Exam 2: Cancer and Genetic Diseases

Question 1

Hereditary

Breast and Ovarian Cancer

Answer 1

• Mutation and Inheritance
  
  • BRCA-1 and BRCA-2
  • Autosomal dominant
• Phenotype
  
  • Adult onset
  • Accounts for 3-10% of all breast CA
• Pathogenetics
  
  • BRCA 1/2 regulate homologous DNA repair
    
    • ∆ cell cycle
  • Defect predisposes for breast and ovarian CA
    
    • Also prostate CA, melanoma, colon CA
• Genetic principles illustrated
  
  • Two-hit hypothesis
  • Founder effect
  • Tumor suppressor gene

Question 2

Chronic Myelogenous Leukemia

Answer 2

• Mutation and Inheritance
  
  • BCR-ABL 1 oncogene
  • Somatic mutation
• Phenotype
  
  • Onset middle to late adulthood
  • Leukocytosis
  • Splenomegaly
  • Fatigue and malaise
  • Philadelphia chromosome
• Pathogenetics
  
  • BCR ⇒ encodes phosphoprotein
  • ABL ⇒ encodes tyrosine kinase
    
    • Cell cycle regulation, stress response, integrin signaling, neural development
  • Chimeric chromosome w/ constitutive TK activity
  • Unregulated proliferation of hematopoietic stem cells
• Genetic principles illustrated
  
  • Oncogene activation
  • Chromosomal abnormalities
  • Fusion proteins
  • Multi-hit hypothesis

Question 3

Familial Adenomatous Polyposis

Answer 3

• Mutation and Inheritance
  
  • Adenomatous polyposis coli (APC) gene mutation
  • AD
• Phenotype
  
  • Onset adolesecne to mid-adulthood
  • Colorectal adenomatous polyps
  • Colorectal CA
  • Multiple primary CA’s
• Pathogenetics
  
  • APC protein regulates transciption, cell adhesion, microtubular cytoskeleton, cell migration, apoptosis, and cell proliferation
  • LoF APC + other mutations ⇒ carcinogenesis
    
    • Cytogenetic instability
• Genetic principles illustrated
  
  • Tumor suppressor gene
  • Multistep carcinogenesis
  • Somatic mutation
  • Cytogenetic + genomic instability
  • Variable expressivity

Question 4

Neurofibromatosis I

Answer 4

• Mutation and Inheritance
  
  • NF1 mutation
  • AD
• Phenotype
  
  • Onset prenatal - late chlldhood
  • Cafe-au-lait spots
  • Lisch nodules
  • Plexiform neurofibromas
  • Optic glioma
  • Osseous lesions
  • Axiallary and inguinal frackling
• Pathogenetics
  
  • NF regulates cell proliferation
  • > 500 mutations identified
• Genetic principles illustrated
  
  • Tumor suppressor gene
  • LoF mutations
  • Variable expressivity
  • Extreme pleiotropy
  • Allelic heterogeneity
  • De novo mutations

Question 5

Retinoblastoma

Answer 5

• Mutation and Inheritance
  
  • RB1 mutation
  • AD
• Phenotype
  
  • Onset: childhood
  • Retinal tumors
  • Leukocoria
  • Strabismus
  • Visual deterioration
  • Conjunctivitis
• Pathogenetics
  
  • Rb regulates exit of differentiated cells from cell cycle
  • Regulates progress of cells through the cell cycle
• Genetic principles illustrated
  
  • Tumor suppressor gene
  • Two-hit hypothesis
  • Somatic mutation
  • Tumor predisposition
  • Cell-cell regulation
  • Variable expressivity