genetics of cancer

Question 1

what are tumour suppressor genes

Answer 1

proteins whose function is to regulate cellular proliferation and maintain cell integrity

Question 2

how many copies of each tumour suppressor gene does each cell have

Answer 2

2

Question 3

what does mutation or loss of one, and then both, copies of tumour suppressor gene mean

Answer 3

mutation/deletion of one gene copy usually insufficient to promote cancer (although some patients have haploinsufficiency); mutation/loss of both copies means loss of control

Question 4

describe Knudson’s 2 hit hypothesis: sporadic cancer

Answer 4

2 acquired mutations from environment leads to tumour

Question 5

describe Knudson’s 2 hit hypothesis: hereditary cancer (predisposition for cancer)

Answer 5

1 inherited mutation, followed by 1 acquired mutation from environment, leads to tumour

Question 6

6 features of inherited cancer susceptibility

Answer 6

family history of related cancers, unusually early age of onset, bilateral tumours in paired organs, synchronous or successive tumours, tumours in different organ systems in same individual, mutation inherited through germline

Question 7

what is a retinoblastoma, and what was it used to learn more about

Answer 7

malignant cancer of developing retinal cells, which led to greater understanding of tumour suppressor genes

Question 8

what does sporadic retinoblastoma usually involve, compared to hereditary retinoblastoma

Answer 8

sporadic retinoblastoma usually involves one eye, hereditary retinoblastoma can be unilateral or bilateral and multifocal

Question 9

what is the inherited “hit” of hereditary retinoblastoma

Answer 9

RB1 tumour suppressor gene on chromosome 13q14

Question 10

what does RB1 encode

Answer 10

nuclear protein involved with CDK4 and 6 (G1 -> S) in cell cycle regulation

Question 11

4 functions of tumour suppressor genes to suppress neoplastic phenotype

Answer 11

regulate cell proliferation, maintain cellular integrity, regulate cell growth, regulate cell cycle

Question 12

4 types of tumour suppressor genes

Answer 12

nuclear transcription factors, DNA repair proteins, cell adhesion molecules, cell death regulators

Question 13

3 examples of cell cycle regulator tumour suppressor genes

Answer 13

p53, BRCA1, p16-INK4A

Question 14

example of tyrosine and lipid phosphatase tumour suppressor gene

Answer 14

PTEN

Question 15

example of cell signalling tumour suppressor gene

Answer 15

APC

Question 16

example of mismatch repair tumour suppressor gene

Answer 16

MLH1

Question 17

what 9 things does p53 (“guardian of genome”) respond to

Answer 17

oxidative stress, nitric oxide, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication stress, double-strand breaks, telomere erosion

Question 18

consequence of p53 responding to so many things

Answer 18

can’t respond to something individually (e.g. double-strand breaks) without affecting everything else

Question 19

2 types of mutations affecting p53

Answer 19

driver (cause cancer) or passenger (have just developed)

Question 20

what protein does p53 partner with, and what does it do

Answer 20

MDM2 (mitotic regulator which regulates p53)

Question 21

in mild and physiological stress, what target genes does p53 regulate

Answer 21

metabolic homeostasis, antioxidant defence, DNA repair, growth arrest, senescence

Question 22

in severe stress, what do protein-protein interactions of p53 cause

Answer 22

apoptosis

Question 23

what do mutants of p53 act in (vs many other tumour suppressor genes)

Answer 23

dominant manner, and mutation of single copy is sufficient to get dysregulation of activity

Question 24

what does APC tumour suppressor gene drive

Answer 24

familial adenomatous polyposis coli

Question 25

what mutation causes loss of APC tumour suppressor gene

Answer 25

deletion in 5q21

Question 26

what is APC tumour suppressor gene involved in

Answer 26

cell adhesion (stroma) and signalling (WNT signalling pathway)

Question 27

presentation of loss of APC tumour suppressor gene

Answer 27

multiple benign adenomatous polyps of colon (90% risk of developing colorectal carcinoma)

Question 28

what protein does APC tumour suppressor gene negatively regulate

Answer 28

B-catenin, preventing uncontrolled cell division and anchors cell to stroma

Question 29

2 possible inherited “hits” (will have to be followed by acquired hit) to cancer via cell growth and proliferation, via proto-oncogenes and tumour suppressor genes

Answer 29

proto-oncogene mutates to oncogene but normal tumour suppressor gene, or normal proto-oncogene but defective tumour suppressor gene

Question 30

development of colorectal cancer involving tumour suppressor genes and oncogene

Answer 30

normal epithelium -> APC tumour suppressor gene mutated and lost -> hyperproliferative epithelium (hyperplasia) -> DNA hypomethylation causing aberrant K-ras (proto-oncogene -> oncogene) -> (metaplasia -> dysplasia) adenoma -> p53 tumour suppressor gene mutated and lost -> carcinoma (carcinogenesis)

Question 31

oncogene vs tumour suppressor gene: activity in tumours

Answer 31

oncogenes active, tumour suppressor genes inactive

Question 32

oncogene vs tumour suppressor gene: mutation types

Answer 32

oncogenes have specific translocations/point mutations which are rarely hereditary, tumour suppressor genes have deletions or mutations which can be inherited

Question 33

oncogene vs tumour suppressor gene: genotype at cell level

Answer 33

oncogenes dominant at cell level (1 mutated copy), tumour suppressor genes recessive at cell level (2 mutated copies)

Question 34

oncogene vs tumour suppressor gene: specificity

Answer 34

oncogenes have broad tissue specificity, tumour suppressor genes have considerable tumour specificity

Question 35

oncogene vs tumour suppressor gene: types of tumour

Answer 35

oncogenes responsible for leukaemia and lymphoma, tumour suppressor genes responsible for solid tumours

Question 36

how many driver mutations required for cancer

Answer 36

2-11 depending on organ affected

Question 37

what is COSMIC

Answer 37

catalogue of somatic mutations in cancer

Question 38

why is COSMIC important

Answer 38

enables precision medicine to be administered