Genetic Changes in Cancer (V. Park <3)

Question 1

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

Answer 1

• 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

Question 2

Why is cancer development take so long?

Answer 2

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

Question 3

Differentiate between Driver and Passenger mutations.

Answer 3

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

Question 4

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

Answer 4

True

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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

Question 7

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

Answer 7

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

Question 8

Can all cancers be detected by a karyotype?

- why not?

Answer 8

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

Question 9

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

Answer 9

Tumor Suppressor Genes

Question 10

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

Answer 10

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

Question 11

Mutations in what gene types leads to cancer?

Answer 11

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)

Question 12

What can be said about Oncogenes with respect to:

• cell growth
• type of mutations that lead to cancer
• Dominant or Recessive CELLULAR phenotype?

Answer 12

• Oncogenes PROMOTE CELL growth (gas pedal)
• GAIN of function causes cancer
• DOMINANT CELLULAR phenotype

Question 13

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?

Answer 13

• Tumor Suppressor Genes Suppress Cell growth
• LOSS of function causes cancer
• RECESSIVE CELLULAR phenotype

Question 14

By what 3 methods do proto-oncogenes become oncogenic?

Answer 14

• Mutation in Coding Sequence
• Gene Amplification
• Gene Rearrangement

Question 15

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

Answer 15

Ras

Question 16

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

Answer 16

Myc
Cyclin D
Erb-B1

Question 17

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?

Answer 17

Myc
Cyclin D
Bcl-2
Src 
Raf

Question 18

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?

Answer 18

Abl

Question 19

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?

Answer 19

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

Question 20

What is an off translocation?

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Imatinib

Question 23

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

Answer 23

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

Question 24

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

Answer 24

Double Minutes

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

Question 25

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

Answer 25

False, Malignant Transformation Requires MANY acquired (SOMATIC) mutations

Question 26

Why are large malignancies often worse?

Answer 26

They have a large burdon of genetic Abnormalities as well as genomic instability **There are tons of Driver and Passenger Mutations

Question 27

What is an Inherited mutation?

Answer 27

- Genetic Variant Inherited from a parent and Present in Gametes and in all somatic cells of the body

Question 28

What is a constitutional mutation? | - how does this differ from a strictly inherited mutation?

Answer 28

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

Question 29

What is an acquired mutation?

Answer 29

- A mutation that occurs ONLY in a somatic cell | - WILL not be passed to offspring

Question 30

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

Answer 30

True

Question 31

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

Answer 31

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

Question 32

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

Answer 32

RET and MEN2

Question 33

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

Answer 33

TUMOR SUPPRESSOR GENES account for the majority of hereditary cancers

Question 34

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

Answer 34

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

Question 35

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

Answer 35

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

Question 36

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

Answer 36

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

Question 37

What are some common genes that apply to the two hit hypothesis? - Cell-Cycle - DNA Repair - Apoptosis

Answer 37

Cell Cycle: - RB1 - NF1 DNA Repair: - MLH1, MLH2, MSH6, PMS2 - BRCA1/BRCA2 Apoptosis: - TP53

Question 38

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

Answer 38

Retinoblastoma

Question 39

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

Answer 39

Neurofibromatosis Type 1

Question 40

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

Answer 40

Lynch-Syndrome (colorectal cancer)

Question 41

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

Answer 41

Li-Fraumini Syndrome

Question 42

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

Answer 42

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

Question 43

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

Answer 43

ANYTHING that results in a LOSS of HETEROZYGOSITY - Deletion - Mitotic Nondisjunction - Mitotic Recombination - Epigenetic Silencing

Question 44

What is Loss of Heterozygosity (LOH)?

Answer 44

One allele seems to vanish

Question 45

What should Bilateral Tumors Clue you into?

Answer 45

- Hereditary Cancer

Question 46

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

Answer 46

- It takes awhile to get two hits

Question 47

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

Answer 47

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