1. BIOL 2416 Chapter 20: Genetics of Cancer

2. Cancer Genetic disease (due to DNA mutations)
Not usually inherited (mutations in somatic, not germ cells)

3. Different kinds of cancer:
(Names assigned
According to
Where cancer
Started)
See

5. Tumor Clonal (descendants of single cell gone wrong)
Transformed cells:
Neoplastic (grow too fast, cannot stop dividing)
No longer show contact inhibition
Are round and do not stick together
immortal

6. Transformation can be seen in tissue culture:
Normal Transformed

7. foci

8. Tumorigenesis: Transformation / immortalization
Deregulated proliferation
Suppressed apoptosis
Angiogenesis
Invasion
Metastasis

9. Whereas normal cells can do damage control:
Detect cellular DNA damage
Arrest cell division to prevent proliferation of damaged cells
Activate damage repair systems - if successful, return to cell cycle
Activate apoptosis (cell-mediated cellular suicide) if damage cannot be repaired = critical part of damage control in normal cells (why suicide? Mostly b/c necrotic cell death would trigger inflammation - bacterial (infection) magnet)

10. Genes implicated in cancer:
Oncogenes
Mutated (or amplified) versions of normal proto-oncogenes; act as stuck gas pedal; e,g, myc, ras, HER2, or may block apoptosis (e.g. Bcl-2)
Oncogenes are usually (1) growth factors, (2) growth factor receptors, (3) transcription factors, or (4) intracellular messengers (signals no longer turned off; many are protein kinases)

11. Cyclins:
Proteins that act as triggers for progression through the cell cycle
Growth factors may upregulate cyclins
Growth inhibitors may downregulat cyclins
High cyclin concentration activates cyclin-dependent kinases (Cdk’s) to stimulate cell division (see iGenetics animation)

12. Genes implicated in cancer, cont’d:
Tumor suppressor genes
Mutated versions act as lost brakes; e.g Retinoblastoma (Rb), P53, APC, DCC
P53 mutated in over half of cancers = “guardian angel” of the cell - coordinator of repair systems - mutated P53 makes damage responses much more likely to fail; defects also lead to increased cell division rates > domino effect > more mutations, chromosome breakages
DNA repair genes (mutator genes)
E.g. xeroderma pigmentosum, heredirtary nonpolyposis colon cancer

13. View two iGenetics animations on normal cell growth and P53

14. Knudson’s 2-hit Hypothesis for Tumor suppressors: Only 1-hit
Fig Comparison of the effects of tumor suppressor gene and proto-oncogene mutations
Knudson’s 2-hit
Hypothesis for
Tumor suppressors:
Only 1-hit
Required for
Oncogenes…
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

15. How can an oncogene (e.g. myc) become deregulated?
Insertion of myc oncogene into cell genome by a retrovirus
Insertion of a retrovirus near cellular myc, disrupting normal control of myc gene expression; get overexpression of myc
Translocation of part of chromosome with myc into trasncriptionally active chromatin (immunoglobulin locus - Burkitt’s Lymphoma)
Myc gene amplification

16. Fig A multistep molecular event model for the development of hereditary adenomatous polyposis (FAP), a colorectal cancer
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

17. What kinds of viruses can cause cancer?
DNA viruses (e.g. Hepatitis B)
Can become provirus that causes infected cells to divide more rapidly
Do not carry oncogenes
Retroviruses
Reverse transcriptase helps produce viral dsDNA that becomes inserted as a prophage
Typical genome includes LTRs and gag, pol, env

19. RSV was 1st identified cancer-causing retrovirus
Encodes src
Src is really a virla version of a normal cellular proto-oncogene picked up by the virus long ago
Src may have been inserted near the viral LTRs that contain powerful enhancers, causing elevated expression at the wrong times, I.e. too much growth and cancer (similar to myc story - insertional mutagenesis)

20. Fig. 18.10 The chicken c-src proto-oncogene and its relationship to v-src in Rous sarcoma virus
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

21. Fig. 18.11 Model for the formation of a transducing retrovirus
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

22. Cancer vaccines Prophylactic
Prevent viral infections that might lead to cancer (e.g. Hepatitis B vaccine)
Therapeutic
By presenting extra antigens to body, boost immune system’s effectiveness to fight the virus and the infected cells

23. What other targets? Surgery
Chemotherapy/radiation to attack rapidly growing cells
unfortunately also attacks gut cells, hair follicles
Causes DNA mutations so devastating to kill cells
Problem: cancer cells may fail to react/lose ability to detect DNA damage - may make things worse
Another potential side effect: drug resistance (e.g. by upregulation of P-glycoprotein pumps to pump poisons out of cells)
Telomere replication
Cancer cells overproduce telomerase (lose internal clock - divide more than normal ~60 times.
Angiogenesis
Pancreatic cancers particularly angiogenic
Idea is to starve tumor cells of O2 and nutrients
Boost immune system
E.g. by giving interferons