Molecular Basis Of Carcinomas Flashcards
Normal pathway and function of APC gene
Binds to Arm/beta-Catenin and anchors it in the cytoplasm
Wnt2 signaling pathway binds APC to LRP embedded in the cell membrane, releasing beta-Catenin
Free beta-Catenin enters the nucleus, binds with TCF transforming it from a repressors of Wnt-targeted-genes to an activator of the same genes including c-myc.
FAP name, associated gene, inheritance pattern, and cause
Familial Adenomatous Polyposis
Autosomal dominant inheritance of defective APC gene
LOH of wild type gene causes expansion of Adenomatous Polyps in the colon, which may become malignant.
90% chance of developing colon cancer by age 50.
What is the status of the Wnt signaling pathway in the absence of APC?
The Wnt pathway is constitutively activated, resulting in rapid cell divisions and polyp growth.
What test can be done to locate beta-Catenin and where would it be found in normal cells? In polyp cells?
An antibody stain of the cytoplasm of a normal cell would be positive for beta-Catenin, while the nucleus would be negative.
An antibody stain of the cytoplasm of a polyp cell would be negative for beta-Catenin, while the nucleus would be positive.
What effect could a mutation in beta-Catenin have on c-myc production?
A mutation inhibiting binding between beta-Catenin and APC would also result in constitutive c-myc production.
What is the normal process for creating new colon cells?
Wnt is produced by stromal cells near the colon stem cells
Wnt binds to Frizzled in stem cells
Frizzled induces APC to release b-Catenin
B-Catenin enters nucleus and binds TCF
TCF transforms from repressor to activator
C-myc is produced and cells divide.
What checkpoints and processes is BRCA1 involved in?
S-Phase checkpoint (w/ BACH1 & TopBP1) G2/M checkpoints (w/ CtlP & MRN) Homologous Recombination (w/ BRCA2 & Rad51) Loss of BRCA1 causes loss of all of these checkpoints
What are checkpoints?
Surveillance mechanisms that survey the quality of the DNA that is made. If defective DNA is detected after synthesis, the cells will arrest at G2/M checkpoints until DNA is repaired.
What is unusual about mutations in p53 compared to those in most other tumor suppressors?
75% of mutations in p53 are missense mutations, allowing for continued production of mutated p53 proteins.
50%+ of mutations in other tumor suppressors are frame shift or nonsense, causing complete loss of function of these genes.
Why are p53 mutations considered “Dominant Negative”?
P53 forms homotetramers
The presence of a mutant copy of p53 inactivates the tetramer and makes it more stable so it persists longer. Thus, one bad copy overrides the function of the good copies.
Why is the mutation at point 175 of the p53 gene called the smoking gun mutation.
This is the most common mutation found in p53 of lung cancer patients. It was also found to be caused by chemicals in tobacco smoke. This conclusively linked tobacco smoke to lung cancer and led to the tobacco settlement.
What are the basic properties common to cancer cells?
Altered Morphology (some with very little cytoplasm)
Loss of contact inhibition (continued growth regardless of number of cells)
Ability to grow without solid substrate to attach to (grow in fluid solution)
Immortalization (no senescence)
Reduced requirement for growth factors, able to reproduce in absence of growth factors or presence of anti-growth signals
High saturation density
Increased transport of glucose (can live in hypoxic conditions, produce lots of lactic acid leading to the diagnostic smell of cancer)
Tumoregenicity
What is BCR/ABL?
BCR/ABL is the mutant gene that results from the non-homologous recombination of chromosomes 22 & 9 (Philadelphia chromosome). It is found on Chr 22. BCR is from B-cells in the lymphatic system, and ABL is a protein kinase that is usually limited in expression. This amplifies the presence of the kinase in the cells.
What is the second most common cancer for patients with familial Rb, and what percentage of familial Rb patients have cancers later in life?
Osteosarcoma. Up to 36% develop additional cancers.
