Overview

Question 1

Why is cancer an old age disease?

Answer 1

Gene mutations accumulate with age.

Question 2

Sporadic cancer

Answer 2

Random chance - not inherited (most common).

Question 3

Familial cancer

Answer 3

Unknown genetic link - genetic predisposition but environment allows expression (higher rates in families).

Question 4

Hereditary cancer

Answer 4

Inherited genes which increases risk of certain cancers.

Question 5

Describe the simple stages of tumour development.

Answer 5

-Mutation to 1 cell
-This cell proliferates/divides
-New cells acuminate more (often random) mutations
-Tumour/lump formed from these cells which have acquired capabilities to outgrow normal cells = clonal evolution

(inc. genetic instability)

Question 6

Will all descendants of the first mutated cell be the same (within tumour)?

Answer 6

No. They will retain the original mutation, but then various cells will pick up different mutations as they continue to proliferate

–> may lead to ‘parallel clonal expansions’
–> causes tumour to have genetically distinct cell pops (genetic signatures)

ALL OF THIS = intra-tumour heterogeneity

Question 7

What is intra-tumour heterogeneity?

Answer 7

Coexistence of cancer cells with different genetic, phenotypic or behavioural characteristics in a primary tumour (& ones which metastasise from it) - i.e., all have different mutations

–> i.e., tumour cells of one bulk tumour sample may form several subclones with similar DNA aberrations within subclones but different DNA aberrations across subclones

Question 8

What are the 10 universal hallmarks of cancer?

Answer 8

-Tumour promoting inflammation = more inf - more likely to pick up DNA damage and so mutations too
-Metastasis = spread of cancer to other organs/tissues
-Angiogenesis = blood vs formation (for nutrition & O2)

Question 9

What are cancer critical genes?

Answer 9

-Genes which should be in equilibrium
-Genes = onco genes (CP) and tumour suppressor (A)
-Cancer = cell proliferation & apoptosis not balanced – otherwise there should be a balance between prolif & apoptosis

Question 10

How are oncogenes produced?

Answer 10

-Translocation of POG to another part of genome - new promotor
-Gene amplification = excess copies of POG
-Mutation:
-In control region = inc. transcription…
-In gene = mutation means gene is always active - (hyperactive) or no degradation of protein once made
–> all = excess protein to stimulate growth

Question 11

What is an example of a chromosomal translocation cause of cancer?

Answer 11

-Reciprocal translocation (part of chromosomes swap)
-abl gene from chromosome 9 and bcr gene from chromosome 22 join on chromosome 22
=> abl-tyrosine kinase is under bcr promotor - so is now always active
-bcr-abl tyrosine kinase involved in cell proliferation
-See this in CML and ALL (leukaemias)

Question 12

How do oncogenes function?

Answer 12

Dominantly - 2 alleles of POG - mutation/activation of 1 = expressed (e.g., in ‘ras’) - uncontrolled activity

Mutations in proto-oncogenes are typically dominant in nature, and the mutated version of a proto-oncogene is called an oncogene. Often, proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death.

Question 13

What is the impact of excess protein (from POG amplification)?

Answer 13

-Hyperactive cell proliferation
-Cell cycle stages faster
-TSGs no impact - at normal levels (equ lost)
-TSGs inactivated (OGs directly act on)
-Hyperactive protein - exceeds regulation threshold
–> all = surge in cell proliferation

Question 14

Role of TSGs & what happens to them in cancer?

Answer 14

-DNA repair
-Cell cycle arrest (checkpoints)
-Apoptosis regulation
-Cancer = mutation & deletion (removing gene) inactivate

Question 15

How can TSGs be inactivated?

Answer 15

-Mutations (both alleles) = recessive genes
-Deletion
-Post translational mechanism (bind to viral oncoproteins)
-Gene silencing (epigenetics) - of promotor

Question 16

How do (mutated) TSGs function?

Answer 16

-Recessive - loss of ability to regulate cell proliferation only if both alleles are mutated/inactivated (= tumour). - e.g., Rb

Classic tumor suppressor genes (TSGs) are recessive at the cellular level, with inactivation of both alleles typically found in tumors.

Question 17

What is a germline mutation?

Answer 17

Occurs in gametes - all cells are then affected

Question 18

How can Rb be explained by the “2 hit hypothesis”?

Answer 18

-Sporadic cases = later onset, one tumour- needed 2 random mutations to Rb alleles
-Familial = earlier onset, many tumours - only needed 1 random mutation - born with 1 mutated Rb allele
All mutations = somatic (except the initial one in familial - somatic = any mut in a cell that isn’t a gamete)

Question 19

When deletions occur to TSGs leads to a loss of activation, what types of deletions are there?

Answer 19

-Homozygous deletion = both alleles deleted
-Heterozygous = ‘loss of heterozygosity’ - loss of function to one allele & deletion of other

Question 20

How are genes silenced - specifically?

Answer 20

DAIM
-DA = remove acyl groups from histones so H=more +ve (DNA = -ve) - so DNA histone complex coils up
-IM = add methyl groups to cytosines - coils up
–> TFs & RNA pol can’t access promotor - no transcription

Question 21

Examples of where germline mutations of TSGs give genetic predispositions.

Answer 21

-Rb (Retinoblastoma)
-BRCA1 (Breast cancer)
-APC (Familial Adenomatous Polyposis - Colorectal cancer)
-MLH1 (Hereditary non-polyposis Colorectal cancer)

Question 22

What is an autosomal inherited condition & give an example.

Answer 22

Where 1 mutated gene is inherited - giving genetic predisposition - e.g., Breast cancer (BRCA1 & 2)

Question 23

Role of BRCA?

Answer 23

-Repairing DNA double strand breaks (DNA repair)
–> so get - genomic integrity/stability if mutation leads to loss
(loss of BRCA1 = mutations more likely to occur)

Question 24

What do normal cells rely on for DNA repair mechanisms - x2?

Answer 24

BRCA & PARP

Question 25

How does cancer use/influence BRCA1 & PARP mechanisms?

Answer 25

-BRCA1 = target and inactivate (gain advantage)
-PARP = rely on for own repair needs (mutant breast cancers addicted to)

Question 26

How can knowledge of breast cancer’s (due to BRCA1) reliance on PARP be useful?

Answer 26

-Give patients with BC PARP inhibitors = synthetic lethality
-Normal cells can still use BRCA2 for DNA repair