DNA repair, oncogenes and the tumour micro-environment

Question 1

What are most cancers initiated by ?

Answer 1

A change in the DNA sequence of the cell, promoting genetic instability

Question 2

Name and explain one of these changes ?

Answer 2

1. Chromosomal translocation
E.g.  
-Chronic myelogenous leukaemia (Philadelphia chromosome) resulting from a translocation between the long arms of chromosome 9 and 22 
- Burkitt’s lymphoma resulting 
from a translocation between 
chromosomes 8 and 14 in B cells

Question 3

What are some other changes that cause cancers?

Answer 3

1. Deletions of chromosomes
   e. g. neuroblastoma (loss of chromosome 1)
   e. g. retinoblastoma (loss of chromosome 13)
2. Additional chromosomes
   e. g. small lung lymphocytic lymphoma (additional chromosome 12)
3. Deletion and additions
   e. g. acute non-lymphocytic leukaemia (deletion of chromosomes 5 and 7 but additional chromosome 8)

Question 4

Most agents known to cause cancer cause ?

Answer 4

Genetic change and instability

Question 5

What are Carcinogenesis (the generation of cancer) linked with ?

Answer 5

Mutagenesis (changes in DNA sequence)

Question 6

What are some examples of direct chemical carcinogens?

Answer 6

1. Dimethylnitrosamine (beer, tyre manufacture)
2. Ethylene dibromide (petrol)
3. N-nitrosodiethanolamine (cosmetics, lotions, shampoos)
4. Polycyclic hydrocarbons (smoke)
5. Nitrofurans (food preservatives)

Question 7

What do some carcinogens have to be activated by ? and give example ?

Answer 7

A metabolic pathway
before they cause mutations by reacting with DNA.
E.g. Aflatoxin and liver cancer

Question 8

What is the AMES test used to determine ?

Answer 8

The mutagenicity of compounds

Question 9

What do tumour promoters act synergistically with ?

Answer 9

Carcinogens to promote DNA damage and loss of growth control

Question 10

How do tumour promoters work on cells?

Answer 10

• Initiator e.g. nitrosodiethanolamine (DNA damage)

- Promoter e.g. phorbol ester (cell proliferation)

Question 11

Examples of metabolic tumour promoters ?

Answer 11

• Insulin = promotes cancer cell proliferation and decreases apoptosis
• Estrogens = induces cancer cell proliferation
• Oxidative stress - can act as cancer initiator and promoter
• Inflammation - strong association between chronic inflammation and cancer
• IGF-1 = potent growth factor for many cancer lines

Question 12

Name some Tumour Anti-Promoters ?

Answer 12

• Folic acid (reducing likelihood of DNA damage)
• Antioxidants (preventing oxidative damage and lipid peroxidation, which compound DNA damage in tumour promotion)
• Phytochemicals
• Low-fat plant-based diet

Question 13

Deletion or alteration of gene on chromosome 5 encodes?

Answer 13

A tumour suppressor gene e.g. Rb allows growth

Question 14

What does mutation of chromosome 12 result in?

Answer 14

The uncontrolled activation of ras

Question 15

Deletion or alteration of gene on chromosome 18 allows ?

Answer 15

Reduced contact between cells

Question 16

Deletion or alteration of gene on chromosome 17 encodes ?

Answer 16

Tumour suppressor e.g. p53

Question 17

What are some influential factors in human carcinogenesis and explain them ?

Answer 17

1. Environment
   - In 1775, a high incidence of nasal and scrotum cancer was
   noticed in chimney sweeps due to exposure to soot.
   - Exposure to UVB radiation and increases the risk of skin cancer
   due to formation of pyrimidine dimers in DNA and subsequent
   mutations.
2. Reproductive life
   - Nuns are least likely to suffer from cervical cancer, but most
   likely to have breast cancer. The former reflects less sexual
   activity, the latter relates to the decreased incidence of breast
   cancer linked with childbirth.
   - Hormonal contraception and fertility treatment also increase the
   risk of cancer due to alterations in ovulation schedules.
3. Diet
   - Incidence of specific cancers varies between populations in
   different geological locations

Question 18

How are dietary carcinogens identified ?

Answer 18

By the Ames test

Question 19

What are some more influential factors in human carcinogens and explain them ?

Answer 19

4. Smoking
   - The clearest example of a lifestyle factor underlying a specific
   cancer. Apart from lung cancer, it is also associated with
   pancreas, bladder, kidney, mouth, stomach and liver cancer.
   - At least 81 carcinogens identified in cigarette smoke.
5. Additional influences
   - There are risk factors inherent to our physiology
   - Aerobic metabolism generates free radicals which are mutagenic
   - The process of DNA replication introduces the chances for error
   and mutations in the DNA sequence

Question 20

Women with harmful mutations in either BRCA1 or BRCA2 have a risk of ?

Answer 20

Breast cancer and ovarian cancer

Question 21

BRCA mutations can also increase risk of ?

Answer 21

Colon, pancreatic and prostate cancers

Question 22

What are some conventional cancer therapies and explain them ?

Answer 22

1. Surgical removal only good for primary site
2. Chemotherapy and radiotherapy for metastasised cells.
   - These rely on cytostatic effects (prevent proliferation) and cytotoxic effects (promote cell death)

• The aim is to achieve maximum effect on the cancerous cells with minimum side effects

Question 23

What is the therapeutic index ?

Answer 23

The value between the

minimum effective dose and the maximum tolerated dose (MTD)

Question 24

What does a higher therapeutic index mean ?

Answer 24

The better the drug (safer)