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Principles > Genetics at Work in Cancer > Flashcards

Genetics at Work in Cancer Flashcards

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1
Q

What is cancer?

A

Cancer is a genetic disease at the somatic cell level.
Uncontrolled growth, invasive, capacity to metastasise.
Common (1/3 people will experience cancer in their life time).
Cancer is a genetic disease.

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2
Q

What is cancer mostly caused by?

A

Cancer is a disease of mosaicism largely caused by post-zygotic mutations.

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3
Q

What are germline mutations?

A

Germline mutations are mutations that occur within the gametes.

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4
Q

What are somatic mutations?

A

Somatic mutations are mutations that occur in the embryo or the human.

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5
Q

What is the multistep process of cancer?

A

Normal cell - Cell with growth advantage due to mutation - Clonal expansion - Some cells gain further mutations - Tumour progression

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6
Q

In what way are cancers are heterogeneous?

A 
Grows new blood vessel
Evades apoptosis
Ability to metastasise
Hypoxia resistant
Drug resistant
Difference between cancer cell lines in the lab and clinical cancer tissue >500 genes have been implicated in cancer.
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7
Q

What are driver mutations?

A

Driver mutations are mutations that drive carcinogenesis.

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8
Q

What are passenger mutations?

A

Passenger mutations are incidental mutations that happen because the tumour is unstable.

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9
Q

You can sequence a cancer to find mutations. What are the two different types of mutations?

A

Driver mutations

Passenger mutations

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10
Q

What makes a cancer cell a cancer cell?

A

Genetic mutations are what makes a cell cancerous.

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11
Q

Gene expression is not just about DNA sequence. What are epigenetics and what are two examples of this?

A

Epigenetics is the study of changes in gene expression without a change in DNA sequence.

  • DNA methylation
  • Interaction with histone proteins
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12
Q

How is DNA wound into chromosomes?

A
  • At the simplest level, chromatin is a double-stranded helical structure of DNA.
  • DNA is complexed with histones to form nucleosomes.
  • Each nucleosome consists of 8 histone proteins around which the DNA wraps 1.65 times.
  • A chromatosome consists of a nucleosome plus the H1 histone.
  • The nucleosomes fold up to produce a 30nm fiber.
  • That forms loops averaging 300nm in length.
    The 300nm fibers are compressed and folded to produce a 250nm wide fiber.
  • Tight coiling of the 250nm fiber produces the chromatid of a chromosome.
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13
Q

Where does methylation usually occur?

A

Methylation usually occurs on cytosine bases just before guanine bases.
ATCAGCC(Me)GTAC(Me)GTGATGAT
Methyl group on the c5 position of cytosine residues. Methyl groups are transferred from S-adenyl methionine by DNA methyltransferates.

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14
Q

What does methylation prevent and how?

A

Transcription.

When Methylated is present, it binds to the promoter, preventing transcription.

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15
Q

What does DNA methylation lead to?

A

DNA methylation leads to modification of histones (including re-acetylation) this repressed transcription.

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16
Q

What compound does cytosine become once it has undergone methylation. And then after what does that compound become when it has undergone deamination?

A

Cytosine undergoes methylation and becomes 5-methyl cytosine.
Once 5-methyl cytosine undergoes deamination, it becomes thymine.

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17
Q

Methylation occurs in carcinogenesis. What are some examples of this?

A

Global hypomethylation occurs in many tumour groups.
DNA hypermethylation occurs in some tumour suppressor gens e.g. BRCA and DNA repair genes e.g. MGMT.
Chronic exposure of tobacco-driven carcinogens to bronchial epithelial cells drives hypermethylation of several TS genes.
Methylation patterns begin to be formed as a fetus-environmental influence during pregnancy - starvation during pregnancy affects the fetus.

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18
Q

What is the definition of carcinogenesis?

A

The initiation of cancer formation.

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19
Q

Driver mutations can be split into 2 classes. What are the two methods of regulation of cell number and what are some examples of each?

A
  • Tumour suppressor e.g. p53, retinoblastoma

- Oncogenes e.g. RAS, MYC (activated by mutation or LOH).

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20
Q

Do normal growth-control intracellular pathways have controls?

A

Normal growth-control intracellular pathways have a number of controls.

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21
Q

Due to genetic mutation, cancer cells may do what differently compared to normal cells?

A

Due to genetic mutation cancer cells may:

  • Produce their own extracellular growth factors
  • Overexpress growth factor receptors
  • Have constitutionally active proteins that do not require phosphorylation.
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22
Q

How are oncogenes activated compared to normal cells?

A

Normal cells rely on positive growth signals from other cells.
Oncogenes are activated from protooncogenes due to dominant gain of function mutations.
Activated by point mutation, translocation or gene amplification.

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23
Q

What three methods cause an oncogene to be activated?

A

A proto-oncogene can:
Have a new promotor
Amplification
Point mutation
A proto-oncogene that has a new promotor or undergoes amplification produces excess amounts of normal protein.
A proto-oncogene that undergoes a point mutation produces a hyperactive protein.
Due to gain of function, mutations over produce, or produce abnormally functioning proteins.

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24
Q

What does the B-RAF oncogene code for and how does the point mutation affect it’s function.

A

BRAF codes for a Raf Kinase protein involved in signal transduction in the MAP-K pathway.
Point mutation removes the need for phosphorylation so the signal is always switched on.

25
Q

What is Vemurafenib?

A

Vemurafenib is a specific tyrosine kinase inhibitor for BRAF and so prevents the increased growth and proliferation.

26
Q

What is the process of FISH (Fluorescence in Situ Hybridization)?

A

A specific sequence of DNA called probe DNA is labelled with fluorescent dye.
Causing it to be denatured and hybridized. It can then be identified on chromosomes.

27
Q

What is the role of Trastuzumab (Herceptin)?

A

HER2 amplification results in too many HER2 receptors, resulting in an increased signal for proliferation.
The Herceptin molecule binds to two receptors, blocking them, preventing signalling for cellular proliferation.

28
Q

What can the translocation of Philadelphia chromosome cause and what does the Philadelphia chromosome have to do with chronic myelogenous leukaemia (CML)?

A

Translocation between chromosome 9 and 22, fusing genes BCR-ABL on chromosome 22 producing a hyperactive fusion protein.
Chronic Myelogenous leukaemia (CML) is a blood cancer, characterized by increased proliferation of the granulocytic cell line. 90% are Philadelphia chromosome positive.

29
Q

What is the role of Imatinib and how does it carry this out?

A

First protein kinase inhibitor is developed.
Competitively binds to the mutated structure of BCR-ABL protein, at the ATP binding site, fixing it in a closed non functional state.

30
Q

Why do cancer cells use tumour suppressors to regulate cell growth?

A

Normal cells rely on anti-growth signals to regulate cell growth. Cancer cells become un-responsive to these signals.

31
Q

What are tumour suppressors?

A

Tumour suppressors are genes whose loss results in carcinogenesis.
Tumour suppressor mutations are recessive.

32
Q

What is Retinoblastoma and how does it occur?

A

pRb is a tumour suppressor protein that functions at the G1 checkpoint.
Mutation in the RB gene, located on chromosome 13q results in loss of function of RB and retinoblastoma.
Retinoblastoma occurs in babies an with family history (hereditary), or slightly older children with no family history (sporadic).
(First Tumour suppressor discovered).
(Prevents transition from G1 phase to S phase. Phosphorylation of Rb releases a mitotic factor to allow progression of the cell cycle into S phase).

33
Q

How does a loss of heterozygosity occur through Knudson’s “Two Hit” hypothesis?

A

Mutated tumour suppressor gene.
1st mutation - susceptible carrier..
1/2 has normal cell growth and 1/2 has a 2nd mutation that leads to cancer and so cancer cell growth occurs.

34
Q

What are the different processes that can lead to a loss of heterozygosity?

A

Chromosome loss
Mitotic recombination
Point mutation

35
Q

What is the difference between hereditary and somatic retinoblastoma?

A

1/3 of retinoblastomas are hereditary. Autosomal dominant as one copy is sufficient to increase risk of cancer.
Variable penetrance.
One mutated copy inherited, need to lose one copy.
2/3 of retinoblastomas are somatic.
No family Hx.
Need to lose both copies.

36
Q

Does a retinoblastoma require one mutation or many mutations?

A

A retinoblastoma requires many genetic mutations.

The Rb gene is just one.

37
Q

What are some examples of tumour suppressor genes and what do they cause?

A

RB - Retinoblastoma, bladder, breast and lung carcinomas
APC - Colon/rectum cancer
p53 - Brain, breast, colon, liver, lung carcinomas
BRCA1 - breast and ovarian cancers
BRCA2 - Breast cancers
PTEN - Brain, kidney and lung carcinomas

38
Q

What are tumour suppressors caused by, what type of mutation are they and what do they allow to happen?

A

Normal function suppresses cell division.
Recessive mutation.
Usually caused by deletions or point mutations.

39
Q

What are oncogenes be caused by, what type of mutation are they and what do they allow to happen?

A

Normal function activates cell division, gain of function.
Dominant.
May be caused by point mutations, gene amplification and chromosomal translocation.

40
Q

Why do tumours get so many mutations?

A

Cancers develop genomic instability - the cells gain a high level of mutability. This promotes the evolution of cancers.
The characteristic of a cancer is determined it’s driver mutations, not so much by it’s tissue of origin.
This is termed “Oncogenic Signature”.
Loss of DNA repair and increased mutability is an essential characteristic that allows evolution of cancers.

41
Q

What is the estimated number of mistakes in our DNA every day and why do these not become a problem?

A

Every day we have around 10000 mistakes in our DNA.

DNA repair genes code for proteins which fix DNA.

42
Q

What happens if a DNA strand breaks?

A

BRCA 1, BRCA 2, RAD 51 are recruited to fix it.

43
Q

What happens if UV or chemical crosslinking occurs?

A

Xeroderma pigmentosa is recruited to fix it.

44
Q

What can occur if there are mismatched bases?

A

This is the cause of hereditary colorectal cancer.

45
Q

If bases are mismatched what is recruited to fix it?

A

Mismatch repair complex.

46
Q

What is lynch syndrome?

A

Hereditary form of hereditary cancer due to mutation in the mismatch repair gene MLH1.

47
Q

What is cancer behaviour?

A

A function of somatic mutation.

48
Q

What is cancer risk?

A

A function of constitutional genotype and environment.

49
Q

Is cancer often inherited?

A

Cancer is rarely inherited as a high penetrance mendelian disorder (5-10%).
More usually I is a multifactorial condition.

50
Q

What must form a combination for a person to get a disease?

A

Genetics and Environment.

51
Q

What is the difference in common disease-common variant for mendelian disorders and common disorders?

A

With mendelian disorders, the mutation/ polymorphism frequency is low but the penetrance is high. (e.g. BRCA pathogenic mutation).
With common disorders, the mutation/ polymorphism frequency is high but the penetrance is low. (E.g. multifactorial mutation)
(Aim of genetic counselling is to estimate risk by identifying highly penetrant mutations and to estimate cumulative risk o multifactorial mutations.

52
Q

What is the definition of penetrance?

A

Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype).

53
Q

What are the features suggestive of inherited cancer susceptibility?

A

Several first or second degree relatives with cancer.
Several close relatives with related cancers e.g. breast and ovary.
An unusually early age of onset.
Bilateral tumours in paired organs.
Tumours in two organ systems in one individual.

54
Q

What is a positive result in genetic testing?

A

Positive result - the lab found the specific mutation associated they were looking for.

55
Q

What is a negative result in genetic testing?

A

Negative result - the lab did not find the specific mutation - it does not mean the individual will not develop cancer.

56
Q

What is a variant of unknown significance I genetic testing?

A

Variant of unknown significance - a variant has been found, but the lab does not know if this specific variant is associated with cancer - leads to uncertainty in the management of the patient.

57
Q

Does cancer risk have to be assessed by looking at genetic sequence?

A

Cancer risk can be assessed by looking at genetic sequence.

58
Q

What can predisposition to cancer be?

A

Predisposition to cancer can be monogenic or multifactorial and follows the common variant commo disease hypothesis.

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