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CMOD-Block 2 Path > Genetic Changes in Cancer (V. Park <3) > Flashcards

Genetic Changes in Cancer (V. Park <3) Flashcards

1
Q

In the most general terms, how does a single cancerous cell arise?

A
  • There are Trillions of cells in your body
  • ~1/3 replications introduces a new mutation
  • Some Cells Gain the ABILITY TO PROLIFERATE FASTER than others
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2
Q

Why is cancer development take so long?

A

MULTIPLE MUTATIONS are required to transform a normal cell mass to a cell mass with the potential to undergo uncontrolled growth

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3
Q

Differentiate between Driver and Passenger mutations.

A

Driver Mutations:

  • Confer a Growth advantage
  • Is a mutation in a “Cancer Gene”

Passenger Mutation:

  • NO GROWTH ADVANTAGE
  • this just happens as a result of genomic instability
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4
Q

T or F: there are typically multiple drivers in a given tumor

A

True

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5
Q

A what point does a group of cells considered ‘free of the normal constraints of’ or somatic cells?

A
  • Benign tumors are considered to be free of normal constraints i.e. they have taken on the MUTATOR PHENOTYPE
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6
Q

What cells accumulated within the heterogenous makeup of a tumor as it grows?

A

Each Persisting cell has some selective advantage that has prevented it from dying

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7
Q

How can cancer cells exist with aneuploidy but the human genome cannot without seeing significant defects?

A

Cancer is a Parasite that depends on the host for nutrients.
- It doesn’t need to perform any specialized function it just needs to live

  • Aneuploidy that confers a survival advantage is allowed
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8
Q

Can all cancers be detected by a karyotype?

- why not?

A

No Karyotypes are only useful for determining if chromosomal abnomalities exist in the cell line

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9
Q

What type of cancer genes can cause cancer by a simple loss of heterozygosity (LOH)?

A

Tumor Suppressor Genes

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10
Q

Why are oncogenes not susceptible to loss of heterozygosity (LOH) mutations?

A

Oncogenes are DOMINANT - losing one won’t make a difference in your phenotype

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11
Q

Mutations in what gene types leads to cancer?

A
  1. Proto-oncogenes
  2. Tumor Suppressor Genes
  3. Apoptosis-regulating genes
  4. DNA repair Genes

***Note: 2-4 can be grouped together (so you just have promotion of growth genes and repair/death genes that can get messed up)

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12
Q

What can be said about Oncogenes with respect to:

  • cell growth
  • type of mutations that lead to cancer
  • Dominant or Recessive CELLULAR phenotype?
A
  • Oncogenes PROMOTE CELL growth (gas pedal)
  • GAIN of function causes cancer
  • DOMINANT CELLULAR phenotype
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13
Q

What can be said about Tumor Suppressor genes with respect to:

  • cell growth
  • type of mutations that lead to cancer
  • Dominant or Recessive CELLULAR phenotype?
A
  • Tumor Suppressor Genes Suppress Cell growth
  • LOSS of function causes cancer
  • RECESSIVE CELLULAR phenotype
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14
Q

By what 3 methods do proto-oncogenes become oncogenic?

A
  • Mutation in Coding Sequence
  • Gene Amplification
  • Gene Rearrangement
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15
Q

What type of Proto-oncogene typically gains function by a mutation in the coding sequence?

A

Ras

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16
Q

What are some oncogenes that a often overexpressed a s a result of gene amplification?

A

Myc
Cyclin D
Erb-B1

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17
Q

What are some oncogenes that are often over expressed as a result of chromosomal rearrangement that puts a gene by a nearby regulatory sequence that causes the protein to get over-produced?

A 
Myc
Cyclin D
Bcl-2
Src 
Raf
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18
Q

What are some oncogenes that are often over expressed as a result of chromosomal rearrangement that fuses the oncogene to an actively transcribed gene that causes the protein to get over-produced?

A

Abl

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19
Q

What genetic mutation is commonly present in patients with Chronic Myeloid Leukemia (CML)?

  • How would you test for this?
  • Would this be considered a driver mutation?
A

ABL-BCR = OFF translocation t(9,22)

  • Results in the formation of a Fusion Protein that is Constituitively Active Because it is connected to BCR
  • YES, this a driver mutation because it gives the cell a survival advantage by pushing it forward into the Cell Cycle
20
Q

What is an off translocation?

A

One that occurs in the middle of a gene rather than in a non-coding region

21
Q

How would you detect ABL-BCR in order to use it to monitor relapse or to make a Dx?

A
  • Use FISH to look and see if the ABL and BCR genes show up on a single chromosome
22
Q

What drug target the ABL-BCR mutation in Chronic Myelogenous Leukemia?

A

Imatinib

23
Q

What are two things seen in cancer cells that make 100’s of copies of oncogenes in order to confer a selective advantage?

A

HSR (Homogeneously Staining Regions)
- Giant Single Band seen on a chromosome

DM (Double Minutes)

  • Extrachromosomal DNA that is circular with no Centromeres or Telomeres
  • SEGREGATE RANDOMLY AT EACH CELL DIVISION
24
Q

The Myc gene undergoes gene amplification, is this through Homogeneously Staining Regions or through Double Minute?
- what disease is associated with this?

A

Double Minutes

**Often seen in Neuroblastomas but can be seen in Lymphomas too

25
Q

T or F: malignant transformation involves only a single acquired Somatic Mutation

A

False, Malignant Transformation Requires MANY acquired (SOMATIC) mutations

26
Q

Why are large malignancies often worse?

A

They have a large burdon of genetic Abnormalities as well as genomic instability

**There are tons of Driver and Passenger Mutations

27
Q

What is an Inherited mutation?

A
  • Genetic Variant Inherited from a parent and Present in Gametes and in all somatic cells of the body
28
Q

What is a constitutional mutation?

- how does this differ from a strictly inherited mutation?

A

Present in in all cells of the Body BOTH germline AND somatic (just like an inherited mutation)

***NOTE: this INCLUDES inherited mutation BUT it may be because of something random that happened during Embryogenesis and NOT from mom or dad mutations

***Could also be germline Mosaicism

29
Q

What is an acquired mutation?

A
  • A mutation that occurs ONLY in a somatic cell

- WILL not be passed to offspring

30
Q

T or F: a constitutional mutation can be inherited in the next generation

A

True

31
Q

T or F: Tumorigenic changes in oncogenes arise as germline mutations

A

FALSE, they arise as somatic mutations –> if present in all cells of the body these things would be LETHAL very early on

**must be Acquired in only some cells of the body

32
Q

What are the two exceptions to the fact that VERY FEW heriditary cancers arise from oncogenes?

A

RET and MEN2

33
Q

If oncogene mutations don’t comprise the major group of heriditary cancers then what does?

A

TUMOR SUPPRESSOR GENES account for the majority of hereditary cancers

34
Q

If you suspect a BRCA cancer in a family what is the first thing you should do?

A
  • FIND A PERSON IN THE FAMILY THAT HAS BREAST CANCER AND SAMPLE THEM, IDEALLY THE MOM
35
Q

T or F: Vermurafenib is good for all patients with melanoma.

A

FALSE, this drug is only good for people with a V600E mutation in BRAF, otherwise the drug is useless

36
Q

For what cancer causing gene type is the two hit hypothesis applicable to?

A

ONLY applicable to Tumor suppressor Genes

**Note: Oncogenes don’t apply- it only takes one knockout so these are usually acquired mutations where you would never see an initial inherited hit occurring like sometimes happens in the two hit model

37
Q

What are some common genes that apply to the two hit hypothesis?

  • Cell-Cycle
  • DNA Repair
  • Apoptosis
A

Cell Cycle:

  • RB1
  • NF1

DNA Repair:

  • MLH1, MLH2, MSH6, PMS2
  • BRCA1/BRCA2

Apoptosis:
- TP53

38
Q

What disease is associated with an inherited hit in the RB1 gene?

A

Retinoblastoma

39
Q

What disease is associated with an inherited hit in the NF1 gene?

A

Neurofibromatosis Type 1

40
Q

What disease is associated with an inherited hit in the MLH1, MLH2, MSH6, PMS2?

A

Lynch-Syndrome (colorectal cancer)

41
Q

What disease is associated with an inherited hit in the TP53 gene?

A

Li-Fraumini Syndrome

42
Q

What can be said about dominant and recessive properties of inherited mutations in Tumor Suppressor gene?

A

At Patient Level:
- DOMINANT - you’ll see it in one generation after the next

At Cellular Level
- RECESSIVE - because another Hit has to happen before anything actually occurs

43
Q

If a 1st hit is acquired as a inherited mutation, how is the second hit acquired?

A

ANYTHING that results in a LOSS of HETEROZYGOSITY

  • Deletion
  • Mitotic Nondisjunction
  • Mitotic Recombination
  • Epigenetic Silencing
44
Q

What is Loss of Heterozygosity (LOH)?

A

One allele seems to vanish

45
Q

What should Bilateral Tumors Clue you into?

A
  • Hereditary Cancer
46
Q

Why do you typically see an earlier age of onset in Hereditary Cancers?

A
  • It takes awhile to get two hits
47
Q

How can you explain why reduced penetrance is often seen in Hereditary cancers?

A
  • Because we can gaurantee that a second hit will actually take place

CMOD-Block 2 Path (22 decks)

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