Cancer Genetics I

Question 1

list the progression of a tumor

Answer 1

Normal –> hyperplastic –> dysplastic –> neoplastic –> metastatic

Question 2

name 3 proofs of monoclonal tumors

Answer 2

• Examination of X-inactivation in cancer
  
  • all cells from cancers have the same copy of the X inactivated
• chromosomal abnormalities of cancers
  
  • all cells in the tumor contain the same translocation/aberration
• multiple myelomas produce a monoclonal Ig
  
  • all myeloma cells in a patient produce the same antibody molecule

Question 3

describe protooncogenes’ role in signal transduction

Answer 3

1. growth factors
2. growth factor receptors
3. intracellular tyrosine kinases
4. G-protein/signal transduction
5. transcription factors

Question 4

describe normal growth factor receptor activation vs mutant

Answer 4

• Proto-oncogenes are normal versions of genes
• mutant receptors (oncogenes) may undero automatic dimerization, even in the absence of the ligand, which then tells the cell to divide
  
  • or receptor is truncated and always on

Question 5

describe Burkitt lymphoma

Answer 5

• Myc oncogene is fused to immunoglobin locus (t 8;14)
  
  • myc is a transcription factor important for G1/S transition
• Level of oncogene expression is increased as myc is now under the regulation of IgH promoter because of translocation (active promoter)

Question 6

describe chronic myeloid leukemia

Answer 6

• Bcr-Abl translocation t(9;22) (Philadelphia Chromosome)
• After translocation, abl (normally a tyrosine kinase) is next to bcr which leads to a hybrid bcr-abl fusion protein
  
  • bcr-abl fusion protein has unregulated tyrosine kinase activity and keeps telling the cell to divide
  • abl stuck in active form

Question 7

describe Gleevec

Answer 7

• Gleevac (imatinib) is a drug that inhibits the bcr-abl from signalling the cell to divide

Question 8

describe mutations in Ras

Answer 8

• point mutation leads to Ras always bound to GTP (active state)
  
  • constitutively active
  • tells cell to divide

Question 9

describe oncogenesis by gene amplification

Answer 9

• Double minutes = extrachromosomal fragments of DNA
  
  • containing an amplified region of the chromosome
  • often seen in tumors where the amplified region includes an oncogene
• EGFR is often amplified as double minute chromosomes
  
  • can be visualized with FISH probes

Question 10

describe homogenously staining regions

Answer 10

• abnormal HSRs of chromosomes in cancers often contain amplified oncogenes (can happen in any oncogenes)
  
  • not production of mutant protein, but overproduction of protein –> uncontrolled cell division
  • N-MYC amplification in neuroblastomas

Question 11

describe Wilms tumor

Answer 11

• results from Loss-of-function in the WT1 gene on ch 11
  
  • encodes a transcription factor that is a tumor suppressor

Question 12

describe tumor suppressor genes

Answer 12

• these are genes that cause cancer when they are lost (Loss of function mutation)
• tumor suppressor genes = cell cycle control genes, apoptosis promoting genes and/or DNA repair genes
• one “good” gene is enough for cell cycle control
  
  • need to lose the function of BOTH to get cancer
  • “two hit” hypothesis

Question 13

describe the familial form of cancer

Answer 13

• 10,000 x incidence of sporadic
• often multiple tumors
• often occur earlier than sporadic

Question 14

describe the two hit hypothesis in sporadic vs familial

Answer 14

• in sporadic, 1st hit is random
• in familial, 1st hit is inherited
  
  • therefore, more likely to cause cancer since 2nd hit is all that is needed for cancer

Question 15

describe the function of Rb protein

Answer 15

• No cyclin/Cdk
  
  • Rb (hypophosphorylated)/E2F complex still binds DNA
  • blocks transcription
• Cyclin/Cdk present
  
  • hyperphosphorylates Rb
  • Rb no longer represses E2Fs
  • E2Fs activate S-phase genes (cell divides)

Question 16

name the 4 genes that regulate the phosphorylation of Rb protein

Answer 16

• RB, CDK4, cyclin D gene and CDKN2A (p16(

Question 17

describe the roles of p53

Answer 17

1. slows cell cycle, allows time to do repairs
2. increase DNA repair capabilities
3. if damage is too great then it initiates apoptosis and eliminates cell

Question 18

how can p53 activate apoptosis

Answer 18

• increases expression of:
  
  • pro-apoptotic Bcl-2 family members
  • Fas receptor (CD95)
  • IGFBP-3 (sequesters cell survival proteins)

Question 19

describe Li-Fraumeni syndrome

Answer 19

• caused by inherited mutation of p53
  
  • 1st hit inherited
  • 2nd hit somatic (responsible for LOH)
• rare disorder that greatly increases the risk of cancer at a young age

Question 20

describe familial adenomatous polypopsis (FAP)

Answer 20

• caused by mutation in the APC gene on ch 5
  
  • affects a tumor suppressor gene
  • allelic heterogeneity
• ~1% of colorectal cancers
• very high penetrance

Question 21

describe the normal APC pathway

Answer 21

• APC is a component of the WNT signaling pathway
• APC encodes a tumor suppressor whole role is to down-regulate growth promoting signals
• WNT signal present
  
  • destruction complex inactivated
  • B-catenin not degraded
  • B-catenin moves to nucleus, forms complex with TCF-4
  • activates growth promoting genes
• NO WNT signal
  
  • APC interacts with B-catenin
  • triggers phosphorylation = ubiquitination and B-catenin degradation
  • therefore, low B-catenin levels
  • No cell growth

Question 22

describe mutation of APC

Answer 22

• mutant APC does not interact with B-catenin in the absence of WNT signal
• B-catenin NOT phosphorylated and NOT degraded
• B-catenin interacts with TCF-4 and activates growth (in the absence of WNT signal)

Question 23

describe Hereditary Non-polyposis Colon Cancer

Answer 23

• few polyps but progress rapidly
  
  • as opposed to many polyps that progress slowly in FAP
• defects in mismatch DNA repair genes (MMR genes)
• cells accumulate mutations at rate up to 1000x higher than normal
• tumors also exhibit microsatellite instability (short repetitive sequences of DNA)

Question 24

contrast FAP and HNPCC

Answer 24

• FAP
  
  • APC mutation
  • numerous polyps
• HNPCC
  
  • MSH2/MLH1 (mismatch repair proteins)
  • fewer polyps
  • microsatellite instability

Question 25

describe BRCA1/BRCA2

Answer 25

* code for breast cancer type 1/2 suspectibility protein * involved in **DNA repair or apoptosis** when DNA can't be repaired * allelic heterogeneity

Question 26

describe HER-2 overexpression and treatment

Answer 26

* HER-2 overexpression is found in sporadic breast cancer * **Herceptin drug (antibody) binds to HER2 and prevents binding of EGF to HER2** * **addition of Herceptin to the treatment results in decreased tumor cell proliferation**

Question 27

describe epigenetics in tumorigenesis

Answer 27

* DNA methylation and histone modifications are frequently altered in tumor cells * tumor suppresor loci are frequently hypermethylated in cancer cells (silencing of tumor suppressor genes)

Question 28

describe the role of miRNAs in tumorigenesis

Answer 28

* miRNAs act to reduce the expression of genes by targeting specific mRNAs * tumorigenesis caused by 2 methods: * reduction of miRNA that could have inhibited oncogene RNA * increase in miRNA that inhibits tumor suppressor RNA