Cancer genetics (26)

Question 1

What is cancer?

Answer 1

derived from single cells continually dividing in an unrestrained manner and invading surrounding tissues
–> bc of changes in DNA sequence of cancer genes

Question 2

What is a benign tumour?

Answer 2

a mass of well-differentiated cells that grows slowly, is encapsulated and lacks the ability to invade neighbouring tissues or metastasise

Question 3

What is a malignant tumour?

Answer 3

not self-limited in its growth (escapes apoptosis and can produce new blood vessels for nutrients), cells are poorly differentiated and can invade into adjacent tissues, and spread to distant tissues through bloodstream (metastasis)

Question 4

What does cancer look like?

Answer 4

• large number of dividing cells
• large, variably shaped nuclei
• large nucleus to cytoplasm ratio
• variation in size and shape
• loss of normal cell features
• disorganised arrangement
• poorly defined tumour boundary

Question 5

Where do carcinomas originate?

Answer 5

from epithelial cells that cover internal and external body surfaces- e.g. lung, breast, colon

Question 6

Where do sarcomas originate?

Answer 6

soft tissues- fat, bone, cartilage, connective tissue and muscle

Question 7

Where do lymphomas arise?

Answer 7

lymph nodes and tissues of the body’s immune system

Question 8

What are leukaemias?

Answer 8

cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream

Question 9

What factors contribute to cancer?

Answer 9

• heredity–> passed-on alterations in genes can make someone more susceptible to cancer
• environment–> chemicals (e.g. smoking) and radiation can damage genes (also diet)
• exogenous factors–> viruses (e.g. HPV) can introduce their own genes into cells

Question 10

What were the 6 hallmarks of cancer in 2000?

Answer 10

1. insensitivity to anti-growth signals–> e.g. lose retinoblastoma suppressor
2. self-sufficiency in growth signals–> e.g. activated H-Ras oncogene
3. evading apoptosis–> e.g. produce IGF survival factors
4. limitless replicative potential–> e.g. turn on telomerase
5. sustained angiogenesis–> produce VEGF inducer
6. tissue invasion and metastasis–> inactive E-cadherin

Question 11

What are the new hallmarks of cancer?

Answer 11

• deregulating cellular energetics
• avoiding immune destruction
• tumor-promoting inflammation
• genome instability and mutation

Question 12

How do cancer cells evade the immune system?

Answer 12

when checkpoint pathways, such as PD-1, are activated, negative signals are sent to T cell from tumour cell via PD-L1 ligand–> shuts down immune response and stops T cell from attacking

Question 13

What is a germline mutation?

Answer 13

• germ cell makes gametes
• a gene change before/during meiosis in egg or sperm that becomes incorporated into DNA of every cell in the body of the offspring
• mutations passed on from parents to offspring
• ‘hereditary mutation’
• rarely cause cancer (10%)

Question 14

What is a somatic mutation?

Answer 14

• occurs during mitosis in any somatic cell (so not egg/sperm)
• acquired/sporadic
• non-heritable
• common cause of cancer (90%)

Question 15

What is a passenger mutation?

Answer 15

can be tolerated by somatic cells (often in heterozygotic state, so mutation will not change phenotype of cells)
- has no impact on fitness of a clone cell

Question 16

What is a driver mutation?

Answer 16

mutations that can confer a selective advantage for the cancer cells (in homozygote state), so change phenotype of cells
- leads to clonal expansion

Question 17

How can mutations in oncogenes cause cancer?

Answer 17

• normal oncogenes regulate cell growth
• mutations generally activate oncogenes by chromosome rearrangements, gene duplication or mutation
• e.g. a chromosome rearrangement/fusion between chromosomes 9+22 can lead to formation of BCR-ABL gene–> promotes proliferations and skips apoptosis–> chronic myeloid leukaemia
• mutation in 1 allele sufficient for cancer: ‘gain of function’ mutation, dominant

Question 18

How can mutations in tumour suppressor genes cause cancer?

Answer 18

• normal tumour suppressor genes act as breaks of excessive proliferation, or cause apoptosis if there is too much DNA damage
• requires 2 mutations for cancer:
  1st mutation (1 allele) makes a carrier susceptible to tumour
  2nd mutation (or loss of gene) leads to cancer
• recessive, ‘loss of function’

Question 19

How can mutations in DNA repair genes cause cancer?

Answer 19

• DNA repair genes code for proteins (e.g. BRCA1 and BRCA2) that correct errors that arise when cells duplicate their DNA before division
• cells w/ too much DNA damage either enter an irreversible state of dormancy, undergo apoptosis, or divide in an unregulated manner, leading to formation of cancerous tumour
• mutations in DNA repair genes can lead to a failure in repair–> allows subsequent mutations to accumulate and remain uncorrected

Question 20

How does UV radiation cause DNA damage?

Answer 20

leads to formation of covalent bonds between 2 adjacent pyrimidines (C and T) in DNA molecule (C becomes deaminated to T)