21 - Carcinogenesis

Question 1

Global epidemiological data for cancer incidence

Answer 1

Need to have large systems
* Developed countries, ↑ incidence
* Data normalised
* Countries may have state-based approaches

Question 2

Cancer mortality - 5 year data set (2017 cf 2022)

Answer 2

Decrease mortality
* Effective treatments
* Pancreas cancer 3rd (instead of 4th) - more diagnosis

Question 3

The biggest and most frequent cancers

Answer 3

The ones that are going to kill us the most
* Prostate
* Breasts
* Melanoma
* Colorectal
* Lung

Question 4

Interpretation of cancer incidence complicated by…

Answer 4

1. ↑ Pop size
2. ↑Life expectancy
3. Changes in diagnosis
4. Changes in record keeping (not too dramatic in AUS)

Question 5

Colorectal cancer detection

Answer 5

Younger people getting diagnosed
* Detection at late stage ➔ putting up with symptoms

Question 6

What is cancer?

Answer 6

Unrestricted tissue growth
* Cells grow outside of where they are supposed to be and not in the same order
* Benign or malignant

Question 7

Types of cancers

Answer 7

1. Adenocarcinomas - Epithelial derived (most)
2. Sarcoma - connective tissue
3. Lymphoma - lymphatic tissue
4. Leukaemia - haematological derived

Question 8

Heterogenity of cancers

Answer 8

1. Solid: VERY heterogenous
2. Lymphoma/Leukemias: LESS heterogeneous (↓ mutations than solid, can detect changes quickly)

Question 9

Main differences between malignant and normal tissue

Answer 9

1. ↑ genetic diversity
2. altered intercellular social behaviour
3. altered cellular growth behaviour

Question 10

Normal tissue development

Answer 10

1. Sequential commitment of cells to specialised tasks
2. Genetic/epigenetic mechanisms control organogenesis
3. NO alteration in gene sequences after fertilization

Question 11

One hit hypothesis

Answer 11

Early hypothesis
* Mutation in germline ➔ OK, diversity
* Mutation in somatic ➔ cancer

Question 12

“Nature” theory

Answer 12

Some pop. get cancer more than others
* Look at particular types
* Epidemiology and importance of enviro

Question 13

Multi-stage carcinogenesis theory

Answer 13

Natural mutations and genetics
* Enviro puts pressure on genetic code
* Putting numbers on mutations (need certain amount of changes to get cancer)

Question 14

Darwinian clonal expansion model

Answer 14

Carcinogens initiate, promote, progress tumor growth and spread

Question 16

Evidence for EFH/ Nurture theory

Answer 16

1. Var in incidence of diff. cancers in diff. communities
2. Changes in incidence with migration
3. Changes in incidence with time
4. Biological cause identified

Question 17

Japanese migration to Hawaii

Answer 17

Gastric cancer common in Japan (↓ migration rate, ↓ pop. mixing)
* ↑ salt, preservatives in veg
* Immigration to US ➔ ↓ gastric, matched incidence of state

Question 18

Carcinogenesis Step 1 - Initiation

Answer 18

Normal cells exposed to physical/chem carcinogen
* Genetic changes
* Initiated cells have “Darwinian” survival advantage

Question 19

What are the possible characteristics a carcinogen?

Answer 19

1. Electrophillic or metabolically activated
2. Genotoxic
3. Alter DNA repair, genomic instability
4. Epigenetic alterations
5. Oxidative stress
6. Chronic inflamm.
7. Immunosuppressive
8. Receptor-mediated effects
9. Immortalisation
10. Alt. cell prolif. + death, nutrient supply

Question 20

Inflammation and tumours

Answer 20

The more aggressive the cancer ➔ more immune cells
* Promote inflamm.
* Tumors evade

Question 21

Mutations that would benefit growth of cancer cells

Answer 21

1. Have own prolif. signal (normal cell needs EGF to bind)
2. Avoid apoptosis
3. Extend telomeres
4. Use alt. energy source

Question 22

Phase 1 metabolism and carcinogens

Answer 22

Metabolism ➔ make more electrophillic and reactive
* If lipophillic enough ➔ get close to nucleus ➔ damage

Question 23

What genes would an electrophillic carcinogen try and switch off in cell

Answer 23

1. Ones that detect mutations and critical points of cell cycle
2. Repair
3. Differentiate to epithelial (instead something with movement)
4. Apoptosis

Question 24

Epigenetics

Answer 24

Cancer genome areas can be HYPO or HYPER methylated
* HYPER ➔ e.g. tumor supressor genes

Question 25

Histones

Answer 25

Keep **DNA** in ***tight*** structures * **Methylated** marks become signals for **microRNAs** to come and ***bind*** on

Question 26

microRNAs

Answer 26

*Small* regions in **genome** * ***Temporarily*** switched **on** and **off** * Tend to have a **enviro** *signal*

Question 27

DNA methylation

Answer 27

*Addition* of **methyl** to 5-carbon of **cytosine** * *Catalysed* by **DNMT** * Steric ***inhibition*** of **transcriptional** complexes binding to regulatory DNA regions * Most common – **CpG island** in ***promoter*** regions

Question 28

Histone modification

Answer 28

Essential for **chromatin** *structure* and gene **transcription** * **Post**-transcriptional alt. of **histones** leads to mod. of ***chromatin*** and ***nucloesomes*** ➔ regulate ***transcription*** * Most common – *loss* of **acetylation** or **methylation** at ***H3*** & ***H4***

Question 29

Genes known to have higher risk of cancer

Answer 29

**90%** show ***somatic*** mutations, **10%** **germline**, 20% both * Most occur by **chromosomal** *translocations* * ↑ **growth** or anti-**apoptotic** * **Tp53** – *most* cancers * **Rb** – retina, *sarcoma*

Question 30

Preparation phase (G) in cell cycle

Answer 30

Check ***whole*** strands of **DNA** * Tumor ***supressor*** genes involved **actively**

Question 31

Microsatellites

Answer 31

*short* **repeats** in DNA sequences (1-6 nucleotides) found throughout the **tumour** ***genome*** * *Prone* to **mutations**

Question 32

Microsatellite instability (MSI)

Answer 32

Molecular phenotype relating to the ***loss*** of one or more DNA **mismatch repair** *enzymes* * ➔ *deficient* DNA mismatch-repair (**dMMR**) function

Question 33

Mutation frequencies in colorectal cancer

Answer 33

Mutation in DNA **repair** *enzymes* and **tp53** * ***Accumulate*** mutations over a lifetime

Question 34

Agents that cause initiating mutations

Answer 34

1. **Toxicological** drugs/agents (*Benzene*) 2. **Mixtures** (*Tobacco*) 3. **Infections** (*HPV*)

Question 35

Carcinogenesis Step 2 - Promotion

Answer 35

**“Promoters”** provide growth ***factor*** & ***enzymes*** for growth, **invasion**, **angiogenesis** and **metastasis** of the *initiated* cells

Question 36

Examples of promoters in carcinogenesis

Answer 36

1. *Chronic* **inflamm.** 2. **Lifestyle** (*Diet*, *Smoking* + *Alcohol*) 5. ***Obesity*** 6. ***Anti*biotics**

Question 37

Carcinogenesis Step 3 – Progression

Answer 37

**≥ 4** mutations * Reach **glucose** diffusion ***limit***

Question 39

Colon cancer progression

Answer 39

Normal → **adenoma** → adeno*carcinoma* ➔ ***metastasis*** * We have a *loss* of **mismatch repair** genes