Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
48 Cards in this Set
- Front
- Back
|
What is the difference between the alleles of a proto-oncogene and those of tumor suppressor genes?
|
Mutant alleles of proto-oncogenes are considered dominant because they transform cells despite the presence of a normal counterpart.
In contrast, both normal alleles of the tumor suppressor genes must be damaged before transformation can occur (exception: haploinsufficiency) |
|
|
What are the seven fundamental changes in cell physiology that together determine the malignant phenotype?
|
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhib. signals 3) Evasion of apoptosis 4) Limitless replicative potential 5) Sustained angiogenesis 6) Ability to invade and metastasize 7) Defects in DNA repair |
|
|
A mutation would convert a proto-oncogene into?
|
An oncogene that would be constitutively active endowing the cell with self-sufficiency in growth.
|
|
|
For the following growth factors, list their proto-oncogenes and the associated human tumors.
PDGF-B TGF-a HGF |
1) PDGF-B
- SIS - Astrocytoma, osteosarcoma 2) TGF-a - TGFA - Astrocytomas, Hepatocellular carcinomas 3) HGF - HGF - Thyroid cancer |
|
|
For the following growth factor receptors, list their proto-oncogenes and the associated human tumors.
EGFR Receptor for neurotrophic factors PDGFR FMS-like tyrosine kinase 3 |
1) EGFR
- ERBB1,ERRB2 - Squamous cell carcinoma of lung, gliomas 2) Receptor for neuro. - RET (point mutation) - Leukemia, MEN2A+B, familial medullar thyroid carcinomas 3) PDGFR - PDGFRB - Gliomas, leukemias 4) FMS - FLT3 - Breast cancer, Ovarian cancer |
|
|
What is the proto-oncogene for the following proteins involved in signal transduction:
1) nonreceptor tyrosine kinase?Cancers associated? 2) RAS signal transduction |
1) ABL (translocation). CML and ALL
2) BRAF (Point mutation). Melanomas |
|
|
C-MYC, N-MYC, L-MYC are proto-oncogenes for what? Associated cancers?
|
Transcriptional activators.
1) Translocation of C-MYC leads to Burkitt lymphoma 2) Amplification of N-MYC leads to neuroblastoma and small-cell carcinoma of the lung 3) Amplification of L-MYC leads to small-cell carcinoma of the lung |
|
|
Cyclin D and Cyclin E mutations lead to what? CDK4?
|
Cyclin D
- Translocation leads to Mantle cell lymphoma - Amplification leads to breast and esophageal cancers Cyclin E - Overexpression leads to breast cancer CDK4 - Amplification or point mutation leads to glioblastoma, melanoma, sarcoma |
|
|
What is the most common abnormality of proto-oncogenes in human tumors ?
|
Point mutation of RAS family genes. There are three HRAS,KRAS,NRAS.
|
|
|
KRAS, HRAS and NRAS mutations are most common in which cancers?
|
KRAS - Carcinomas (particularly colon and pancreas)
HRAS - Bladder tumors NRAS - Hematopoietic tumors |
|
|
RAS plays an important role in what?
|
Signaling cascades downstream of growth factor receptors (such as MAP kinase which signals for cell proliferation) , resulting in mitogenesis. They are members of small G proteins that bind GTP and GDP
|
|
|
A mutation in neurofibromin 1, a GTPase activation protein (GAP), would result in?
|
Familial neurofibromatosis type 1.
GAPs bind to active RAS and augment its GTPase activity leading to termination of signal transduction. |
|
|
In CML and some ALL, describe the genetic malformation that occurs?
|
ABL gene is translocated from chromosome 9 to chromosome 22 where it fuses with the BCR gene. This chimeric gene (Philadelphia chromosome) encodes an oncogenic BCR-ABL tyrosine kinase.
|
|
|
Functions of MYC?
|
1) Role in cell replication
2) Can reprogram somatic cells into pluripotent stem cells 3) May enhance self-renewal and/or block differentiation |
|
|
Functions of:
CDK1 CDK2 CDK4 |
CDK1 - forms a complex with cyclin B that facilitates G2/M transition
CDK2 - forms a complex with cyclin E in late G1 (G1/S transition). Forms a complex with cyclin A at the S phase (G2/M transition) CDK4 - forms a complex with cyclin D that phosphorylates RB, allowing the cell to progress through G1 restriction point. |
|
|
Function of CIP/KIP (p21 and p27)? INK4/ARF?
|
CIP/KIP - blocks the cell cycle by binding cyclin-CDK complexes. p21 is induced by p53 and p27 responds to growth suppressors such as TGF-B.
INK4/ARF - p16/INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB. p14/ARF increases P53 levels by inhibiting MDM2 activity |
|
|
p53 is required for which checkpoint ?
|
G1/S
However, it is a main component of the G2/M checkpoint as well. |
|
|
What is ataxia-telangiectasia mutated?
|
It is a protein kinase that is activated by double-stranded DNA breaks. It transmits signals to arrest the cell cycle after DNA damage.
1) Acts through p53 in G1/S 2) Acts through p53 and through inactivation of CDC25 phosphatase (disrupts cyclin B-CDK1) in G2/M |
|
|
Cells damaged by ionizing radiation activate which checkpoint?
|
G2/M and arrest in G2
|
|
|
Difference between G1/S and G2/M checkpoint regulation?
|
G1/S cycle arrest is mostly mediated through p53
G2/M involves both p53-dependent and p53 - independent mechanisms. Defects in these checkpoint components are a major cause of genetic instability in cancer cells. |
|
|
Part 1
For the following tumor suppressors, list the tumors associated with somatic and inherited mutations. TGF-B E-cadherin NF1 and NF2 APC/B-catenin |
1) TGF-B
- Somatic: carcinomas of colon 2) E-cadherin - Somatic: carcinoma of stomach - Inherited: Familial gastric cancer 3) NF1 - Somatic: Neuroblastomas - Inherited: Neurofibromatosis type 1 and sarcomas NF2 - Somatic: Schwannomas and meningiomas - Inherited: Neurofibromatosis type 2, schwannomas and meningiomas 4) APC - Somatic: Carcin. of stomach, colon, pancreas. Melanoma - Inherited: Familial adenomatous polyposis coli/colon cancer |
|
|
Part 2
For the following tumor suppressors, list the tumors associated with somatic and inherited mutations. RB1 p53 WT1 P16/INK4a |
5) RB1
- Som: retinoblastoma, osteosarcoma, carcinoma of breast, colon, ling - Inherited: Retinoblastomas, osteosarcoma 6) p53 - Som: Most human cancers - Inherited: Retinoblastomas, osteosarcoma 7) WT1 - Som: Wilms' - Inherited: Wilms' 8) P16/INK4a - Som: Pancreatic, breast and esophageal cancers - Inherited: Malignant melanoma |
|
|
What is the normal function of BRCA1 and 2?
|
DNA repair
|
|
|
What is the most common target for genetic alteration in human tumors?
|
TP53 gene (protein is p53). A little over 50% of tumors contain mutations in this gene.
|
|
|
What are the three leading causes of cancer death?
|
Lung
Colon Breast |
|
|
What sort of allelic loss of p53 occurs in every type of cancer?
|
Homozygous
|
|
|
Inheritance of one mutant allele of TP53 is involved in?
|
Li-Fraumeni syndrome. These individuals have a 25-fold greater chance of developing tumors (two hit hypothesis)
|
|
|
What is p53? Where do most mutations of p53 occur?
|
It is a transcription factor that prevents the propagation of genetically damaged cells. p53 links cell damage with DNA repair, cell cycle arrest and apoptosis. 80% of p53 point mutations occur in the DNA-binding domain of the protein.
|
|
|
How does p53 thwart neoplastic transformation?
|
1) Activates the temporary arrest of the cell cycle (quiescence)
2) Induces permanent cell cycle arrest (senescence) 3) Triggers apoptosis |
|
|
How is p53 involved in apoptosis of cells with irreversible DNA damage?
|
p53 directs the transcription of pro-apoptotic genes (like BAX and PUMA)
|
|
|
Are tumors that retain normal p53 more likely to respond to chemotherapy and irradiation or not?
|
Yes. These two modalities cause DNA damage and subsequent apoptosis which is regulated by p53.
|
|
|
Germline mutations at the APC loci are associated with?
|
Familial adenomatous polyposis. All individuals born with one mutant allele develop thousands of polyps in the colon during their teens or 20s. Almost invariable, one or more of these polyps undergoes malignant transformation.
|
|
|
What is APCs normal function?
|
It is a component in the WNT signalling pathway which has a major role in controlling cell fate, adhesion and cell polarity in embryonic development. It has an important function in down-regulating B-catenin. Thus, cells with loss of APC behave as if they are under continous WNT signaling.
|
|
|
How can tumor cells evade apoptosis?
|
1) Reduced levels of CD95/Fas
2) High levels of FLIP 3) Overexpression of BCL2 4) Loss of p53 |
|
|
What is abnormal about tumor vasculature ?
|
It is leaky and dilated with a haphazard pattern of connection
|
|
|
What is angiogenesis required for in malignancy ?
|
1) Continued tumor growth (nutrients and new endothelial cells secrete growth factors -> growth of adjacent tumor cells)
2) Provides access to the vasculature (metastasis) |
|
|
What are three potent angiogenesis inhibitors ?
|
1. Angiostatin
2. Endostatin 3. Vasculostatin |
|
|
How may loss of p53 in tumor cells provide a permissive environment for angiogenesis?
|
- Stimulate expression of anti-angiogenic molecules such as thrombospondin-1, and repress expression of pro-angiogenic molecules such as VEGF.
|
|
|
Mutations of RAS or MYC have what effect on VEGF?
|
They up-regulate the production of VEGF
|
|
|
List the steps in metastasis
|
1) Adhesion to and invasion of the basement membrane
2) Passage through the ECM 3) Intravasation 4) Interaction with host lymphoid cells /platelets 5) Tumor cell embolus 6) Adhesion to basement membrane 7) Extravasation 8) Metastatic deposit 9) Angiogenesis 10) Growth |
|
|
Describe the invasion of the ECM by tumors
|
4 steps occur:
1) Loosening up of tumor cell-cell interactions (mediated by E-cadherins) 2) Degradation of the basement membrane and interstitial CT (tumor cells may either secrete or induce stromal cells to elaborate proteases - ex. MMPs) 3) Changes in attachment of tumor cells to ECM proteins 4) Locomotion |
|
|
Where do most metastases occur?
|
In the first capillary bed available to the tumor.
|
|
|
What is the role of chemokines in metastasis?
|
They have an important role in determining the target tissues for metastasis. For example, BRCA cells express CXCR4 and CCR7 receptors and the chemokines that bind to these are highly expressed in tissues to which breast cancers commonly metastasize.
|
|
|
HNPCC results from a defect in? What is one of the hallmarks of this defect?
|
In genes involved in DNA mismatch repair. Microsatellite instability is seen in these patients. Microsatellites are tandem repeats of one to six nucleotides found throughout the genome. In normal people the length of these microsatellites remains constant. In people with HNPCC, these satellites are unstable and increase or decrease in length in tumor cells, creating alleles not found in normal cells of the same patient.
|
|
|
Xeroderma pigmentosum results from the loss of?
|
Proteins involved in nucleotide excision repair
|
|
|
What do Bloom syndrome, ataxia-telangiectasia and Fanconi anemia have in common? Phenotype?
|
They are characterized by hypersensitivity to other DNA-damaging agents such as ionizing radiation (Bloom and ataxia-t) or DNA cross-linking agents, such as chemo (Fanconi anemia). Apart from predisposition to cancer, features such as neural symptoms (ataxia-t), bone marrow aplasia (Fanconi) and developmental defects (Bloom) occur.
|
|
|
What is the Warburg effect?
|
It is the phenomenon where cancer cells shift their glucose metabolism away from the oxygen hungry mitochondria to glycolysis (aerobic glycolysis). One hypothesis for why this is advantageous is the fact that tumors are still relatively hypoxic even with angiogenesis.
|
|
|
Tell me two ways in which translocations can activate proto-oncogenes
|
1) They result in overexpression of proto-oncogenes by swapping their regulatory elements with those of another gene (such as those that occur in lymphoid tumors)
2) The translocations allow normally unrelated sequences from two different chromosomes to recombine and form hybrid fusion genes that encode chimeric proteins that variously promote growth and survival, or enhance self-renewal and block differentiation. |
