L20 - Carcinogenesis - causes of cancer

Question 1

Give some examples of occupational carcinogens

Answer 1

• cadmium and nickel
• radon (mining)
• solvents and preservatives (painters and furniture makers)
• tannins (leather footwear manufacture)

Question 2

Give examples of chemical carcinogens

Answer 2

• PAHs

- nitrosamines

Question 3

Give examples of infectious agents as carcinogens

Answer 3

• HPV

- H. pylori

Question 4

Give examples of radiation as a carcinogen

Answer 4

• UV light

- radon

Question 5

Give examples of mineral carcinogens

Answer 5

• asbestos

- heavy metals

Question 6

Give examples of physiological carcinogens

Answer 6

• oestrogen

- androgens

Question 7

What are the carcinogens involved in chronic inflammation?

Answer 7

• free radicals

- growth factors

Question 8

Which organ does aflatoxin target?

Answer 8

Liver

Question 9

Which organs does alcohol target?

Answer 9

Pharynx, larynx, oesophagus, liver

Question 10

Which organ does asbestos target?

Answer 10

Lung pleura

Question 11

Which organ do X-rays target?

Answer 11

Bone marrow (leukaemia)

Question 12

Which organ does UV light target?

Answer 12

The skin

Question 13

Which organ does oestrogen target?

Answer 13

Breast

Question 14

Which organs does tobacco smoke target?

Answer 14

Mouth, lung, oesophagus, pancreas, kidney, bladder etc

Question 15

Which organ does HBV (hepatitis B virus) target?

Answer 15

Liver

Question 16

Which organ does HPV (human papilloma virus) target?

Answer 16

Cervix

Question 17

Carcinogen can also be non-genotoxic. What does this mean?

Answer 17

Induce proliferation and DNA replication

Question 18

What is an INITIATOR?

Answer 18

A carcinogen that can modify or damage DNA (genotoxic)

Question 19

What is a PROMOTER

Answer 19

A carcinogen that can induce proliferation and DNA replication (non-genotoxic)

Question 20

What is a “complete” carcinogen?

Answer 20

A carcinogen that can both initiate and promote.

eg. UV light

Question 21

What does mutation induction (initiation) require?

Answer 21

• chemical modification of DNA

- replication of modified DNA and mis-incorporation by DNA polymerase

Question 22

How might chemical modification of the nucleotides involved in base-pairing occur?

Answer 22

Through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes

Question 23

Agents that are good promoters contribute to carcinogenesis in 2 important ways. What are they?

Answer 23

• stimulate the 2 rounds of DNA replication

- stimulate clonal expansion of mutated cells, enabling the accumulation of mutations

Question 24

Give some common genetic abnormalities

Answer 24

• base pair substitution
• frameshift
• deletion
• gene amplification
• chromosomal translocation
• chromosomal inversion
• aneuploidy

Question 25

What is a base pair substitution also known as?

Answer 25

Point mutation

Question 26

What is a frameshift mutation?

Answer 26

Gain or loss of one to several base pairs

Question 27

What can gene amplification result in?

Answer 27

A cell having up to a hundred copies of a gene that would normally only have two copies of

Question 28

Chr 9:22 exchange is a specific translocation. What is it known as and what is it associated with?

Answer 28

Philadelphia chromosome Associated with chronic myeloid leukaemia

Question 29

Chromosomal translocations can result in what?

Answer 29

- genes being moved to a more transcriptionally active region of the chromosome - genes being recombined into new gene fusions

Question 30

What is aneuploidy?

Answer 30

Any departure from the normal structure or number of chromosomes

Question 31

Mutations found in oncogenes lead to what? | Mutations found in TSGs lead to what?

Answer 31

Mutations found in oncogenes lead to a gain in function Mutations found in TSGs lead to a loss of function

Question 32

What are direct acting carcinogens?

Answer 32

Interact directly with DNA eg. oxygen radicals, nitrosamines, UV light, ionising radiation

Question 33

What are procarcinogens?

Answer 33

Require enzymatic (metabolic) activation before they react with DNA eg. aromatic amines, polycyclic aromatic hydrocarbons (PAHs)

Question 34

Are the majority of carcinogens that we ingest direct acting or procarcinogens?

Answer 34

The majority are pro carcinogens and require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals

Question 35

What are the products in the metabolic activation of benzopyrene?

Answer 35

Benzopyrene Benzopyrene 7,8-epoxide Benzopyrene 7,8-dihydrodiol Benzypyrene 7,8-diol, 9,10-epoxide Ultimate carcinogen = BPDE

Question 36

What are the enzymes involved int he activation of benzopyrene?

Answer 36

P450 mixed function oxidases Epoxide hydrolase P450 mixed function oxidases

Question 37

Give a classic example of a procarcinogen and state how it can be generated

Answer 37

Benzopyrene Can be generated through the combustion of most organic material such as meat, tobacco and fuel

Question 38

BPDE causes mutation in which gene?

Answer 38

TP53 | seen in this gene in the lung tumours of smokers

Question 39

What are the 4 general stages in DNA damage and repair?

Answer 39

1. Damaging agent 2. DNA lesions 3. Repair process 4. Disease syndrome

Question 40

Give a pathway from carcinogen exposure to cancer

Answer 40

- carcinogen exposure - metabolic activation (eg. cytochrome P450s) - DNA damage (- DNA repair) - DNA replication - DNA mutation (eg. in proto-oncogene or tumour supressor gene) - progression - cancer

Question 41

At which stages of the pathway from carcinogen exposure to cancer may genetic modulation occur?

Answer 41

- metabolic activation - detoxification and excretion - DNA repair (may explain why exposure does not always lead to cancer)

Question 42

Which cancers is alcohol linked to?

Answer 42

``` Oral Oesophageal Pharynx Larynx Breast Bowel Liver (Pancreatic) ```

Question 43

What is alcohol converted into that can cause DNA damage?

Answer 43

Acetaldehyde

Question 44

Alcohol increases levels of which hormones?

Answer 44

Oestrogen and testosterone

Question 45

Alcohol increases the uptake of what?

Answer 45

Carcinogenic chemicals into cells within the upper GI

Question 46

Alcohol reduces levels of what?

Answer 46

Folate, needed for accurate DNA replication

Question 47

Alcohol can kill what?

Answer 47

Surface epithelium leading to unscheduled proliferation

Question 48

All of the strongest risk factors for breast cancer are associated with what?

Answer 48

Increased exposure to oestrogen - can both stimulate cell division and induce DNA damage

Question 49

Breast cancer risk decreases 20% for what?

Answer 49

Risk decreases 20% for each year that menarche is delayed

Question 50

What procedure leads to 90% decrease in risk of breast cancer?

Answer 50

Oopherectomy | removal of ovaries

Question 51

What procedure reduces incidence of prostate cancer?

Answer 51

Orchidectomy | removal of a testis

Question 52

Which types of chronic inflammation have an association with cancer?

Answer 52

- colitis - hepatitis - Barret's oesophagus - metaplasia - gastritis - gallstones

Question 53

Inflammatory response results in a 'double whammy'. What does this mean?

Answer 53

- DNA damage from release of free radicals by immune cells - initiation - growth factor induced cell division to repair tissue damage - promotion

Question 54

Which cell is key in the link between inflammation and cancer?

Answer 54

Tumour-associated macrophages (TAMs)

Question 55

what 2 consequences can mutations have?

Answer 55

- gain of function (activation of proto-oncogenes) | - loss of function (inactivation of tumour suppressor genes)

Question 56

what defence does the human body have against carcinogenesis?

Answer 56

- Dietary antioxidants - Detoxification mechanisms [by enzymes] - DNA repair enzymes - Apoptotic response to unrepaired genetic damage - Immune response