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MCD Genetics > 4 Cancer in Families and Individuals > Flashcards

4 Cancer in Families and Individuals Flashcards

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Biology 101 flashcards
1
Q

Q: What do mutations allow the development of? (6)

A

A: hallmarks of cancer

  • dysregulated growth
  • evasion of apoptosis
  • limitless replication
  • sustained angiogenesis
  • invasion/metastasis
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2
Q

Q: What is angiogenesis?

A

A: new blood vessels form from pre-existing vessels

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3
Q

Q: What causes dysregulated growth? (2)

A

A: autologous progrowth signalling

insensitive to antigrowth signalling

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4
Q

Q: Why is cancer called the master of evolution? (3)

A

A: -cumulative changes

  • cells in tumour are not clones (one tumour is polyclonal)
  • confer a selective advantage to cell but fatal to organism
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5
Q

Q: What are driver mutations? arrive from? Function? In relation to tumour?

A

A: typically somatic mutations, i.e. they arise de novo in cancer cells -> drive the development of cancer are defined as driver mutations. Driver mutations allow cancer to grow and invade the human body

since its in the first cancer cell and every cell in tumour derives from it-> is central mutation of tumour

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6
Q

Q: Why are driver mutations key to the genetic research of cancer? (4)

A

A: -understand how disease develops

  • diagnose more accurately
  • devise targeted therapy
  • monitor response therapy
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7
Q

Q: What are proto oncogenes? Role? 3 examples of proteins?

A

A: proto-oncogene is a normal gene that could become an oncogene due to mutations or increased expression.

Proto-oncogenes code for proteins that help to regulate cell growth and differentiation

  • growth factors
  • transcription factors
  • tyrosine kinases
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8
Q

Q: What are tumour suppressor genes? How can they lead to cancer?

A

A: normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer

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9
Q

Q: Explain knudson’s two-hit hypothesis.

A

A: -most tumour suppressor genes require damage to both alleles

  • hit 1 reduces transcript/protein level but is insufficient to cause phenotypic effect
  • requires inactivation of second allele (hit 2) causing total loss of transcription -> malignant potential
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10
Q

Q: What is a retinoblastoma protein (pRB)? Function? Damage?

A

A: tumor suppressor protein

One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide

  • normally is a red light protein that binds to a green light protein: E2F
  • stops progression of cell cycle
  • until releases E2F-> goes into S phase and continues

means can’t halt cell division and it will go ahead unplanned

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11
Q

Q: What is familial RB? Sporadic?

A

A: child is born with one RB mutation (hit 1) -> acquires second somatic mutation (hit 2)

acquire one somatic mutation (hit 1) -> get hit 2= second somatic mutation in same cell

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12
Q

Q: What is loss of heterogeneity?

A

A: -normal sequencing= have 2 different bases at one point (eg AG)

  • heterozygous SNP-> one chromosome has A and one has G
  • can get lots of SNPs in genome -> causes genetic variety (can lose whole sections as part of a mutation-> one hit)

one allele is lost, leading to part of the genome appearing homozygous in the tumour where heterozygous in matching normal DNA

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13
Q

Q: What are oncogenes? Role in cancer?

A

A: no gene is inherently one

-activated oncogenes ‘override’ apoptosis -> damaged cells survive and proliferate

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14
Q

Q: Inherited cancer syndromes are?

A

A: rare but important

risk of cancer from them = high but not 100%

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15
Q

Q: What causes an inherited predisposition to breast and cervical cancer? (3)

A

A: -BRCA1 and 2 (2-4% of breast cancers are caused by germline mutations in them)

  • age above 90 (60% risk)
  • BRCA2 - predispose breast cancer in men
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16
Q

Q: What are BRCA mutations in? Role? Why are they susceptible to mutation?

A

A: -tumour suppressor genes

  • gene repair, homologous recombination (takes out wrong bits and inserts correct
  • very large (lots of room for it)
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17
Q

Q: What causes an inherited predisposition to colorectal cancer? (2)

A

A: -FAP familial adenomatous polyposis (<1% of all cases but virtually 100% lifetime risk of cancer)
-HNPCC lynch syndrome (3% of all cases and life… 80% and not just colorectal)

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18
Q

Q: What are polyps? What can happen to them?

A

A: abnormal growth of tissue projecting from a mucous membrane

can become cancerous

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19
Q

Q: Which genes are affected in HNPCC?

A

A: DNA mismatch repair genes (when point mutation is present= cut it out and replace)

20
Q

Q: What does patient management for inherited cancer syndromes involve? (5)

A

A: -first need positive family history-> genetic screening and counselling
-if positive-> surveillance, chemoprevention, preventative measures in other family members possibly,

21
Q

Q: What percentage of breast cancer cases have no family history? Explore?

A

A: around 80, could be polygenic

can explore this possibility with GWAS

22
Q

Q: Why are some rare variants called mutations?

A

A: variance occurs in <1% of pop

23
Q

Q: How can GWAS be used to investigate the polygenic possibility cancer? (hows it conducted?) (3) Effect?

A

A: -SNP fishing for SNPs near area of interest
-large cohort studied
-identifies possible candidate genes/genomic regions
often very small individual effect

24
Q

Q: How can transciptome analysis be used to investigate the polygenic possibility cancer? (hows it conducted?) Useful when? Can’t?

A

A: -compares expression prfile of malignant vs normal tissues

  • large patient cohort studied
  • identifies possible candidate genes

when finding dysregulated pathways

can’t determine whether upregulation of that gene causes it to become malignant or vice versa

25
Q

Q: Use the KLK14 gene as an example of transcriptome analysis.

A

A: -upregulated in malignant breast tissue

-found 2 alleles in general population -> one drives higher activity of KLK14 gene

26
Q

Q: What do most cancers have? (2) Can be? 4 examples?

A

A: cytogenic changes (visible changes in chromosome structure and number) as well as molecular mutations.

These can be causal (driver) or accumulate during disease progression.

Aneuploidy, Translocation, Macrodeletion and Macroduplication

27
Q

Q: How do translocations cause cancer?

A

A: Translocation - parts of different chromosomes undergo a reciprocal swap.

The translocation gives rise to two new chromosomes with abnormal morphology.

If there were genes at the breakpoint of the chromosomes, then the point at which the new junction is formed, a new gene may be formed made up of half of the gene of chromosome 20 and half of the gene of chromosome 4.

So this leads to the production of a new protein which could potentially have oncogenic properties.

28
Q

Q: What is Chronic Myeloid Leukaemia? Who’s mainly affected? Symptoms? (5)

A

A: -typical example of a leukaemia with a chromosome translocation (of haematological stem cells)
-Clonal myeloproliferative disorder -> overproduction of mature form of the blood cells - granulocytes

middle age and elderly

  • typical anaemia (no RBC)
  • fatigue
  • shortness of breath
  • no platelets-> easy bleeding from ears and nose
  • no WBC, susceptible to infection
29
Q

Q: What are the 3 phases of Chronic Myeloid Leukaemia?

A

A: 1. chronic (benign)

  1. accelerated (ominous)
  2. blast crisis (acute leukaemia, invariably fatal)
30
Q

Q: What can cause Chronic Myeloid Leukaemia?

A

A: -ABL is in Chr 9
-BCR is in Chr 22

  • chromosomes break - Chr 9 breaks in the middle of ABL and Chr 22 breaks in the middle of BCR.
  • translocation takes place - there is a fusion between BCR and ABL in the Changed Chromosome 22 to form a new oncogenic fusion.

This recombined Chr 22 is called the Philadelphia Chromosome.

  • Following splicing, the BCR-ABL1 mRNA is formed.
  • The mRNA is translated to produce BCR-ABL1 protein tyrosine kinase - this causes CML.
31
Q

Q: Explain the targeted molecular therapy for CML. Resistance

A

A: Imatinib (Glivec) - INHIBITS BCR-ABL1 TYROSINE KINASE

Imatinib blocks the ATP binding site of tyrosine BCR-ABL1 molecule rendering it inactive which ultimately leads to cell death.

It kills CML cells

32
Q

Q: Why is it important to monitor disease management when CML is treated with Imatinib?

A

A: Some patients may develop resistance to imatinib but there is a second TKI (Tyrosine Kinase Inhibitor) that can replace it

33
Q

Q: What are the different techniques to quantify the level of disease at different levels of treatment?

A

A: Cytogenetics

FISH (Fluorescence in situ Hybridisation) : more sensitive

RT-qPCR (Reverse Transcriptase Quantitative PCR) : most sensitive

34
Q

Q: What is cytogenetics? When can it be used? Downside? (2)

A

A: technique to quantify the level of disease

look at the chromosomes themselves and count the number of cells with the chromosomal abnormality which is characteristic of CML.

only be used in the first 6-12 months because it has a low resolution. It is laborious.

35
Q

Q: What is FISH (Fluorescence in situ Hybridisation)? Compared to cytogenetics? When can it no longer be used?

A

A: apply fluorescently labelled probes to the genes at the break point. There is a coloured probe for the BCR and a different coloured probe for ABL1. You look for a fusion of the two colours.

This has higher resolution.

When the disease drops to less that 1%, something more sensitive is needed.

36
Q

Q: What is RT-qPCR (Reverse Transcriptase Quantitative PCR)? When can it be used?

A

A: measure of the amount of gene transcript of BCR-ABL1 in peripheral blood. You hope not to detect any transcript whatsoever - many patients achieve this after 18-24 months.

37
Q

Q: Why quantify residual disease in CML with cytogenetics and a molecular response? Therapy change? What is predictive of survival? Change treatment?

A

A: Cytogenetic and molecular response within 3-12 months accurately defines long-term response to TKI and helps guide clinical management.

Absence of cytogenetic response by 12 months or >10% RT-qPCR at 3 month = CHANGE OF THERAPY

Degree of response over time is predictive of survival

If the disease level doesn’t drop very quickly then they may need to change treatment.

38
Q

Q: What is AML? Compared to CML? Cause? Divided?

A

A: -Acute Promyelocytic Leukaemia (APML)
-Potentially presents more aggressively than CML.
-by a balanced chromosome translocation.
=> abnormal accumulation of immature granulocytes called promyelocytes

-divided into FAB M0-7

39
Q

Q: What causes AML?

A

A: fusion gene

chromosome translocation involves the Retinoic Acid Receptor Alpha (RARA) gene on Chromosome 17 and the Promyelocytic Leukaemia (PML) gene on Chromosome 15. (t(15;17)(q22;q12))

40
Q

Q: What is FAB M3?

A

A: medical emergency - DIC and haemorrhage (acute promylelocytic form)

41
Q

Q: What is FAB M5?

A

A: gum infiltration and or minus lymphadenopathy large nodes), hepatomegaly (large liver), splenomegaly (large spleen)

42
Q

Q: What is RAR alpha? What does it do?

A

A: -form of nuclear receptor bound by reinoic acid

  • regulator of gene transcription
  • PML-RARalpha (abnormal oncogene fusion) protein binds too strongly to DNA

If the protein is a different shape (i.e. when part of the PML gene is with it) it acts in a different way - it binds to the DNA it is supposed to be regulating too strongly and these genes become silenced. The cell proliferate.

43
Q

Q: What’s the treatment of AML? Length? Monitoring

A

A: Simple Treatment - All Trans Retinoic Acid (ATRA) - dissociates co repressors allowing normal transcription

It is not chemotherapy - it does not kill cells. APML sufferers have to take ATRA all their lives. Residual leukaemic cells do remain.

monitored like CML with Cytogenetics and/or FISH and/or RT-qPCR

44
Q

Q: Match the translocation to the gene product and cancer (fusion transcripts).

t(8;14) t(9;22) t(15;17) t(11;22)

RARA-PML, BCR-ABL, FLI1-EWS, cMYC-IgH

Ewings sarcoma, burkitts lymphoma, APML, philadelphia (CML)

A

A: 8;14 and cMYC-IgH and burkitts lymphoma

9;22 and BCR-ABL and philadelphia, CML

15;17 and RARA-PML and APML

11;22 and FLI1-EWS and Ewings sarcoma

45
Q

Q: What is pharmacogenomics? Uses? (3)

A

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

  • planning chemotherapy
  • identifying which patients are most likely to respond to certain cancer drugs
  • assay presence/absence of particular somatic mutations
46
Q

Q: Describe 3 example of the use of pharmacogenomics in cancer treatment.

A

A: KRAS test with cetuximab for colorectal cancer
-KRAS mutation = less likely to respond

EGFR test with gefitinib for non-small cell lung cancer
-EGFR mutation = greater likelihood of response

BCR-ABL1 “T315I” test with dasatinib for chronic myeloid leukaemia
-BCR-ABL1 mutation = unlikely to respond

MCD Genetics (7 decks)

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