Cancer Genomics

Question 1

What are the three classifications of germ line DNA changes?

Answer 1

VariantMutationPolymorphism

Question 2

Define polymorphism

Answer 2

= variant not causing disease

Question 3

Define mutation

Answer 3

= variant causing disease

Question 4

Define variant

Answer 4

= any change from the reference DNA sequence

Question 5

What are the three classifications of cancer DNA changes?

Answer 5

somatic mutation (variant)driver mutationpassenger mutation

Question 6

Define somatic mutation (variant)

Answer 6

= any change from the patient’s germ line DNA sequence

Question 7

Define driver mutation

Answer 7

= somatic mutation contributing to cancer development

Question 8

Define passenger mutation

Answer 8

= somatic mutation not contributing to cancer development

Question 9

What are the small scale nucleotide sequence changes called?

Answer 9

Point mutationInsertion or deletion

Question 10

What are the large scale nucleotide sequence changes called?

Answer 10

TranslocationAmplificationInsertion or deletion

Question 11

What is the DNA change in epigenetic changes?

Answer 11

Promoter methylation

Question 12

Genes involved in cancer are either..?

Answer 12

1. Oncogenes or 2. Tumour suppressor genes

Question 13

What are oncogenes?

Answer 13

Gene function promotes cancer formationMutations causes increased gene functionMutations are dominant (only one allele mutated)

Question 14

What are TSGs?

Answer 14

Gene function normally inhibits cancer formationMutations cause loss of gene function or expressionMutations are recessive (both alleles must be knocked out)

Question 15

What is a driver mutation?

Answer 15

Driver mutation drive the tumour and contribute to cancer dvpmtInvolve oncogenes and TSGConfer advantage in growth or survival, therefore are positive selected(5-10 driver mutations per cancer?)

Question 16

What are passenger mutations?

Answer 16

Mutations that do not confer any advantage (along for the ride) Just happens to be in the same cell as the driver mutations(1000-100,000 passenger mutations per cancer)

Question 17

What is a driver mutation?

Answer 17

Driver mutation drive the tumour and contribute to cancer dvpmtInvolve oncogenes and TSGConfer advantage in growth or survival, therefore are positive selected(5-10 driver mutations per cancer?)

Question 18

What is the MAPK signalling pathway in cancer?

Answer 18

Hallmark: sustained proliferative signallingKey genes: - EGFR (growth factor receptor)- HER2 (growth factor receptor)- (K)RAS- (B)RAF

Question 19

What is HER2?

Answer 19

HER2 is a growth factor receptor which signals via the MAPK pathway (and other pathways)App. 20% of breast cancers have HER2 gene amplification i..e more growth factor receptors on the cell surface

Question 20

Which drug targets the HER2 receptor in breast cancer?

Answer 20

Trastuzumab - monoclonal Ab that interferes with HER2 function and/or induces immune destruction of cells baring HER2*monoclonal Ab act on the cell surface

Question 21

What is BRAF V600E?

Answer 21

BRAF is an important protein in the MAPK pathway.BRAF V600E is a mutation seen in 50% of melanomas that causes constitutive activation of MAPK signalling

Question 22

Which drug targets V600E mutant BRAF?

Answer 22

Vemurafinib - small molecule inhibitor of V600E mutant BRAF*a small molecule inhibitor means that it acts in the cytoplasm

Question 23

What is EGFR?

Answer 23

Growth factor receptor which signals via the MAPK pathway (and other pathways)15% of non-small cell lung cancers (NSCLC) have activating EGFR mutations

Question 24

What drugs target EGFR?

Answer 24

Gefitinib and erlotinib: small molecule EGFR inhibitors

Question 25

What is BRAF V600E? What disease is commonly associated with?

Answer 25

BRAF is an important protein in the MAPK pathway.BRAF V600E is a mutation seen in 50% of melanomas that causes constitutive activation of MAPK signalling

Question 26

What is EGFR? What disease is commonly associated with this mutation?

Answer 26

Growth factor receptor which signals via the MAPK pathway (and other pathways)* 15% of non-small cell lung cancers (NSCLC) have activating EGFR mutations * EGFR is expressed in most colorectal cancers

Question 27

What drugs target EGFR in non-small cell lung cancers?

Answer 27

Gefitinib and erlotinib: small molecule EGFR inhibitors

Question 28

What drugs target EGFR in colorectal cancers?Which patient group does not respond to this drug?

Answer 28

Cetuximab: monoclonal Ab that inhibits EGFR function*patients who have tumours that have activating KRAS mutations DO NOT respond to cetuximab (even if they have EGFR) therefore must test

Question 29

What is imatinib?

Answer 29

Inhibits multiple tyrosine kinases In: BCR-ABL fusion gene in CML and some ALL; CKIT in GI stromal tumours

Question 30

What is sorafenib?

Answer 30

Inhibits RAF, VEGFR in hepatocellular carcinoma and renal cell carcinoma