How and why neoplasms occur

Question 1

How can a carcinogen be an initiator vs promotor? What is a complete carcinogen? Give an example

Answer 1

Initiator by causing a mutation e.g. UV radiation
Promotor by causing uncontrolled monoclonal cell proliferation that predisposes to mutations e.g. infection (regeneration of cells) (polycyclic aromatic hydrocarbons)

A complete carcinogen is both an initiator and a promotor e.g. cigarette smoke

Question 2

What occurs during cancer progression?

Answer 2

Additional mutations –> in TSG/protooncogenes leading to genetic instability and deregulated cell pathways. Eventually leading to the 6 hallmark signs of cancer

Question 3

How is an inherited mutagen different to a somatic mutation from a carcinogen?

Answer 3

It speeds up the promotor phase as it is already present in all cells due to being germline –> often present with malignancies younger

Question 4

What is 2-napthylamine?

Answer 4

An industrial chemical that is an initiator causing a mutation that leads to bladder carcinoma –> seen in factories back in the day

Question 5

Why is there a long delay from somatic mutation –> cancer

Answer 5

Because after the initiator you need a promotor to lead to increased cell proliferation –> and then progression where you have more mutations that eventually lead to the hallmarks of cancer. These take time.

Question 6

What is a procarcinogen? How is it made a carcinogen?

Answer 6

Inactive made active by P450 in the liver

Question 7

Are cancers most commonly due to intrinsic (genetic) factors or extrinsic (behaviours/environment)?

Answer 7

85% extrinsic

Question 8

How can radiation predispose to cancer (2)?

Answer 8

Either direct damage to DNA

or via free radicals that then cause damage to DNA e.g. single strand/double strand breaks/damages to DNA bases.

Question 9

Which two ways can infections predispose to cancer?

Answer 9

1) Either by acting on genes causing cell growth

2) Affecting growth indirectly by chronic tissue injury –? regeneration predisposes to cancer

Question 10

How does regeneration in tissue predispose to cancer?

Answer 10

Either by acting as a promotor for any preexisting mutations or causes new mutations via DNA damage repair errors

Question 11

How does Human Papilloma Virus predispose to cancer (2)? Is it a direct or indirect carcinogen?

Answer 11

It expresses proteins E6 E7 which act directly to inhibit Rb protein and p53 respectively.

This means the cell cycle is uninhibited even if damaged at the check point

And it means damaged cells will survive as p53 would cause apoptosis –> genetical instability —> cervical cancer

Direct as directly affects Tumour Suppressor Genes and Proto-oncogenes

Question 12

How are HepB and HepC indirect carcinogens?

Answer 12

Via chronic liver damage –> regeneration leads to increased chance of mutations

Question 13

Name two other infections that lead to chronic inflammation and carcinomas?

Answer 13

Helico bacter pylori - chronic gastric inflammation –> gastric carcinoma

Fluke worm - chronic bile duct inflammation and bladder —> cholangio/bladder carcinoma

Question 14

How does AIDs predispose to cancer and which type in particular?

Answer 14

Lowes immune system so allows for potentially carcinogenic infections –> Kaposi’s sarcoma caused by HHV8

Question 15

What is the two hit hypothesis and how does it relate to retinoblastoma?

Answer 15

That both tumour suppressor gene alleles need to be knocked out in order to suppress their function for favour of neoplastic growth. E.g. retinoblastoma

Can either occur via one germline mutation, one other mutation

Or de novo 2 mutations

Example of neoplasm that can be genetic and de novo

Question 16

How many proto-oncogenes need to be mutated to favour neoplastic growth? Give an example - is it mutated in one or more cancers?

Answer 16

Only one

RAS - G protein that when mutated causes cell cycle to pass uninhibited past check point. Mutant RAS encodes a protein that is always active. Mutated in 1/3 of all cancers

Question 17

Name 7 functions/types of photo-oncogenes that are altered in cancer

Answer 17

1) Growth factors PDGF
2) Growth factor receptors HER2
3) Plasma membrane signal transducers RAS
4) Intracellular kinases BRAF
5) Transcription factors MYC
6) Cell cycle regulators CYCLIND1
7) Apoptosis regulators BCL2

Question 18

Are the functions similar but opposite for TSG? Give an example of one

Answer 18

TP53 yes

Question 19

Give an example of a germline defective DNA repair mutation leading to cancer (there are 3 here)

Answer 19

XP - Xeroderma Pigementosum - autosomal recessive
Error in NER
Predisposes to skin cancer

HNPCC - Heredity non polyposis colon cancer - autosomal dominant
Error in Mismatch repair

Familial Breast Carcinoma - BRCA1 BRCA2
Error in DSB repair

Question 20

How do chromosomal segregation errors in cancer cells enhance cancer? What kind of genes protect against this?

Answer 20

Because they lead to increased mutations —> polyclonal expansion and increased genetic instability.

Caretaker genes protect against this

Question 21

Give an example of adenoma –> carcinoma

Answer 21

Colon cancer

Question 22

How many mutations approx needed to develop malignant neoplasm?

Answer 22

10 or less

Question 23

What are the 6 hallmarks of cancer?

Answer 23

1) Self sufficient growth factors
2) Resist antigrowth factors
3) Grow indefinitely
4) Resist apoptosis
5) Invade and metastasise
6) Angiogenesis

Question 24

How do cancers grow indefinitely?

Answer 24

Most have the gene for telomerase activated –> can regenerate telomeres which allows them to undergo mitosis indefinitely