Download Genetics of Cancer

BIOL 2416
Chapter 20: Genetics of
Cancer
Cancer
• Genetic disease (due to DNA
mutations)
• Not usually inherited (mutations in
somatic, not germ cells)
Different kinds of cancer:
(Names assigned
According to
Where cancer
Started)
• See http://www.cancer.gov
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
Transformation can be seen in tissue
culture:
Normal
Transformed
foci
Tumorigenesis:
• Transformation / immortalization
– Deregulated proliferation
– Suppressed apoptosis
• Angiogenesis
• Invasion
• Metastasis
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)
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)
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 cyclindependent kinases (Cdk’s) to stimulate cell
division (see iGenetics animation)
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
View two iGenetics animations
on normal cell growth and P53
Fig. 18.12 Comparison of the effects of tumor suppressor gene and
proto-oncogene
mutations
Knudson’s 2-hit
Hypothesis for
Tumor suppressors:
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Only 1-hit
Required for
Oncogenes…
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
Fig. 18.15 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.
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
RSV was 1st identified cancercausing 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)
Fig. 18.10 The chicken c-src proto-oncogene and its relationship to vsrc in Rous
sarcoma virus
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 18.11 Model for the formation of a transducing retrovirus
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
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
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