Cancer as a genetic disease

Question 1

What is the difference between somatic and germline mutation?

Answer 1

Somatic can’t be passed to offspring (90%)

Germline, mutations in gametes which can be passed onto offspring

Question 2

What is the difference between driver and passenger mutations?

Answer 2

Passengers = mutations that don't contribute to the development of cancer (occurred during growth)
Drivers = contribute to cancer development

Question 3

INHERITED CANCER DISORDERS

-Familial adenomatous polyposis

Answer 3

Thousands of intestinal polyps, 1 or more are likely to be cancerous
>1% of all colorectal cancers
-Mutation of APC gene which controls cell division (Adenomatous polyposis coli)
-100% lifetime risk of cancer

Question 4

INHERITED CANCER DISORDERS

-HNPCC (Hereditary non polyposis colorectal cancer)

Answer 4

• 3% of all cases
• most common inherited form (90% of familial cases)
• Mutation of MLH1/MSH2 (DNA repair genes)
• 80% lifetime risk of cancer

Question 5

What are oncogenes?

Answer 5

• promotes growth and proliferation in cells

- Growth, transcription factors and tyrosine kinases

Question 6

What is the function of tumour suppressor genes?

Answer 6

-Regulate cell division
-apoptosis
-DNA repairs
-Monitors DNA damage
Inactivation results in uncontrollable cell division. Checkpoints created by the TSGs during the cell cycle are eradicated (TSGs are recessive

Question 7

What types of genetic changes that can result in cancer?

Answer 7

POINT MUTATIONS:

• Silent mutation = no change in primary structure, same protein is produced
• Missense mutation = different protein and primary structure
• Nonsense mutation = mutated codon becomes a stop codon, creates a truncated protein

CHANGES IN CHROMOSOME STRUCTURE OR NUMBER

Question 8

Outline the Two Hit Hypothesis

Answer 8

Need at least 2 genetic changes to give rise to cancer

• Hit 1 = reduces transcript/protein level but isn’t enough to cause a phenotypic effect (mutation)
• Hit 2 = removes the other allele, total loss of transcription (larger deletion)

Question 9

What is haploinsufficiency?

Answer 9

1 hit can give the cell a selective advantage - a 50% decrease in protein is enough

Question 10

What can be a result of the second hit?

Answer 10

Loss of heterozygosity = alleles which are originally heterozygous may be removed, this means that only one allele will remain, it will appear as though the gene in homozygous

Question 11

What genes predispose to breast and ovarian cancer ?

Answer 11

BRCA1 + BRCA2 (germline mutations)
Inactivation of 2nd allele is usually via somatic deletion
Lifetime risk = 60%

Question 12

Describe the patho-genetic mechanism of BRCA genes

Answer 12

Involved in DNA repair (homologous recombination)

Mutated genes = impaired proteins = dysfunctional DNA repair proteins = more mutations

Question 13

What are cytogenic changes?

Answer 13

Visible changes in chromosome number or structure

e.g. translocation, deletion, duplication

Question 14

How can translocations cause cancer?

Answer 14

Lead to the formation of new fusion gene that encodes a protein with oncogenic properties

Question 15

Explain the cause of Chronic Myeloid Leukaemia

Answer 15

Translocation between chromosome 9 (ABL gene)and 22 (BCR gene) = Philadelphia chromosome
-Fusion of genes encode BCR-ABL1 tyrosine kinase = promotes CML

Question 16

What protein does the CML fusion gene produce?

Answer 16

BCR-ABL1 tyrosine Kinase

Question 17

Describe a targeted therapy for CML

Answer 17

Imatinib = inhibits the BCR-ABL1 tyrosine kinase by blocking the ATP binding site
-Leads to cell death

Question 18

What are the 3 techniques of quantifying the level of CML In order of sensitivity?

Answer 18

• Cytogenetic analysis
• Fluorescence in situ hybridisation
• RT-qPCR( reverse transcriptase quantitative PCR)

Question 19

What is another example of a translocation causing cancer

Answer 19

APML (Acute Promyelocytic Leukaemia) = Between chromosome 15(PML gene) and 17(RARA gene/ Retinoic Acid Receptor Alpha)

Question 20

How does the APML translocation cause cancer?

Answer 20

RARA receptor binds to Vit A and then DNA = regulates transcription
-The fusion causes RARA to bind too strongly = genes are silenced = cell proliferates

Question 21

Describe the treatment for APML

Answer 21

All Trans Retinoic Acid (ATRA) binds to DNA with a greater affinity than the mutated RARA. This stops the gene silencing
-Doesn’t kill cells, have to take the treatment for the rest of their lives

Question 22

What is pharmacogenomics?

Answer 22

Use genetics to determine which patients will respond the best to a particular treatment
-Based on the presence/absence of somatic cells