Genetics of Oncogenes

Question 1

Evidence of Monoclonality (3)

Answer 1

1. Examination of X-inactivation pattern in cancers (cancer tissue have the same copy of the inactivated X-chromosome)
2. Chromosomal Abnormalities-all cells in the tumor contain the genetic aberration (EX: Philadelphia Chromosome)
3. Multiple Myeloma produce a monoclonal Immunoglobulin-all myeloma cells produce the same antibody

Question 2

Proto-oncogene mutation

Answer 2

Normally encode proteins that promote cell growth
Mutation results in 2 things:
1. Excessive increase in one or more normal functions
2. Gain of function

Usually a single copy mutation is sufficient to cause cancer despite the presence of a normal copy

Question 3

Tumor Suppressor Genes-Mutation

Answer 3

Normally produce genes that inhibit cell cyle and preventing proliferation
Results in a LOSS of a function

*Both alleles must be affected before malignant transformation can take place

Question 4

Major Cellular Proliferative Pathway
(MAP Kinase Pathway)
Under Normal Physiologic Conditions

Answer 4

1. Growth factor presence outside of the cell
2. Binds to the receptor
3. Autophosphorylation
4. Exchange of GDP (inactive RAS) to GTP (active RAS)
5. RAS binds to RAF and begins a phosphorylation cascade
6. Upregulation and downregulation transciption of different genes favoring cell survival and proliferation

RAS: G protein, signal transducer, has GTPase activity

Question 5

Growth Factor Receptor to know

Answer 5

c-erbB: EGF receptor kinase

Question 6

G protein/signal transduction (1)

Answer 6

RAS

Question 7

Intracellular Tyrosine Kinases (1)

Answer 7

c-abl

Question 8

Transcription Factors (3)

Answer 8

1. c-myc
2. c-fos
3. c-jun

Question 9

Trastuzumab

Answer 9

Monoclonal antibody to HER2 receptors

Pt’s w/ breast carcinomas w/ ERBB2 amplification and HER2 overexpression

Causes tumor regression, stop tumor growth, induces apoptosis

Question 10

How are Oncogenes Activated by Gene Amplification?

Answer 10

1. Double minutes (Extrachromosomal Elements)
2. Homogeneously staining regions (HSRS): attached to the chromosome

Question 11

Truncation or point mutations can render a Growth Factor Receptor what?

Answer 11

Constitutively active because it is always dimerized

Question 12

Imatinib Mesylate (Gleevac)

Answer 12

BCR-ABL tyrosine kinase inhibitor.

Effective against CML-suppresses tumor proliferation

CML: translocation of philadelphia chromosome t(9;22)