Cancer genetics

Question 1

Define cancer

Answer 1

Abnormal gene function & expression => proliferation => Invasion of local tissue => metastasize

Question 2

Explain the Knudson’s Two-Hit hypothesis (theory of carcinogen)

Answer 2

• Recessive hereditary: require 2 alleles to be affected/expressed
• Multistep process: involves 1+ mutation

Question 3

Describe the Multi-step nature of Carcinogens (theory of carcinogen)

Answer 3

1. Mutation: metabolism/repair process altered but not yet cancer
2. Promoters allow cells to acquire more mutations while proliferating => benign/ pre-cancerous lesions
3. Selection/ growth adv. of cell => proliferates
4. Epigenetic changes => local invasion => metastasize
5. DNA instability inc. further

Question 4

What’s the difference b/w SMT vs TOFT? (theory of carcinogen)

Answer 4

SMT (Somatic mutation theory): Carcinogenic agents => inc. new/current mutations => affect cell growth differentiation or function
TOFT (Tissue Organisation Field Theory): Carcinogenic agents disrupt interactions b/w cells => affect organisation, repair & regulation
* Epigenetic factors involved in both - can turn off/on expression

Question 5

list the epigenetic factors that also cause genetic changes (ie. epigenetic modifications)

Answer 5

• proteins/molecules e.g. Growth factors
• Adjacent stromal cells e.g. epith. cells
• ECM framework surrounding tumour cells

Question 6

Differentiate between a proto-oncogene and an oncogene?

Answer 6

• Proto-: responsible for normal cellular functions (growth & differentiation)
• Oncogene: mutated gene => overexpressed constitutively => inc. malignancy of a cell (Dominant affect - 1 allele affected = expressed)

Question 7

Mechanism of oncogene activation

Answer 7

1. Proto -> Oncogene (MUTATION in protein regulatory regions) => uncontrolled expression
2. Gene AMPLIFICATION = more expressed
3. Chromosomal rearrangements (translocation, inversion): can happen if
   i) regulatory cntl is moved = deregulate expression OR
   ii) forms hybrid fusion gene => transforming activity

Question 8

What is a tumor suppressor gene? How does it work?

Answer 8

> inhibit cells w/ mutations from becoming cancerous by:

• stopping proliferation to allow DNA repair mechanisms to fix mutated DNA (if damage is small)
• promotes apoptosis if damage is unrepairable
• stop cell cycle to avoid stop cell division
• induce senescence (deteriorate)

Question 9

briefly compare difference b/w Oncogene & tumour suppressor gene (TSG)

Answer 9

Oncogene | TSG
Dominant | Recessive (except TP53)
Inc. prolif. | Inhibit proliferation
Inhibit apop | Promotes apoptosis

Question 10

list 2 important tumour suppressor genes (TSG)

Answer 10

(Dominant negative, recessive) TP53

(recessive) Retinoblastoma (RB), APC, BRCA1, BRCA2

Question 11

How would varying expression occur for TP53? (recessive, dominant negative)

Answer 11

• 2 normal TP53 gene => TP53 TSG expressed
• Homozyg. recessive mutation (both affected) => no TP53 made
• Heterozy. recessive mutation (one affected) => TP53 TSG expressed (from the 1 normal allele)
• Dominant nee. mutation (one allele altered) => altered TP53 proteins cancel normal TP53 made => overal non-functional TP53

Question 12

What are double minutes (mi-nutes) aka dmins?

Answer 12

small pseudochromosomes that are extrechromosomal DNA fragments. Labelled as A (=additional) at bottom of karyotype