Genetics Of Disease

Question 0

What proportion of cancers are affected by somatic mutations?

Answer 0

80%

Question 1

What are the different classes of cancer genes?

Answer 1

DNA repair genes, tumour suppressor genes, oncogenes.

Question 2

What proportion of cancers are affected by germline mutations?

Answer 2

10%

Question 3

Define the term sporadic cancers.

Answer 3

Cancers stemming from somatic mutations, ie single mutations in a single cell leading to a random cancer.

Question 4

What are the features of genetic predisposition in cancer?

Answer 4

Family history, early onset cancer, multiple cancers. You don’t inherit a cancer, you inherit a predisposition towards a cancer.

Question 5

How can predisposing cancer genes be identified?

Answer 5

Conventional positional cloning, ie linkage analysis, chromosomal abnormality, allele loss studies, whole genome sequencing.

Question 6

What are the classes of predisposing genes?

Answer 6

Controlling DNA damage - indirect involvement. (DNA repair genes and genes involved in carcinogen metabolism).
Primary cause of cancer - direct involvement. (Tumour suppressor genes and proto-oncogenes).

Question 7

What are the symptoms of ataxia telangiectasia?

Answer 7

Dilated capillaries.
Immune deficiency.
Sensitivity to ionising radiation (cells more easily killed by ionising radiation).
Predisposition to leukaemia or lymphoma.
Heterozygotes have an increased cancer risk.

Question 8

Which gene is responsible for ataxia telangiectasia?

Answer 8

ATM. The protein is involved in sensing DNA damage, has kinase activity and phosphorylates p53 after DNA damage.
AT cells cannot stop the cell cycle in response to DNA damage.

Question 9

What is xeroderma pigmentosa? What are its symptoms?

Answer 9

A rare autosomal recessive condition.
Can feature dwarfism, mental retardation and blindness but doesn’t always.
Always features a severe sensitivity to UV and skin and eye cancers.

Question 10

What causes xeroderma pigmentosa?

Answer 10

A mutation in one of seven genes involved in DNA excision repair.

Question 11

Describe the process of carcinogen metabolism.

Answer 11

Cytochrome P450-dependant enzymes may be involved.
Can measure the activity of CYP2C9 by ability to hydroxylate debrisoquine (hypertension drug).
Rapid metabolisers may have increased cancer risk.

Question 12

Outline knudsons two hit theory.

Answer 12

Hereditary tumours: 1st hit = germline. 2nd hit = somatic.

Sporadic tumours: 1st hit = somatic. 2nd hit = sporadic.

Question 13

What are the dominant mutations In oncogenes?

Answer 13

Point mutations.
Gene amplification.
Chromosome translocations.

Question 14

What are the dominant mutations in tumour suppressor genes?

Answer 14

Point mutations.
Deletions.
Epigenetic silencing.

Question 15

What are the properties of RB1 tumour suppressor gene?

Answer 15

Retinoblastoma tumour suppressor gene.
Mutated in retinoblastoma and a few other cancers.
Involved in cell cycle regulation.

Question 16

What is WAGR syndrome?

Answer 16

Wilms tumour, aniridia, genitourinary abnormalities, retardation.
Results from cloning of WT1 gene.

Question 17

What is wilms tumour?

Answer 17

Childhood kidney tumour.

Question 18

What is p53?

Answer 18

Tumour suppressor gene, transcriptional regulator. Commonest genetic alteration in human cancer.

Question 19

What happens when p53 is mutated?

Answer 19

Loses transcriptional ability, can’t up regulate mdm2.

Question 20

Why is too much p53 a bad thing?

Answer 20

P53 makes sure DNA damage is repaired properly, too much leads to premature ageing.

Question 21

What is RET?

Answer 21

A proto-oncogene. Encodes receptor tyrosine kinase. Ligand = GDNF.
Mutations cause ligand independent receptor activation.

Question 22

Which three autosomal dominant syndromes map to chromosome 10q?

Answer 22

MEN2A (multiple endocrine neoplasia 2A). Thyroid cancer, parathyroid hyperplasia, pheochromocytoma.
MEN2B. Ganglioneuromas.
FMTC (familial medullary thyroid carcinoma). Thyroid cancer.
All have germline mutations in RET.

Question 23

What does MET proto-oncogene do?

Answer 23

Encodes receptor tyrosine kinase.
Ligand = HCF.
Gene on chromosome 7q.

Question 24

What do germline missense mutations in MET cause?

Answer 24

Hereditary papillary renal carcinoma.

Question 25

What does KIT do? (PO).

Answer 25

Encodes tyrosine kinase receptor for stem cell factor.
Important in development.
Somatic and germline mutations lead to GI tumours.

Question 26

What do mutations in ALK do?

Answer 26

Germline and somatic mutations cause neuroblastoma.

Question 27

What does CDK4 do?

Answer 27

CDK4/cyclin D complexes phosphorylate RB1 allowing entry into the S phase.
P16 is a tumour suppressor gene that inhibits CDK4.

Question 28

What do missense mutations in CDK4 lead to?

Answer 28

Familial melanoma. Inhibit p16 binding to CDK4.

Question 29

What are the clinical applications of genetics in cancer?

Answer 29

Screening, diagnosis (especially useful in undifferentiated tumours), and prognosis and therapy (new gene based treatments).

Question 30

Outline gene therapy in cancer.

Answer 30

Tumour suppressor gene replacement

Antisense RNA to oncogenes.

Question 31

Outline other new cancer therapies.

Answer 31

Anti-p53 virus - selectively kills cells with mutant p53.

Rational drug design.