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Genetics > Cancer Genetics > Flashcards

Cancer Genetics Flashcards

1
Q

How many mutations does it take for the average cell to transform into a malignancy?

A

3-7 mutations

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2
Q

What are the six hallmarks of cancer?

A
  1. Self-sufficiency in growth signals
  2. Insensitive to antigrowth signals
  3. Evasion of apoptosis
  4. Sustained angiogenesis (for oxygen)
  5. Limitless replication potential
  6. Tissue invasion and metastasis
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3
Q

What is an oncogene vs a proto-oncogene and some basic examples?

A

Proto-oncogene - gene functioning normally for cell growth and survival that can easily mutate and cause problems

Oncogene - mutated form that stimulates uncontrolled cell division and proliferation (gain of function)

i.e. growth factors + receptors, transcription factors, telomerase, anti-apoptosis proteins

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4
Q

What is meant by a qualitative vs quantitative mechanism of oncogene activation?

A

Qualitative - a modified or novel product is produced

Quantitative - increase in the amount of normal product produced

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5
Q

What is KRAS, and how does it relate to qualitative activation of proto-oncogenes?

A

K-RAS - member of intracellular GTP-binding proteins, “on-off” switch active when GTP is bound

Point mutations (insertion/deletion) can cause constitutive activation of KRAS

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6
Q

How can translocations lead to gene fusions + qualitative activation of proto-oncogenes?

A

Precise - 5’ end of fusion gene controls expression (promoter), 3’ end controls the function.

Most commonly a transcription factor controlling expression with a kinase controlling the function

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7
Q

What is the cause of 95% of chronic myelogenous leukemia (CML)?

A

Reciprocal translocation between chromosomes 9 and 22, leading to a chimeric protein with extra tyrosine kinase activity

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8
Q

What are two other rearrangements which can lead to gene fusion and cancer?

A
  1. Inversion - as in non-small cell lung cancer

2. Deletion - as in two exons fusing and increasing Down Syndrome risk of ALL

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9
Q

How can translocation lead to quantitative oncogenesis?

A

Translocating a gene to a more transcriptionally active part of the chromosome, i.e. c-MYC in B-cell lymphoma

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10
Q

What is an example of a promoter mutation leading to quantitative oncogenesis?

A

TERT promoter is mutated in melanoma cases. The TERT gene encodes telomerase. Telomeres lose 35 bp in each division.

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11
Q

What are the two mechanisms of copy number increases which can lead to quantitative oncogenesis?

A
  1. Double minute - very small accessory chromosomes are made with oncogenic gene
  2. Homogenously staining regions - tandem duplications within the chromosome
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12
Q

What is the function of tumor suppressor genes?

A

Regulate progression thru the cell cycle at check points or by promoting apoptosis

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13
Q

What are the three cell cycle checkpoints and what are they looking for?

A
  1. G1/S - is the environment favorable for cell division, and is the DNA not damaged?
  2. G2/M - is replication complete? is the environment still favorable
  3. Metaphase - are all chromosomes attached to the spindle?
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14
Q

What is the normal function of retinoblastoma protein? What will happen if lost?

A

When active, is binds transcription factor E2F (unphosphorylated state). It prevents the transcription of genes needed for S phase - operates at G1/S checkpoint.

Inactivated by phosphorylation.

Loss of RB1 gene prevents cell cycle arrest in response to DNA damage

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15
Q

What gene is one of the most common mutations in cancer? What is the function of that protein?

A

TP53 - encodes p53, which is a transcription factor accumulating in response to DNA damage or stress. Arrests cell at G1/S and G2/M checkpoints if DNA damage is present, and can initiate apoptosis.

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16
Q

What is the two-hit model of Tumor Suppressor Gene inactivation?

A

Requires 2 hits for total gene inactivation

  1. Mutation including missense, nonsense, or insertions / deletions
  2. Another mutatino, or transcriptional silencing of a non-mutated allele
17
Q

In actively transcribed DNA, how does it appear epigenetically?

A

DNA is unmethylated, histones are acetylated

18
Q

What is the mechanism of epigenetic silencing which can lead to the “second hit”?

A

Hypermethylation at CpG via DNA methyltransferase, and de-acetylation of histones, leading to heterochromatin.

19
Q

How can loss of heterozygosity lead to tumor suppressor gene inactivation?

A

Provides the second-hit, losing the nonmutated allele. Mechanisms include:

  1. Chromosome loss
  2. Loss and reduplication
  3. Deletion
  4. Mitotic recombination leading to gene loss in one of daughter cells
  5. Unbalanced translocation
20
Q

What is the function of loss of DNA repair genes in causing cancer?

A

Loss of function in protecting the DNA from normal damage indirectly promotes cancer

21
Q

What bases are frequently deaminated in DNA damage?

A

Cytosines -> uracils

Adenines -> hypoxanthine

22
Q

What is base excision repair vs nucleotide excision repair? What do they both do?

A

Nucleotide repair cleaves out the entire thing, including the phosphate.

They both repair damaged nucleotides with chemical adducts. thymidine dimers are NER only

23
Q

What causes Xeroderma Pigmentosum? What is it?

A

Autosomal recessive condition that causes defects in the nucleotide excision repair pathway, predisposes patient to skin cancer and internal neoplasms

24
Q

What is mismatch repair? What is one syndrome where this is common to cause cancer?

A

Wrong base matching due to strand slippage during DNA replication.

Defective mismatch repair in Lynch syndrome causes colon cancer. Also commonly mutated in sporadic cases.

25
Q

What can cause a double strand break?

A

Errors in replication or recombination, or ionizing radiation

26
Q

What are the two major pathways of double strand break repair?

A
  1. Homologous recombination - homologous chromosome used as a template for DNA that was lost
    i. e. BRCA1/2
  2. Non-homologous end-joining - broken ends are ligated together
27
Q

Why does karyotyping have a high false negative rate?

A

Only 20 cells are analyzed

28
Q

What are the two forms of allele specific PCR? What is this good for?

A
  1. Primers specific for wild type and mutant allele
  2. Primers specific for locus, but probing for mutant allele

Good for detecting point mutations, and small in/dels

29
Q

What is RT-qPCR used for?

A

Quantifying fusion transcript produced by chromosomal translocations (i.e. in chronic myelogenous leukemia)

Also for monitoring residual disease in remission patients (sensitive to 1/100,000 cells)

30
Q

What are the two types of gene expression microarrays and why are they used?

A
  1. Whole genome
  2. Targeted

Used for diagnosis of tumors of unknown origin, and evaluation of prognostic markers in genes

31
Q

What is Sanger sequencing’s appeal?

A

It is the most accurate, but only has sensitivity if 20-25% of the sample is mutant DNA. It can detect point mutations, duplications, and in/dels. Also it is very labor intensive. Considered the gold standard

32
Q

Why is next gen sequencing favorable?

A

Can text small insertions, deletions, and point mutations just as well, but only need <1% of sample to be cancerous to analyze. It has a faster turn around time than sequential testing, and comparable costs.

33
Q

What is the most common cause of leukemia-related mortality in the US?

A

acute myeloid leukemia (AML)

34
Q

How are cytogenetics + molecular genetics used together?

A

Used for diagnosis (AML), specific treatments based on genes (breast cancer), and monitoring of therapy (proportion of cells with genetic abnormalities should decrease with treatment)

35
Q

What is the sensitivity of Karyotype vs FISH?

A

Karyotype - 20 cells tested. So 5%

FISH - 200 cells tested. So 0.5%.

36
Q

What is hematologic vs cytogenetic vs molecular remission?

A

Hematologic - Normal CBC
Cytogenetic - karyotype / FISH are genetically normal based on sensitivity
Molecular - no transcript detected by RT-PCR.

37
Q

How does the drug work which treats CML?

A

Binds the ATP binding pocket of the fusion protein, which works as a tyrosine kinase.

Genetics (20 decks)

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