Cancer Genetics pt.1 Flashcards
(30 cards)
What are cancer stem cell?
Subpopulations of cancer cells that can self renew, generate diverse cells in the tumor mass and sustain tumoriogenesis
What is the theory on how tumors arise?
The theory is that they originate as a result of mutational hits on normal stem cells, by the transformation of restricted progenitor cells or even the differentiated cells that acquire self renewing capacity.
What are proto oncogenes?
They normally promote normal cell growth and encode transcription factors which stimulate expression of other genes, signal transduction molecules that stimulate cell division and cell cycle regulatros that move the cell through the cell cycle. In normal cells, proto onco genes become quiscient
What are Oncogenes?
These are cancer causing genes and in tumor cells they are often mutated or expressed at high levels
Explain acutely transforming retrovirus steps
Cell is infected with retrovirus and proto oncogene is integrated
new host cell is infected
integration and expression of viral oncogene takes place
neoplastic transformation occurs
Explain slow transforming retrovirus infection.
Infection of cell with retroviruse carrying promoter gene
integration of promoter gene adjacent to proto oncogene
conversion of proto oncogene to oncogene
neoplastic transformation takes placve
What is a tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function
What are the 2 general groups of tumor supressor with examples of each?
Governors of cell cycle: Retinoblastoma gene
Guradian” P53 gene
Explain the role of the Governors like RB gene
They stop the cell cycle at the G1-S phase
They are classic tumor suppressor genes whos mutation leads to transformation of the cell by removing an important brake of cell proliferation
Its active form blocks the cell cyle at the G1-S phase but mutated or inactive forms result in loss of the break
It is recessive
Explain sporadic retinoblastoma.
2 hits of mutations are acquired in both alleles after birth
explain inherited/familial retinoblastoma
Children inherit one defective copy of RB gene while the other one is normal. During life one hit occurs leading to mutation of the 2nd allele
Explain the role of Guardians such as p53 gene.
They are responsible for sensing genomic damage and stopping the cell cycle to prevent proliferation
They also stimulate DNA repair but if he damage is too great, they induce apoptosis by activating BAX and induce Permanent cell arrest
Activated p53 controls the expression and activity of genes involved in cell cycle, DNA repaur, cellular senescence and apoptosis
Describe regulatory genes involved in apoptosis.
In normal cell, apoptosis is guided by
Pro apoptotic factors
anti apoptotic factors and cell death receptor CD95(fas)
Normally p53 activates pro apoptotic gene BAX
What happens to apoptosis regulation when mutations occur in p53 gene?
p53 cannot activate BAX and over expression of BCL2(anti-apoptotic gene) occurs hence the transformed tumor cells escape from apoptosis.
CD95 receptors are depleted in hepatocellular carcinoma and escape apoptosis.
Explain how DNA repair fails when mutation occurs.
During mitosis, normal cells suffer from minor DNA damage which is detected and repaired before mitosis by p53. However when this system becomes damaged, the defect is unrepaired and the defected DNA is passed to the next progeny of cells resulting in cancer
Define Xeroderma pigmentosum.
An inherited disorder where there is a defect in DNA repair mechanism and upon exposure to sunlight, DNA damaged by UV radiation cannot be repaired. Such patients are more prone to skin cancer.
Briefly describe the epidemiological studies of Breast cancer.
Reproductive and menstrual histories are important factors.
Women who have borne children are less likely to develop breast cancer and the lower her age when having her first pregnancy, the lower her risk of developing breast cancer.
The later the age at menarche, the lower the risk of breast cancer
Breifly describe the epidemiological studies of Gastric cancer
People from lower socioeconomic groups have a greater risk of developing gastric cancer
Potential carcinogens include: Specific dietary irritants( salt and preservatives) or potential environmental agents (nitrates)
it is 8X more common in japanese and chinese population than wester europeans.
What is chronic myeloid leukemia.
An acquired abnormality found in blood or bone marrow cells but not in other tissue.
Philadelphia chromosome (Ph1) long arm material has been reciprocally translocated to and from the long arm of Ch#9
What is Epigenetics?
Refers to DNA and chromatin modification that persist from one cell division to the next despite a lack of change in the underlying DNA sequence
Explain Lyonization.
The lyon hypothesis states that during early development, one of the X xhromosomes in a female gets turned off and this is maintained in all descendant cells of the clone
1) condensed X chromosome is genetically in active
2) Its inactivation occurs early in development when the embryo consists of 32 cells
3) at this stage, each of the 32 cells, one of the X chromosomes is randomly inactivated
4) Inactivation is mitotically stable
5) Net effect of this is to equalize phenotypes in males and females for genes that are carried on the X chromosome
N/B: inactivation is due to DNA methylation
Explain X reactivation in females.
In the female fetus, future germ cells undergo lyonization along with somatic cells
X inactivation occurs in the early female embryo leading to mosaicism
The inactive X chromosome is the barr body, seen in female somatic cells
Following differentiation of female fetus, the inactivated X chromosomes are reactivated during female gametogenesis
When germ cels develope into oocytes and enter meiodis, their inactivated X chromosomes become reactivated so that every egg produced has an activated X chromosome prior to fertilization
What are the fundamental epigenetic mechanisms?
DNA methylation
Chromatin remodelling
Histone modification
Non coding RNAs
Explain DNA methylation
This is the addition of methyl groups to certain cytosine in DNA sequence resulting in 5-methylcytosine
Methylation of CpG islands results in transcriptional repression.
Methylation of promoter regions can block access of proteins needed for transcription and serve as binding sites for proteins that condesne chromatin
