Familial Colon Cancer as a Model of Carcinogenesis Flashcards
Explain the relationship between a colonic adenoma and colonic carcinoma.
- Germline inactivation of one allele = Adenoma (Genomic instability)
- Acquire additional independent secondary mutations = Carcinoma
Discuss the genetic changes that occur sequentially in the development of colon cancer in those with APC mutation in the Germline.
• Classical Familial Adenomatous Polypos
o Autosomal dominate
o 100% colon cancer
• Sporadic Colorectal Cancer
o Similar to what is named above but sporadic
List three intracellular functions that APC can play.
• Truncation mutation in the APC gene
o Can’t bind β-Catenin
o Can’t bind actin
Diminshed appropriate migration within the crypt
o Constitutive expression of WNT signaling = constant proliferation
Genomic instability
Mutants persist and do not die and basically move out normal cells
• Adenomatous Polypsis Coli (APC)
o Cell proliferation, migration & adhesion = Actin
o Gene expression = Wnt signaling
o Degradation of β-Catenin = Stop cell proliferation
Discuss the role of β-Catenin in the colonic epithelial cell.
• In Cytoplasm
o Binds to target in nucleus
o Initiate cell cycle & proliferation
o G1 phase to S phase
o Creates a proliferative state
o Binds to APC so that it can be cleared\destroyed
o The crypt stem cells ALWAYS have free β-Catenin so in a proliferative state
• In cell Junction
o Adhesins
Describe the sequential histological changes that occur as the colonic epithelium progresses from normal through
adenomatous to carcinoma.
• Pre-neoplasic changes
o Crowding
o Irregular branching
o Abnormal crypt fission (joined together instead of separated)
• Tubular adenoma
o Dysplasia & dyspalctic crypts
o Multilayered
o Blue dots = apoptosis
o Hyper-chromatic and elongated
• Adenocarcinoma
o Now has polyps and very intricate looking crypts
o Loss of polarity
o Clearing of chromatin
o Glandular epithelium
o Invasive adenocarcinoma
o Abnormal crypt fusion
o Necrosis
