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PoM - Principles of Medicine Week 3 > Cancer Genetics > Flashcards

Cancer Genetics Flashcards

1
Q

What is cancer?

A

Derived from single cell - acquired characteristics in the genome to divide in uncontrolled manner Invade surrounding tissues Due to changes in DNA sequence These genes are called cancer genes

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2
Q

Is every cancer a genetic disease?

A

Yes - as uncontrollable cell division due to change in DNA sequence / expression of gene

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3
Q

Benign Vs Malignant

A

Benign - well differentiated cells, grows slowly, capsulated, lacks the ability to invade neighboring tissue or metastasise Maligant - poorly differentiated cells, escapes apoptosis, can grow their own blood vessels, can metastasise

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4
Q

What is the multi-step process of carcinogenesis? (Use colon cancer as an example)

A

There are normal epithelial cells

Accumulation of mutations e.g. in oncogenes, tumour suppressor genes, DNA repair genes

e.g. Mutation in APC gene for colon cancer - controls gene stability and transcription factors

Early adenoma - hyper proliferation of cells

New errors during further divisions Intermediate adenoma

Additional mutations causes it to become a carcinoma

Metastasis

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5
Q

What do cancer cells look like under the microscope conpared to normal cells?

A

Large number of dividing cells

Much bigger and strangely shaped nuclei

Can be very big or very small cells

No clear boundary - disorganised arrangement gives the tumours asymmetry

Disorganised / mishapen cell membrane, many pores

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6
Q

What are the 4 types of cancers and where do they get their names?

A

From where they originate:

Carcinoma - epithelial cells, most common type of cancer

Sarcoma - soft tissue and supportissue i.e. bone, muscle, cartilage, connective tissue and muscle

Lymphoma - immune system

Leukemia - derived from immature blood cells

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7
Q

Risk factors that can cause cancer?

A

Environment - chemicals (e.g. from smoking) and radiation (e.g. UV rays)

Exogenous factors - Viruses inserting own genes into host cells

Genetics - alterations in genes making people more susceptible to cancer can be passed down, rare and uncommon

All ultimately lead to abnormal cellular regulation

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8
Q

How can genes be mutated?

A

idk

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9
Q

What are the most common causes of cancer mortality in the UK?

A

Lung cancer (2010) - highest mortlity (usually due to carcinogens e.g. smoking)

Bowel / intestinal cancers

Breast cancers in females / Prostate cancers in males

In young people - lymphomas, leukemias, germ cell tumours etc.

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10
Q

What are the 6 hallmarks of cancer in the 2000s (outdated version)?

A

Cells must acquire certain capabilities to become a cancer cell:

  1. Self sufficient with growth signals to proliferate - cannot proliferate further independently if dependent on growth signals from the outside
  2. Insensitive to cell cycle check points e.g. anti-growth signals
  3. Evade apoptosis - damage to normal cells normally results in apoptosis but mutations in the genes responsible for this can cause them to evade apoptosis
  4. Limitless replicative potential - turn on telomerase
  5. Sustained angiogenesis - building of new blood vessels for adequate blood supply
  6. Invade other tissues and metastasis - inactivate the tumour genes E-cardherine
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11
Q

What are the updated (2011) hallmarks?

A

Avoid immune detection - develop mechanism to avoid destruction by the immune system

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12
Q

How are cancer cells normally destroyed by the immune system?

A

(Look at the diagram)

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13
Q

How do cancer cells evade the immune response?

A

Tumour cells have counteracting receptor to shut down immune response

PD-1 - programmed cell death receptor found on T cells is responsible for the suppression of the T cell activity

Tumours cells have developed to overexpress the ligand (PD-L1) that binds to the PD-1 protein, hence the T cell response is suppressed more greatly, and the immune response is shut down

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14
Q

How have new cancer drugs (immuno-therapy drugs) been developed to counteract the suppression of the immune response?

A

Develop monoclonal antibodies that recognise the PD-1 receptor on T cells, therefore binding to and activating it

The T cells can destroy the tumour cells, very effective therapy, particularly for melanomas

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15
Q

What are the 4 types of mutations that can cause cancer?

A
  1. Somatic
  2. Germline
  3. Passenger
  4. Driver
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16
Q

Differences between germline and somatic mutations?

A

Germline - mutation in the reproductive cells, egg or sperm If this mutated cell is fertilised, it is encorporated into every cell of the offspring (hereditary mutation)

Somatic - acquired or sporadic mutations in body cells arising from mitosis, usually cancers derive from this (90%), and it is not passed onto offspring

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17
Q

How to identify germline mutations in acncer?

A

Look at pattern of cancer passing through families

Do family tree gene mapping

Analyse DNA of affected from pedigree for gene identification

Identify location of the gene mutation - clone it (positional cloning)

Find which nucleotide is different from the normal

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18
Q

What is positional cloning?

A

Clone the region of the DNA/ chromosome that is believed to have the cancer mutation

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19
Q

What are some other types of genetic mutations?

A

Deletions

Duplications

Inversions

Translocations

Single base substitutions (can be silent)

20
Q

What happens if the cancer is caused by a mutation in the DNA repair gene (i.e. what does it do to the other genes)?

A

Can cause other genes to mutate too, as the checking mechanism during cell replication is inactive so more mutations accumulate

Eventually causes chromosomal instability, even sometimes aneuploidy (lose parts or whole chromosomes)

21
Q

How do in vitro studies identify cancer somatic mutations?

A

Absolutely don’t understand AT ALL

22
Q

Explain this chart:

A

1 mega base = 1000 bases

Data given in number of mutations per megabase - by sequencing the cancer, you can see the mutation frequency of cancers - which can vary by thousand folds

23
Q

What derives distinct somatic mutations?

A

Carcinogens e.g. UV radiation - forms covalent bonds between tyrosine and cytosine, crosslinking, which leads to complications

Smoking e.g. in lung cancers like 30%

24
Q

What type of mutation (tranversions) is common for lung cancer patients, especially those who smoke?

A

G to T

25
Q

What is the most common mutation that arises from UV light radiation and why?

A

C to G e.g. especially in carcinomas

Because the UV radiation damages the DNA by leading to the formation of covalent bonds between 2 adjacent pyrimidines (class of nucleotides including C and T)

In the image, the cytosine becomes deaminated to form a T nucleotide, causing a mutation from CT to TT

26
Q

How to understand which of the genes are important for the development of cancer?

A

By defining passenger and driver mutations

27
Q

What is a passenger mutation?

A

Mutations that can be tolerated in the somatic cells (often in heterzygous state) - does not change the behaviour of the cells

28
Q

What is a driver mutation?

A

Mutations that can confer a selective advantage and are found in tumours (usually in the homozygote state)

29
Q

Explain this diagram:

A

Cell life - see the accumulations of different types of mutations, but it is always and only the driver mutations that cause a mutator phenotype (giving the cells the capacity to create a clonal expansion)

30
Q

What is the correlation between the life time risk of developing cancer and how often stem cells divide in that tissue?

A

r=0.8

Strong, positive correlation

31
Q

Are cancers due to ‘bad luck’?

A

No, all cancers are genetic!

Spreading that message is terrible - people may not take to prevention through lifestyle

32
Q

What are proto-oncogenes and oncogenes, and how many mutations are required in these genes to cause cancer?

A

Proto-oncogenes - normal genes responsible for cell dicision / the growth of the cell e.g. code for kinases, growth factors etc.

Oncogenes - mutation in the proto-oncogene causing the function of it to increase, dominant (one allele is sufficient for cancer development)

33
Q

Where can acquired mutations in oncogenes come from?

A

From chromosomal rearrangement, gene duplication, mutationse.g. reciprocal translocation between chromosome 9 and 22 leads to chronic myeloid leukemia

34
Q

How can protein production / protein concentrations increase?

A
  1. Increase of protein expression (through misregulation)
  2. Increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell
  3. Gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
35
Q

What is Ras and how can it cause cancer?

A

Ras proteins function as binary molecular switches that control intracellular signaling networks responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation

KRAS (K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation. When it is mutated, negative signalling is disrupted

36
Q

Can mutations in oncogenes be inherited and what are some examples?

A

Very rarely - mutations in proto-oncogenes are inherited, turning on oncogenes

e.g. inherited mutation in the gene called:

RET –> people often develop an uncommon thyroid cancer

KIT –> hereditary gastrointestinal stromal tumors (GISTs).

MET –> hereditary papillary renal cancer

CDK4 –> malignant melanoma

37
Q

What are tumour supressor genes and how many mutations in these are required to cause cancer?

A

Normal genes that act to break excessive proliferation - regulate cells during cell division and replication

Recessive, often required 2 mutations, one in each of the tumour suppressor genes for the expression that can lead to cancer

1 mutation makes you a susceptible carrier for cancer development

38
Q

What are some examples of cancers caused by mutations in the tumour supressor genes and how do they work?

(Hint: e.g. retinoblastoma, p53)

A

Retinoblastoma - one faulty tumour suppressor gene germline inherited, then other tumour suppressor gene damaged throughout life, which caused the development of cancer

Much less likely to get two hits on the same cell if this condition was not inherited

Gene p53 - important for many functions e.g. DNA repair, inducing apoptosis, transcription, and regulating the cell cycle

Normally p53 found in normal cells in low concentrations as they are bound to other molecules e.g. MDM2. When the cell is damaged, the MDM2 unbinds, kinases phosphorylate the p53, p53 concentration increases so it is able to induce apoptosis

So abnormalities in p53 have been linked to many cancers - some may inherit only one functional copy of the TP53 gene and so most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome

39
Q

Although MDM2 acts to bind to p53 so it is less expressed, and unbinds when p53 needs to induce apoptosis, what type of mutation in MDM2 can also affect apoptosis and lead to cancer?

A

If the MDM2 becomes an oncogene, over-regulation means during cell damage, p53 concentrations may still be too low to induce apoptosis

40
Q

In how many cancers is the p53 gene lost and how does it cause the cancer / make it more aggressive?

A

Over 50% of human cancers (almost 100% in ovarian cancer)

The cancer cells are genetically unstable because they cannot:

  • Stop the cell cycling to allow time for DNA repair
  • Carry out efficient DNA repair
  • Undergo apoptosis
41
Q

Why is DNA repair important?

A

To maintain stability of the genome

42
Q

What are DNA repair genes and what do they do?

What happens to the cell if there is too much DNA damage (what are the 3 options)?

Aand how can damaged / mutated DNA repair genes cause cancer?

A

They code for proteins that correct errors when cells duplicate their DNA prior to cell division

Too much DNA damage means the DNA repair system cannot work efficiently, so the cell has three options:

  • an irreversible state of dormancy
  • cell suicide (apoptosis or programmed cell death)
  • unregulated cell division, which can lead to the formation of a tumor that is cancerous

Mutations in DNA repair genes can lead to failure in repair, therefore mutations can accumulate, and perhaps lead to cancer

43
Q

What are the 2 most common mutated genes in breast cancer?

What is their function?

A

BRCA1 and BRCA2

Both work together (with some other molecules) to form a complex that is involved in DNA repair

44
Q

How can a virus cause cancer? (use an example if it helps)

A

Some viral infections can cause cancer. When the viral DNA mixes with the host cell’s DNA, it can trigger changes in the cell to make it grow and multiply

e.g. HPV which causes genital warts - responsible for 99.7% of cervical cancers

Hence girls are now given the HPV vaccine

45
Q

Can bacteria cause cancer?

A

It is currently unknown, there have been associations with bacteria and development of cancer, but the mechanism is unknown (still being researched)

e.g. Helicobacter pylori, which can cause stomach ulcers, has been linked to increased risk of stomach cancer

46
Q

What is GWAS and why are they useful?

A

Genome wide association studies

They can look for specific genes associated with cancer, comparing the frequency of the mutation against the risk of devloping cancer

PoM - Principles of Medicine Week 3 (9 decks)

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