Cancer genetics

Question 1

Why can solid tumors be considered as organs?

Answer 1

As they consist of a variety of cell types and are thought to be maintained by a small population of stem cells

Question 2

How many mutation events are needed to drive a normal cell to a cancer cell?

Answer 2

6

Question 3

Oncogenes

Answer 3

Promote cell proliferation. A single mutant allele may affect the behaviour of a cell. The nonmutant version are called proto-oncogenes

Question 4

Tumor suppressor genes

Answer 4

Inhibit cell proliferation. Loss of function. Both alleles must be inactivated to change the behaviour of the cell

Question 5

How do DNA viruses cause tumours?

Answer 5

By rare anomalous integrations

Question 6

Acute transforming retroviruses

Answer 6

Retrovirus particles which transform the host cell rapidly and with high efficiencies: their genome contains the oncogene

Question 7

Retroviral life cycle

Answer 7

1. Invasion of host cell. Reverse transcriptase provides a dsDNA copy of viral genome
2. The viral genome is integrated into host DNA which is then transcribed into viral mRNA
3. The viral mRNA is translated into viral proteins
4. VIral proteins leads to the assembly of virus particles that bud off from cell membranes

Question 8

What do oncogenes require?

Answer 8

A gain of function mutation

Question 9

4 ways of activating oncogenes

Answer 9

1. Amplification
2. Point Mutations
3. Translocation creating a novel chimeric gene
4. Translocation into a transcriptionally active chromatin region

Question 10

Amplification

Answer 10

Oncogene expressed at high levels in a cell

Question 11

Point mutations

Answer 11

overactivation of protein: HRAS is a small GTPase and when we point mutations on specific residues on the catalytic site of the GTPase it results in oncogenic activation of the RAS signal

Question 12

Translocation creating a novel chimeric gene

Answer 12

most famous example: philadelphia chromosome: translocation between chromosomes 9 and 22: breaks 2 genes: ABL1 gene and BCR gene

Question 13

What do we get from Philadelphia chromosome?

Answer 13

Leukemia because we have a new protein that contains exons on both of the 2 genes

Question 14

Translocation into a transcriptionally active chromatin region

Answer 14

Burkitt lymphoma
MYC oncogene is activated as it is placed close to IGH—> transforms B cells to lymphomas

Question 15

When are tumor suppressor genes common?

Answer 15

If one of the mutations is present in all cells as it has been inherited

Question 16

Retinoblastoma

Answer 16

If you acquire the allele at the heterozygous state sooner or later, you will develop a tumor in the retina

Question 17

Inheritance and molecular level of retinoblastoma

Answer 17

Inheritance: dominant
Molecular level: recessive

Question 18

What has been used as a marker to locate tumor suppressor genes?

Answer 18

Loss of heterozygosity

Question 19

What are most tumor suppressors?

Answer 19

Proteins controlling cell-cycle pregression

Question 20

Which is the most relevant checkpoint in the cell cycle?

Answer 20

G1-S checkpoint controlled by Cdk2 and cyclin E

Question 21

Proteins that stop cell cycle progression

Answer 21

pRB: retinoblastomal cell tumor suppressor
p53: tumor suppressor that increases when there is DNA damage
p14 and p16

Question 22

pRB function

Answer 22

acts as an inhibitor of the E2F protein that is a kinase activating CDK complex

Question 23

p53 function

Answer 23

promotes p21 that will block cell cycle progression

Question 24

Li-Fraumani Syndrome

Answer 24

mutation of one copy of p53 characterises this syndrome

Question 25

2 types of instability of the genome

Answer 25

1. Chromosomal instability
2. Microsatellite instability

Question 26

methods used to survey cancer cells for chromosomal changes

Answer 26

1. Array- comparative genomic hybridisation of tumor DNA compared with normal DNA
2. Hybridisation of tumor DNA to a high resolution SNP chip
3. Multiolour FISH using a cocktail of different coloured chromosome paints

Question 27

What is the primary detector of damage?

Answer 27

ATM protein

Question 28

Describe the function of the ATM protein

Answer 28

The protein is activated by DNA double strand breaks: ATM kinase phosphorylates numerous substrates such as p53, CHEK2, BRCA1, NBS1

Question 29

What does a loss of ATM function cause?

Answer 29

ataxia telaniectasia

Question 30

Which forms of repair can suffer defects which are associated with types of cancer?

Answer 30

• nucleotide excision repair
• base excision repair
• double-stranded break repair
• replication error repair

Question 31

2 categories of colon cancer

Answer 31

1. Familial adenomatous polyposis
2. Hereditary non-polyposis colon cancer

Question 32

Cause of Familial adenomatous polyposis

Answer 32

Inherited mutation in the APC tumor suppressor gene

Question 33

What are replication errors associated by?

Answer 33

hMUtSa, a dimer of M2H2 and M2H6 proteins. The proteins translocate along the DNA, bind the MLH1-PMS2 dimer hMutLa, then assemble the full repairosome, which strips back and resynthesizes the newly synthesised strand

Question 34

What is used to distinguish tumors from healthy tissues?

Answer 34

Microarray expression

Question 35

Sequence coverage

Answer 35

represents the number of sequenced reads that cover the site; affects the ability to detect point mutations

Question 36

Physical coverage

Answer 36

Measures the number of fragments that span the site; affects the ability to detect the rearrangement, based on paired reads that map to different chromosomes