Cancer Genetics I and II

Question 1

Define whether a gene that regulates cell division, immortality, apoptosis, angiogenesis, or metastasis is an oncogene or tumor suppressor gene.

Answer 1

Cell division - Oncogene
Immortality - Oncogene
Apoptosis - Tumor Suppressor
Angiogenesis - Oncogene
Metastasis - Oncogen

Question 2

Explain how oncogenes act in a dominant fashion and tumor repressor genes in a recessive fashion.

Answer 2

Only one mutant oncogene is needed to significantly alter cell cycle activity.

If one tumor suppressor gene is bad, the other one produces enough gene product (p53, etc.). If two tumor suppressor genes are bad, there is no gene product, and that would alter cell cycle activity.

Question 3

Explain the concept of penetrance.

Answer 3

Even though a dominant mutation has been passed on, the effects may not be passed on to all progeny.

Question 4

Describe the steps leading to the activation of the caspase cascade in both the death receptor and mitochondrial pathways.

Answer 4

Death receptor:
Death signal binds Fas receptor/ Tnf receptor —> FADD/TRADD —> activation of caspase 8. Caspase 8 can then stimulate tBID as well as the effector caspases.

Cytokine deprivation activates BH3-only proteins—> BH3 only’s inhibit Bcl2, allowing Bax and Bak to form a pore
–>
cytochrome c and SMAC released –> cytochrome c activates Apaf1, which activates caspase 9; SMAC inhibits XIAP, which halts inhibition of caspase 9

Question 5

List the different processes that may activate the mitochondrial apoptotic pathway.

Answer 5

Cytokine deprivation
Intracellular damage
Oncogene upregulation

Question 6

Explain a mechanism by which Bcl-2 and Bak/Bax regulate cytochrome C release
from the mitochondria.

Answer 6

Bcl2 inhibits Bak/Bax

BH3-only proteins inhibit Bcl2

Question 7

Describe the roles of other protein factors released from the mitochondria in addition to cytochrome C.

Answer 7

SMAC inhibits XIAP

Question 8

How are caspases 8 and 9 activated?

Answer 8

Caspase 9 is activated by the apoptosome (6 cytochrome c’s and apaf1’s in a ring), which cleaves it and allows it to become activated.
Caspase 8 is activated by FADD and TRADD receptor complexes, forming a DISC complex. The caspase is then cleaved and activated.

Question 9

What is the role of p53 in apoptotic responses?

Answer 9

p53 upregulates the Noxa and other genes that code for BH3 only proteins. An increase in BH3 only proteins means increased inhibition of Bcl2

Question 10

How do different survival factors inhibit apoptosis?

Answer 10

Transcription regulators increase txn of Bcl2 gene
Survival factor activates Akt kinase, which phosphorylates a BH3-only protein that is inhibiting Bcl2
A survival factor activates MAPk, which phosphorylates (and in doing so, deactivates) Hid. This stops Hid from inhibiting the IAPs (inhibitors of apoptosis)

Question 11

Distinguish between carcinomas and sarcomas.

Answer 11

Carcinomas form from epithelial cells

Sarcomas form from connective tissues and muscles

Question 12

Explain the concept of tumor clonality.

Answer 12

Tumors arise from one single mutant cell.

Question 13

Describe the steps and barriers to the metastatic process (i.e. from the dissociation of a tumor cell from the tumor mass to its growth as a new tumor at a distant site).

Answer 13

Entering the blood/lymph vessel is difficult, as it is hard to escape from the parent tissue.
Flowing through a blood vessel, stopping at a capillary, and exiting the vessel are all easy.
Surviving in a new tissue is difficult.

Question 14

Explain how changes in telomerase activity lead to genetic

instability and immortality.

Answer 14

As a cell ages, its telomers shorten, and telomerase is usually downregulated. At this point, p53 would normally be upregulated halt any progression toward S phase, and drive the cell into replicative senesence.

Since p53 is shut down, in the absence of telomerase, chromosomes will eventually fuse together and many translocations will be observed in cell progeny. If these mutations don’t kill the cell, telomerase is reactivated, and these configurations are stabilized. Thus, changes in telomerase activity can drive genetic instability and immortality.

Question 15

List other mechanisms that generate genetic instability in cancers.

Answer 15

The same could be said if the cell maintained or increased telomerase regardless of telomere size.

Question 16

Understand the concept of the Warburg effect in altered glucose metabolism associated with cancer cells

Answer 16

In cancer cells, 10% of glucose is used to produce building blocks for the cell. Then, following glycolysis, 85% of the pyruvate is converted to lactate. Because so little pyruvate is transferred to oxidative phosphorylation,
the mitochondria can effectively be shut down. This eliminates the mitochondrial apoptotic pathway.

Question 17

Explain the role of laminin receptors in the three-step mechanism for basement membrane invasion by tumor cells.

Answer 17

A tumor cell must bind laminin receptors in order to start invading a membrane. By binding, the cell can secrete collagenase to digest the basal lamina, and attain motility.

Question 18

Describe the contribution of EMT to cancer progression and metastasis

Answer 18

EMT allows cancer cells to transition from epithelial cells to mesenchymal cells.

Loss of E-cadherin
Loss of cell-cell and cell matrix contacts
Increased protease secretions
Rounded shape
Pluripotent txn factors activated

This transition means that said cells can now invade other tissues (metastasize).

Question 19

Explain how invasion in angiogenesis by non-transformed endothelial cells has a mechanistic similarity to invasion by metastatic cells.

Answer 19

They are similar in that the cells increase their protease activity, invade the basement membrane, proliferate and go somewhere else.

Question 20

How do cancer cells signal to epithelial cells to initiate new blood vessel growth?

Answer 20

They secrete growth factors, including VEGF and FGF, to signal the blood vessel endothelial cells to increase protease secretion (collagenase, urokinase plasminogen activator (upa) and decrease protease inhibitor txn.

This allows endothelial cells to invade the vascular basement membrane to proliferate and supply the cancer with nutrients and oxygen.

Question 21

Define driver and passenger mutations in cancer.

Answer 21

Driver mutations are the mutations that are most commonly found in cancer tissues and “drive” the cancer forward into a later stage, whereas passenger mutations, while found in a significant amount, aren’t found as frequently as driver mutations and likely play a less significant role in cancer progression.

Question 22

Know the various ways that genes can be made overactive (oncogenes) and the mechanisms for generating second hits in tumor suppressor genes.

Answer 22

Many oncogenes result from increased activity through changes in expression or stacked missense mutations. Tumor suppressor mutations result from loss of activity, either by various nonsense mutations or epigenetic silencing (loss of hetoerozygosity).

Question 23

Distinguish between genetic and epigenetic mechanisms for generating a cancer phenotype.

Answer 23

Epigenetic mechanisms do not directly involve DNA bases. They consist of methylation of CpG islands on DNA, methylation and acetylation of histone tails, and nucleosome remodeling

Genetic modifications involve changes within the DNA bases. May be heritable.

Question 24

Explain features of the cancer stem cell phenotype and their function in cancer: its pluripotent potential characterized by a specific group of transition factors, membrane and cytoskeleton changes, slow cell division rate, apoptotic resistance, self-renewal, protease secretion and motility.

Answer 24

Pluripotent potential - it can become many things and exist in many tissues

Membrane and cytoskeleton changes - these changes counteract the usual features of apoptosis, counteracting them

Slow cell division rate - can’t be targeted by anti-cancer drugs

Apoptotic resistance - the cell lives longer and can divide more

Self-renewal - cells are immortal and can continue producing neoplastic cells

Protease secretion - Cell can break through ECM proteins, such as collage n, and invade blood vessels a/o lymphatic ducts

Motility - cell lacks contact inhibition and can move

Question 25

Describe how the role of the tumor microenvironment in support of the cancer stem cell phenotype and the role of the TGFβ and Wnt signalling pathway.

Answer 25

Cancer stem cells interact with the tumor microenvironmment to allow the tumor to continue living by interacting with the ECM and activating signal transduction pathways in nearby cells.
TGFβ and Wnt are extracellular signals that drive the transition to mesenchymal cells. They are produced by other cells or the tumor cells themselves. TGF-beta is cleaved from a proto-protein.

Question 26

Explain the epithelial to mesenchymal transition (EMT) and its function in cancer.

Answer 26

EMT represents the transition between a stationary cancer cell and a metastatic cell.

Question 27

Define cell plasticity in the metastatic cell and the purpose of the MET reversion in metastasis.

Answer 27

Cell plasticity refers to the presence of multiple transcription factors (pluripotent), meaning they can survive and proliferate in another tissue. MET reversion occurs so the cells can form a tumor in another tissue.

Question 28

Describe how the characteristics of a cancer stem cell that gives it a resistance to therapeutics.

Answer 28

They are slowly dividing, meaning a lot of drugs cannot target them.

Lots of ABC transporters that pump drugs out.

Question 29

Explain the process of developing cancer cell heterogeneity.

Answer 29

A certain mutation arises that alters the cell cycle. Due to this disregulation, progeny cells will have other mutations, with those that drive cell life ultimately selected for.

Question 30

Explain some how the progression of oncogenesis from benign to malignant growths and the late onset of cancers after exposure to a mutagen support this conclusion of the requirement for multiple mutations in a cancer (lung cancer example).

Answer 30

Increasing mutations provoke the transition between benign to malignant growths.

Late onset of cancers following exposure to a mutagen (eg. smoking cigarrettes) demonstrate that cancers progress after a series of genetic and epigenetic mutations that build upon each other.

Question 31

Explain the consequences of tumor cell heterogeneity for prognosis and treatment.

Answer 31

Heterogeneity of cancers make them difficult to assess and difficult to treat.
All cancers are different.

Question 32

Understand the role of transit amplifying cells

Answer 32

They are progeny of stem cells. They do not exist as stem cells but can retain stem cell qualities. They thus “amplify” the effect of stem cells.

Question 33

Epigenetic changes in the stem or progenitor cell can result in cancer stem cells.

Answer 33

If said changes methylation or deacetylation of tumor suppressor genes or acetylation of an oncogene result in immortality and pluripotence, these cells can become cancer stem cells.

Question 34

Explain the role of epigenetic gatekeepers in preventing early tumor progression

Answer 34

Epigenetic silencing of cell-cycle inhibitor genes (such as p16) in stem and precursor cells may lock these cells into stem cell-like states that foster abnormal clonal expansion.

These genes are called gatekeepers, because their normal expression allows them to be activated during differentiation to control renewal.

This allows for abnormal survival of the cells during stress, and the cells are now dependent on survival pathways. This creates selection for mutations in genetic gatekeeper genes.

Question 35

Explain the concept of common genetic mutations leading to stages in the progression to the malignant form of a cancer.

Answer 35

Common genetic mutations include those that influence the progression of the cell cycle, those that induce apoptosis.
Cancer progression then proceeds in stages, with each major mutation driving it into a new stage.

Common ones include loss of Apc, activation of K-ras, loss of tumor suppressor genes, loss of p53

Question 36

Explain the types of DNA and histone modifications that are often associated with cancer

Answer 36

Acetylation of oncogenes and proteases

Methylation or deacetylation of tumor suppressor genes

Question 37

Explain why epigenetic gene silencing is frequently associated with cancer.

Answer 37

If tumor suppressor, or pro-apoptotic genes are silenced, the cancer can progress.

Question 38

Relate differences in DNA methylation in gene promoter regions to gene activity (hypermethylated versus hypomethylated)

Answer 38

Hypermethylated gene promotors suggest gene silencing (found in cancer cells), whereas hypomethylated promotors suggest gene activity.

Question 39

Describe the role of Polycomb group proteins in gene silencing and possible roles in tumor development

Answer 39

The PRC2 (Polycomb repressive complex 2) binds to target tumor suppressor genes.
PRC1 is able to recognize the trimethylated H3K27 (H3K27me3) mark. 

This appears to inhibit the the transcriptional machinery, compact the chromatin and recruit DNA methyltransferases that target gene PRC2.

Question 40

Explain how a small drug can inhibit specific oncogenic proteins

Answer 40

Gleevac can block the tyrosine kinase synthesized from the Bcr-abl gene.

Question 41

Provide an example of immunotherapy in tumor destruction.

Answer 41

Cancer cells are protected by an immunosuppressive environment. They do so by expressing proteins on their surface that inhibit T cells. If an antibody is given that binds these proteins, the T-cells may be able to attack the cancer cells. When that environment is removed, they are killed by T-cells.

Question 42

Explain why the existence of redundant pathways may result in treatment failure

Answer 42

Different pathways exist to drive the cell cycle, inhibit apoptosis, and induce angiogenesis and metastasis. Inhibition of a single driver mutation, thus, will likely result in compensation by the others. You would need to inhibit multiple pathways at the same time.