Cancer genetics 25/10/22 Flashcards
What are the main features of a tumor?
Growth signal autonomy
Uncontrolled growth
Insensitivity to anti-growth signals
Invasion and metastasis
Unlimited replicative potential
Sustained angiogenesis
Evading apoptosis
What is anchorage-independent growth?
This is when tumor cells can grow without a surface to anchor to. Normal cells have an absolute requirement for tethering to a solid substrate before they would grow and were therefore considered to be anchorage-dependent. Anchorage-independent cells in vitro are good predictors of their ability to form tumors in vivo.
What is loss of sensitivity to contact-inhibition of growth?
In normal cells high cell density or contact with neighbors causes these cells to stop dividing. In tumor cells they have clearly lost contact (density) inhibition and consequently continued to proliferate, piling up on top of one another and creating multilayered clumps of cells so thick that they could often be seen with the naked eye.
What are telomeres in cancer?
Telomere regeneration can be done through the actions of the telomerase enzyme. Telomerase activity is detectable in 85 to 90% of human tumor cell samples but is present at very low levels in most types of normal human cells.
What is telomerase?
Telomerase is a ribonucleoprotein containing human telomerase reverse transcriptase activity.
This maintains telomere length in certain cell types, such as stem cells. Telomerase transforms normal fibroblasts into cancer cells in vitro (tumourigenesis) and several oncogenes have been demonstrated to regulate the expression of telomerase.
What is the invasion-metastasis cascade?
Step 1 - cancer cells invade through the basement membrane and migrate through the tumor stroma.
Step 2 - intravasation into vasculature.
Step 3 - survival in the circulation is characterized by circulating tumor cells in the bloodstream undergoing shear stress and evading clearance by the immune system before reaching distant organs. After attaching to blood vessels around secondary sites, tumor cells enter.
Step 4 - extravasation through the endothelial barrier.
Step 5 - Colonization in the metastatic target organ. (Hapach, L.A., et al, 2019).
What is Boveri’s somatic mutation theory?
Carcinogens interact with and cause damage to
DNA. If not repaired, the damage is fixed as mutations. Mutations involving genes controlling growth can result in neoplastic transformation. The cancer cell has inherited mutations and is immortal.
How are cancer mutations inherited?
Genes associated with cancers are 90% somatic mutations and 20% are germline mutations. Germline cancers can be passed on while somatic mutations can not.
What is rhabdomyosarcoma?
Rhabdomyosarcoma is a malignant tumor of the muscles that are attached to the bones. This cancer mostly affects children.
What is alveolar rhabdomyosarcoma?
This is the cause of around 20% of RMS cases. They are small, round, and undifferentiated cells and result in a worse prognosis. The mutation is a translocation.
What is embryonal rhabdomyosarcoma?
This is the cause in around 60% of RMS cases. They are small, round cells with variable degrees of differentiation. This is a favorable prognosis. The mutation is a chromosomal gain in 2,8,12, and 13, or a chromosomal loss in 9 and 16.
Where is the chromosomal location of the Rb gene?
The Retinoblastoma gene (RB1), located on chromosome 13, is a tumor suppressor gene that was discovered in genetic studies of hereditary retinoblastoma.
What is the function of the Rb protein?
Growth suppression:
-E2F is a transcription factor that mediates growth-dependent activation of genes required to make the transition into and through the S phase
-Rb binds and inactivates E2F under conditions of growth suppression
-There are several ways to alleviate growth suppression resulting in controlled or uncontrolled cell growth
Relief of growth suppression:
*G1 phase phosphorylation releases E2F
*Adenovirus E1A oncoprotein binding releases E2F
*Gene mutation affecting binding pocket releases E2F
What is Knudson’s ‘two-hit’ theory?
This is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or by epigenetic silencing, to cause a phenotypic change. It was first formulated by Alfred G. Knudson in 1971 and led indirectly to the identification of tumor suppressor genes.
What was Knudson’s theory with retinoblastoma?
Alfred Knudson Jr. studied the kinetics with which
bilateral and unilateral retinoblastomas appeared in children. He calculated that the bilateral cases (tumors in both eyes) arose with one-hit kinetics, whereas the unilateral tumors (affecting only one eye) arose with two-hit kinetics. Each of these hits was presumed to represent a somatic mutation. The fact that the two-hit kinetics involved two copies of the Rb gene was realized only later.
What is Knudson’s theory about tumour suppressor genes?
The inactivating mutation of one copy of a TSG (tumour suppressor gene) usually creates a recessive null allele whose presence is not felt by the cell because of the activities of the surviving wild-type allele. Only when the 2nd gene copy is inactivated or eliminated, then the cell will be free from the inhibitory actions of the gene.
What is Knudson’s theory about tumour suppressor genes?
The inactivating mutation of one copy of a TSG (tumour suppressor gene) usually creates a recessive null allele whose presence is not felt by the cell because of the activities of the surviving wild-type allele. Only when the 2nd gene copy is inactivated or eliminated, then the cell will be free from the inhibitory actions of the gene.
Who named oncogenes?
Huebner-Todaro (1969).
How were oncogenes discovered?
Viral mRNA particles in vertebrate cells. Viruses induce cancers in experimental animals. Normal cells have the capacity to activate latent tumour viruses. This led to the identification of retroviral oncogene src (Rous sarcoma in chicken) and the realization that these viral genes were derived
from functional cellular genes or proto-oncogenes.
The identification of cellular proto-oncogenes as
precursors of transforming cancer genes.
How do oncogenes play a role in cancer?
In normal cells, proto-oncogenes increase cell growth and proliferation, and tumor suppressor genes will decrease cell growth and proliferation. In cancer cells, mutated or activated oncogenes lead to a massive increase in cell growth and proliferation which results in a malignant transformation, and the tumor suppressor gene is mutated so it’s function is lost.
What is an oncogene?
Oncogene - mutated forms of proto-oncogenes that promote abnormal growth and cell division.
Oncogenes are described by a three-letter code usually derived from their first discovery. Oncogenes are usually dominant (gain of function) whose activities are increased as a consequence of genetic alteration. The gain of function can be due to qualitative or quantitative changes in the protein products.
A group of cellular genes includes -
*DNA viruses
*Homologous to the transforming genes of RNA viruses (retroviruses)
*Normal cellular genes actively transcribed in a variety of neoplasm: such as growth factor genes and genes for cyclins.
What is a proto-oncogene?
Proto-oncogenes are normal genes that can become oncogenes, they are found in many animals and code for growth factors that stimulate cell division. For a proto-oncogene to become an
oncogene, a mutation must occur in the cell’s DNA.
Different processes of a proto-oncogene becoming an oncogene?
- Proto-oncogene has a mutation within the gene which causes a hyperactive growth-stimulating protein to be produced.
- Multiple copies of the gene result in normal growth-stimulating protein becoming excessive.
- A gene is moved to a new DNA locus and is under new control which results in a normal growth-stimulating protein becoming excessive.
What are oncogene products?
Growth factors
– Epidermal growth factor (EGF)
– Fibroblast growth factor (FGF), PDGF-b encoded by SIS
* Growth factor receptors
– EGF receptors encoded by ERBB1, HER2/NEU, MET
* Signal transduction proteins
– G-protein encoded by RAS
– Tyrosine kinase encoded by ABL
* Nuclear transcription factors
– MYC, MYB, JUN, FOS
* Cyclins and cyclin-dependent kinases
– CDK4, CDKN2A, cyclin D
What are the growth factors and their receptors?
PDGFa - PDGF-R (Platelet-derived growth factor) EGFb - EGF-Rc (Epidermal growth factor)
NGF - Trk (Nerve growth factor)
FGFd - FGF-Re (Fibroblast growth factor)
HGF/SF - Met (Hepatocyte growth factor/Scatter factor)
VEGFf - VEGF-R9 (Vascular endothelial growth factor)
IGFh - IGF-R1 (Insulin-like growth factor)
GDNF - Ret (Glial cell derived neurotrophic factor)
SCF - Kit (Stem cell factor)
VSMC (Vascular smooth muscle cell)
What is the cell signaling growth factor to receptor cascade?
- Secreted growth factor
- Growth factor receptors
- Cytoplasmic Signal Transduction proteins
- Nuclear proteins - transcription factors - cell growth genes
How is autocrine signaling changed in cancer cells?
In many types of cancer, tumor cells acquire the ability to make a ligand for a growth factor receptor that they also display. This creates an auto-stimulatory or autocrine signaling loop.
How is autocrine signaling changed in cancer cells?
In many types of cancer, tumor cells acquire the ability to make a ligand for a growth factor receptor that they also display. This creates an auto-stimulatory or autocrine signaling loop.
