutation
  3. 50-70 years - PI3K cell cycle/ Apoptosis TGF -Beta
49
Q

Describe inheritance of cancer.

A
  1. Autosomal dominant pattern of inheritance
  2. Majority are associated with loss of function germ-line mutations in tumour suppressor genes.
  3. Four exceptions where gain-of -function germ -line mutations in oncogenes cause familial cancers.
50
Q

Clues to inherited predisposition

A
  1. Common cancer in close blood relatives.
  2. Uncommon cancers in two or more close blood relatives
  3. Early age at diagnosis/ onset
  4. Multifocal/ bilateral origin of tumours.
51
Q

Compare between oncogenes and tumour suppressor genes.

A

Oncogene vs tumour suppressor gene
1. Gene active in tumour vs gene inactive in tumour
2. Specific translocation/ point mutation vs deletion or point mutations
3. Mutations rarely hereditary vs mutations can be inherited
4. Dominant at cell level vs recessive at cell level
5. Broad tissue specificity vs considerable tumour specificity
6. Especially leukaemia and lymphoma vs solid tumour

52
Q

Why do males have a higher susceptibility to lynch type 1 syndrome ?

A
  1. More likely to be heavier smokers
  2. More likely to eat more red meat
  3. Less likely to screen for cancer of genetic mutations
53
Q

mismatch repair for correcting replication errors

A
  1. Replication errors on a newly synthesized strand result in base mismatches that can be recognized by a MutS–MutL complex.
  2. The MutS component works as a clamp that can slide along the DNA, allowing it to scan for a base–base mismatch (MutSα) or unpaired insertion/deletion loop (often MutSβ).
  3. MutLα, which has an endonuclease function, can form a ternary complex with MutS and DNA.
  4. After the newly replicated DNA has been identified (by having a preexisting nick in the DNA), PCNA (proliferating cell nuclear antigen) and RFC (replication factor C) are loaded onto the newly replicated DNA, where they help trigger the endonuclease function of PMS2 to make a new nick close to the replication error.
    5.EXO1 exonuclease is recruited to excise the sequence containing the replication error, making a gapped DNA.
  5. The resulting stretch of single-stranded DNA (stabilized by binding the RPA protein) is used as a template for the resynthesis of the correct sequence using high-fidelity DNA polymeraseδ, followed by sealing with DNA ligaseI.

GTS 368 (7 decks)

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