Cancer Genetics and Genomics

Question 1

Distinguish between genetics and genomics

Answer 1

Genetics: individual genes
Genomics: considering all genes and their interactions

Question 2

Distinguish between variant, mutation and polymorphism

Answer 2

Variant: any change from reference DNA sequence
Mutation: variant causing disease
Polymorphism: variant not causing disease

Question 3

Distinguish between somatic, driver and passenger mutations

Answer 3

Somatic mutation (variant): any change from pt’s germline DNA
Driver mutation: somatic mutation contributing to cancer development
Passenger mutation: somatic mutation not contributing to cancer development

Question 4

What is a mutator phenotype?

Answer 4

Occurs in cancer when DNA repair mechanisms are lost, thereby increasing the rate of mutation

Question 5

How many driver and passenger mutations are there estimated to be per cancer?

Answer 5

5-10 driver

1000s-100,000s passenger

Question 6

List the 10 hallmark functional characteristics of cancer cells

Answer 6

Sustained proliferative signalling
Evading growth suppression
Resisting cell death
Inducing angiogenesis
Replicative immortality
Invasion and metastasis
Deregulated cellular energetics
Avoiding immune destruction
Genome instability and mutation
Tumour-promoting inflammation

Question 7

What healthy tissues are also damaged in standard chemotherapy?

Answer 7

BM
GIT
Skin

Question 8

What are the key genes involved in the MAPK signalling pathway?

Answer 8

EGFR
HER2
KRAS
BRAF

Question 9

What is the hallmark of alterations to the MAPK signalling pathway?

Answer 9

Sustained proliferative signalling

Question 10

What is HER2?

Answer 10

Growth factor receptor which signals via the MAPK and other pathways

Question 11

What % of breast cancers have a HER2 gene amplification? How and why is this tested for?

Answer 11

~20%
In situ hybridisation (ISH) testing for HER2 amplification performed on all breast cancers to guide use of targeted therapies

Question 12

What is trastuzumab?

Answer 12

Monoclonal Ab which interfers with HER2 function and/or induces immune destruction of cells bearing HER2

Question 13

What is BRAF?

Answer 13

An important signalling protein in the MAPK pathway

Question 14

In what cancer is the BRAF V600E mutation commonly seen?

Answer 14

Melanomas (~50%)

Question 15

What is vemurafinib?

Answer 15

Small-molecule inhibitor of V600E mutant BRAF

Question 16

When is BRAF V600E mutation testing commonly performed?

Answer 16

For metastatic melanoma

Question 17

In what cancer are activating EGFR mutations seen?

Answer 17

Non-small cell lung cancers (~15% of all NSCLC)

Question 18

What are gefitinib and erlotinib?

Answer 18

Small-molecule EGFR inhibitors

Question 19

When is EGFR mutation testing performed?

Answer 19

Standard of care for NSCLC

Question 20

What is cetuximab and when is it used?

Answer 20

Monoclonal Ab that inhibits EGFR

EGFR is expressed in most colorectal cancers but is unmutated; despite this, cetuximab is an effective treatment

Question 21

When is cetuximab not effective in treating colorectal cancer? Why? What are the clinical implications?

Answer 21

In pts whose tumours have activating KRAS mutations
RAS is downstream in the MAPK pathway; if the pathway is activated at this level, treatment targeted to the receptor will have no effect
KRAS mutation testing is required before commencing cetuximab

Question 22

What is imatinib? When is it indicated?

Answer 22

An inhibitor of multiple TKs

In case of the BCR-ABL fusion gene in CML and some ALLs, and c-Kit mutation in GI stromal tumours

Question 23

What is sorafenib? When is indicated?

Answer 23

Inhibits RAF and VEGFR

Used in HCC and RCC

Question 24

What is the transcriptome?

Answer 24

RNA expression analysis

Question 25

Give an example of an AD inherited cancer syndrome

Answer 25

FAP, caused by germline mutation in APC gene