Chapter 6

• Tumor Suppressor Gene (Strict Knudson Definition) 


  Gene in which a germline mutation (on a single allele) predisposes an individual to higher cancer risk
• Mutations on TSG are 


  Usually recessive
• Examples of TSG


  TP53, BRCA1, and BRCA2
• 5-7% of all BCa cases have mutations and loss of function of 


  BRCA1/2
• RB1 gene function 


  Transcriptional regulator of cell cycle
• Human tumors associated with sporadic mutation of RB1 


  Retinoblastoma and osteosarcoma
• Cancer syndrome associated with RB1


  Familial retinoblastoma
• Tumor phenotype of knock-out mouse mutants of RB1

  MTC, pituitary adenocarcinoma, pheochromocytomas
• p53 gene function


  Transcriptional regulator/growth arrest/apoptosis
• Human tumors associated with sporadic mutation of p53


  Sarcomas, breast/brain tumors
• Associated cancer syndrome with p53

  Li-Fraumeni
• Tumor phenotype of knock-out mouse mutants of p53

  Lymphomas, sarcomas
• APC gene function


  Binds/regulates β-catenin activity
• Human tumors associated with sporadic mutation of APC


  Colon Cancer
• Associated cancer syndrome with APC

  Familial adenomatous polyposis
• Tumor phenotype of knock-out mouse mutants of APC


  Intestinal polyps in Apc min
• BRCA1/2 gene function


  Transcriptional regulator/DNA repair
• Human tumors associated with sporadic mutation of BRCA1/2


  Breast/ovarian tumors
• Associated cancer syndrome with BRCA1/2

  familial breast cancer
• PTEN gene function 


  Dual-specificity phosphatase
• Human tumors associated with sporadic mutation of PTEN

  Glioblastoma, prostate, breast
• Associated cancer syndrome 


  Cowden syndrome, NZS, and Ldd
• Tumor phenotype of knock-out mouse mutants of PTEN

  Lymphoma, thyroid endometrium, prostate
• MSH2 gene function


  mut S homolog, mismatch repair
• Human tumors associated with sporadic mutation of MSH2 and MLH1

  Colorectal cancer
• Associated cancer syndrome with MSH2 and MLH1

  HNPCC
• Tumor phenotype of knock-out mouse mutants of MSH2

  Lymphoma, colon/skin carcinoma
• MLH1 gene function


  mut L homolog, mismatch repair
• Tumor phenotype of knock-out mouse mutants

  Lymphoma, intestinal adenoma/carcinoma
• PMS1/2 and MSH6 gene function 


  Mismatch Repair
• Human tumors associated with sporadic mutation PMS1/2 ans MSH6

  Colorectal cancer
• Associated cancer syndromes with PMS1/2 and MSH6

  HNPCC
• Tumor phenotype of knock-out mouse mutants of PMS2


  Lymphoma and sarcoma
• Tumor phenotype of knock-out mouse mutants of MSH6


  Lymphoma, intestinal adenomas/carcinomas
• PTEN stands for


  Phosphatase and TEnsiN homolog on chromosome 10
• PTEN and the PIP system

  downregulator
• Dual specificity of PTEN

  it can act as both a protein and a lipid phosphatase.
• Net result of PTEN

  loss of apoptosis function and hyper cell proliferation through IP3 pathway
• Knudson's two-hit hypothesis 


  two separate mutations—one in each of the two retinoblastoma alleles—are needed to inactivate the two copies of the RB1 allele and prevent the expression of the RB protein.
• What does CIP p27 do?


  inhibit cell cycle progression