DDT 3 - Cancer Genetics

Question 1

Cancer Development Risk Factors

Answer 1

Lifestyle
- Smoking
- Diet high fat & low in fruits/vegetables
- Lack of exercise
- Unprotected exposure to the sun, (UV) rays
- Obesity

Environment
- Viral
- Second hand smoke
- Air pollution
- Industrial pollution
- Chemical exposures

Family History
- Increased risk with Heredity Breast/Colon cancer

Question 2

Causes of Cancer

Answer 2

Biological - viral/genetic
Chemical - mutagen
Physical - radiation

Question 3

Biological Mutagens causing Cancer

Answer 3

Viral and bacterial mutagens may use complex mechanisms that cause the cell to become cancerous

Viral :
Human papilloma (cervical cancer)
Human T-cell lymphocyte virus (lymphoma)
Hepatitis B virus (liver cancer)

Bacterial :
Helicobacter pylori (stomach cancer)

Question 4

Chemical Mutagens causing cancer

Answer 4

Mutation caused by foreign molecules binding to cell’s DNA causing it to be misread

Benzopyrene (in cigarette smoke).
Vinyl chloride (in the plastics industry).
Aflatoxin (in certain moulds).
Hetrocyclic amines (in over-cooked foods)

Question 5

Physical Mutagens causing Cancer

Answer 5

Can be caused by ionizing radiation, ultraviolet radiation and by mineral fibres .

Ionizing radiation :
* punches holes in the DNA breaking the correct genetic sequence
* Can come directly from X-rays / solar radiation and indirectly from radon gas

Ultraviolet radiation :
* causes mutations by causing certain portions of DNA to remain bound together (even when they shouldn’t) causing misreading of the DNA.

Mineral fibres :
* Certain natural mineral fibres like asbestos, because of their size, can cause damage directly to DNA resulting in carcinogenic mutations

Question 6

Inherited Gene Mutations

Answer 6

Passed from parent to child through egg/sperm
In every body cell

Question 7

Acquired (Somatic) Mutations

Answer 7

Mutations acquired at some point in lifetime
More common than inherited mutations
Occurs in one cell, passed on to any new cells that are the offspring of that cell

Question 8

Mutagenesis

Answer 8

All chemical carcinogens are mutagens
Chemical is incubated with a liver extract to allow metabolic activation
Then added to several different bacterial cultures designed to detect specific mutation types
Positive result in Ames test shows compound has potential to be carcinogenic

Question 9

DNA Damage / Lesions

Answer 9

Sites of damage in base pairing / structure of DNA
Most repaired by DNA repair enzymes
Carcinogens increase with error rate of mitotic cell, may interfere with normal repair mechanisms of cell

1) Abasic Site
- base missing
- due to rise in temp, drop in pH, alkylations on base that destabilize N-glycosidic bonds

2) Mismatch
- replication error
- tautomerization, or spontaneous deamination of cytosine to uracil

3) Modified Bases
- changes to bases themselves
- e.g. UV-induced creation of thymine dimer

4) Single Strand Break
- nick in sugar-phosphate backbone of one strand
- caused by peroxides, Cu++ ion, oxygen radicals, ionizing radiation

5) Interstrand Crosslinks
- actual covalent linkage between 2 strands
- DNA rep cannot proceed past this point (helicase can’t melt apart base-pairs for polymerase)
- caused by mitomycin C, cisplatins, psoralens

6) Double-stranded breaks
- most lethal
- both strand backbones are broken
- caused by ionization
- could cause upregulation of cell cycle, leading to cancer

Question 10

Oncovirus

Answer 10

Virus which can infect a cell and cause tumors

Question 11

Viral DNA Damage

Answer 11

During viral replication, vDNA can insert and interrupt host gene coding sequences, cell cycle may be affected
- Oncoviruses may upregulate cell cycle for increased viral replication

e.g. Hep B&C (hepatocellular carcinoma)
e.g. Human T-lymphotrophic virus (tropical spastic paraparesis, adult T-cell leukemia)
e.g. Human papullomaviruses (cervical, skin, anus, penis , mouth, throat, lung cancers)
e.g. Kaposi’s sarcoma herpesvirus (Kaposi’s sarcoma, body cavity lymphoma)
* e.g. Epstein-Barr virus (Burkitt’s Lymphoma, Hodgkin’s Lymphoma, B lymphproliferate disease, Nasopharyngeal carcinoma)

Question 12

Onco-retrovirus

Answer 12

Codes for oncogenes
Can insert reverse transcribed DNA (cDNA) into host cell
Host cell will begin to transcribe and translate oncogenes as well as viral proteins

Question 13

Chromosome Damage

Answer 13

• Translocation can result in regions containing cell cycle genes being moved to another chromosome
• New loci result in upregulation and overexpression of the gene

Question 14

DNA repair

Answer 14

100 kinds of repair enzymes in bacteria, 130 in humans,

During DNA rep, DNA polymerase proofreads each newly added nucleotide against the nucleotide template, preventing harmful/lethal mutations

Question 15

DNA repair Mechanisms

Answer 15

• Mismatch repair
• Nucleotide excision repair
• Base excision repair

Question 16

Mismatch repair

Answer 16

After DNA rep, template strand has been methylated, but newly synthesized strand is not methylated
- Mut proteins bind and cleave mismatched base pairs
- Cleavage occurs by exonuclease
- Gap filled by DNA poly I
- DNA ligase closes breaks in sugar-phosphate backbone

Question 17

Nucleotide Excision Repair

Answer 17

• Endonuclease cleaves open the strand for exicision
• Proteins can remove damaged nucleotides (e.g. dimers formed by UV light)
• Gap filled by DNA poly I
• DNA ligase closes the breaks in the sugar-phosphate backbone

Question 18

Base Excision Repair

Answer 18

DNA bases may be modified by deamination or alkylation

Question 19

Other DNA repair mechanisms

Answer 19

• If no parental strand => homologous recombination, homo chromosome can align and form template for damaged chromosome
• If no parental strand or homologus chromosome => non-homologous recombination, non-homo chromosomes align and form template for damaged chromosome
• Translesion repair (SOS response) => use of Y-DNA polymerase, fill in blanks at random