Genetic Changes in Cancer (V. Park <3) Flashcards
In the most general terms, how does a single cancerous cell arise?
- 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
Why is cancer development take so long?
MULTIPLE MUTATIONS are required to transform a normal cell mass to a cell mass with the potential to undergo uncontrolled growth
Differentiate between Driver and Passenger mutations.
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
T or F: there are typically multiple drivers in a given tumor
True
A what point does a group of cells considered ‘free of the normal constraints of’ or somatic cells?
- Benign tumors are considered to be free of normal constraints i.e. they have taken on the MUTATOR PHENOTYPE
What cells accumulated within the heterogenous makeup of a tumor as it grows?
Each Persisting cell has some selective advantage that has prevented it from dying
How can cancer cells exist with aneuploidy but the human genome cannot without seeing significant defects?
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
Can all cancers be detected by a karyotype?
- why not?
No Karyotypes are only useful for determining if chromosomal abnomalities exist in the cell line
What type of cancer genes can cause cancer by a simple loss of heterozygosity (LOH)?
Tumor Suppressor Genes
Why are oncogenes not susceptible to loss of heterozygosity (LOH) mutations?
Oncogenes are DOMINANT - losing one won’t make a difference in your phenotype
Mutations in what gene types leads to cancer?
- Proto-oncogenes
- Tumor Suppressor Genes
- Apoptosis-regulating genes
- 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)
What can be said about Oncogenes with respect to:
- cell growth
- type of mutations that lead to cancer
- Dominant or Recessive CELLULAR phenotype?
- Oncogenes PROMOTE CELL growth (gas pedal)
- GAIN of function causes cancer
- DOMINANT CELLULAR phenotype
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?
- Tumor Suppressor Genes Suppress Cell growth
- LOSS of function causes cancer
- RECESSIVE CELLULAR phenotype
By what 3 methods do proto-oncogenes become oncogenic?
- Mutation in Coding Sequence
- Gene Amplification
- Gene Rearrangement
What type of Proto-oncogene typically gains function by a mutation in the coding sequence?
Ras
What are some oncogenes that a often overexpressed a s a result of gene amplification?
Myc
Cyclin D
Erb-B1
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?
Myc Cyclin D Bcl-2 Src Raf
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?
Abl
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?
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
What is an off translocation?
One that occurs in the middle of a gene rather than in a non-coding region
How would you detect ABL-BCR in order to use it to monitor relapse or to make a Dx?
- Use FISH to look and see if the ABL and BCR genes show up on a single chromosome
What drug target the ABL-BCR mutation in Chronic Myelogenous Leukemia?
Imatinib
What are two things seen in cancer cells that make 100’s of copies of oncogenes in order to confer a selective advantage?
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
The Myc gene undergoes gene amplification, is this through Homogeneously Staining Regions or through Double Minute?
- what disease is associated with this?
Double Minutes
**Often seen in Neuroblastomas but can be seen in Lymphomas too
T or F: malignant transformation involves only a single acquired Somatic Mutation
False, Malignant Transformation Requires MANY acquired (SOMATIC) mutations
Why are large malignancies often worse?
They have a large burdon of genetic Abnormalities as well as genomic instability
**There are tons of Driver and Passenger Mutations
What is an Inherited mutation?
- Genetic Variant Inherited from a parent and Present in Gametes and in all somatic cells of the body
What is a constitutional mutation?
- how does this differ from a strictly inherited mutation?
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
What is an acquired mutation?
- A mutation that occurs ONLY in a somatic cell
- WILL not be passed to offspring
T or F: a constitutional mutation can be inherited in the next generation
True
T or F: Tumorigenic changes in oncogenes arise as germline mutations
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
What are the two exceptions to the fact that VERY FEW heriditary cancers arise from oncogenes?
RET and MEN2
If oncogene mutations don’t comprise the major group of heriditary cancers then what does?
TUMOR SUPPRESSOR GENES account for the majority of hereditary cancers
If you suspect a BRCA cancer in a family what is the first thing you should do?
- FIND A PERSON IN THE FAMILY THAT HAS BREAST CANCER AND SAMPLE THEM, IDEALLY THE MOM
T or F: Vermurafenib is good for all patients with melanoma.
FALSE, this drug is only good for people with a V600E mutation in BRAF, otherwise the drug is useless
For what cancer causing gene type is the two hit hypothesis applicable to?
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
What are some common genes that apply to the two hit hypothesis?
- Cell-Cycle
- DNA Repair
- Apoptosis
Cell Cycle:
- RB1
- NF1
DNA Repair:
- MLH1, MLH2, MSH6, PMS2
- BRCA1/BRCA2
Apoptosis:
- TP53
What disease is associated with an inherited hit in the RB1 gene?
Retinoblastoma
What disease is associated with an inherited hit in the NF1 gene?
Neurofibromatosis Type 1
What disease is associated with an inherited hit in the MLH1, MLH2, MSH6, PMS2?
Lynch-Syndrome (colorectal cancer)
What disease is associated with an inherited hit in the TP53 gene?
Li-Fraumini Syndrome
What can be said about dominant and recessive properties of inherited mutations in Tumor Suppressor gene?
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
If a 1st hit is acquired as a inherited mutation, how is the second hit acquired?
ANYTHING that results in a LOSS of HETEROZYGOSITY
- Deletion
- Mitotic Nondisjunction
- Mitotic Recombination
- Epigenetic Silencing
What is Loss of Heterozygosity (LOH)?
One allele seems to vanish
What should Bilateral Tumors Clue you into?
- Hereditary Cancer
Why do you typically see an earlier age of onset in Hereditary Cancers?
- It takes awhile to get two hits
How can you explain why reduced penetrance is often seen in Hereditary cancers?
- Because we can gaurantee that a second hit will actually take place
