HRR: cancer genetics and genomics I

Question 1

What are the 4 functional classes of genes to which mutation can cause malignant transformation

Answer 1

• proto-oncogenes
• tumor suppressor genes
• DNA repair genes
• apoptosis genes

Question 2

what are somatic mutations

Answer 2

Non-heritable mutations that do not pass down; could be from smoking or sun damage

Question 3

what are germline mutations

Answer 3

These are heritable, as they occur in the germline. This also means all cells will be impacted.

Question 4

What is a gain of function mutation

Answer 4

This is usually found in proto-oncogenes, and only one copy needs to be mutated. The mutation confers enhanced or new activity of a protein.

Question 5

What is a loss of function mutation

Answer 5

This is usually found in tumor suppressor genes, and a defect in both copies is needed. The mutation results in reduced or abolished protein function

Question 6

What are passenger mutations

Answer 6

Mutations found in the tumor that don’t really play a role

Question 7

What are driver mutations

Answer 7

Occur in cancer-related genes and are presumed to be involved in the development or progression of the cancer

Question 8

Describe proto-oncogenes

Answer 8

These promote survival and growth of cells. When they have a gain of function mutation, they are driver-mutations and are activated oncogenes. These are often dominant and only require one mutation.

Question 9

Ras and BRAF are examples of…

Answer 9

proto-oncogenes

Question 10

The most common mutations in
proto-oncogenes are…

Answer 10

constitutive action; this means the proto-oncogene becomes an oncogene that proliferates and behaves independant of regular stimuli and signalling

Question 11

Define tumor suppressor gene

Answer 11

they inhibit cellular proliferation in response to stimuli such as damage. When activated via a loss-of-function mutation, they can lead to cancer. These are often recessive and require issues in both alleles.

Question 12

Describe the CDKN2A gene

Answer 12

It encodes two tumor suppressor genes: p14 and p16.

Question 13

Describe the action of p14

Answer 13

P14 activates the p53 pathway, leading to cell cycle arrest in damaged cells

Question 14

Describe the action of p16

Answer 14

it inhibits CDK4 and CDK6, preventing phosphorylation of Rb. when Rb is phosphorylated, it releases from E2F, which translocates to the nucleus and promotes transcription and thus movement from G1 to S. p16 inhibits this movement.

Question 15

What is the “guardian of the genome”

Answer 15

p53

Question 16

What does the TP53 gene encode

Answer 16

P53, a really important tumor suppressor gene

Question 17

Mutations and epigenetic changes accumulate in cell lineages via…

Answer 17

Clonal selection and expansion

Question 18

What is tumor growth dependent on

Answer 18

Their ability to develop blood supply to continue to feed the growing population of cells

Question 19

Describe exon 14 skipping

Answer 19

Alternative splicing results in the exclusion of exon 14 out of the MET gene. This leads to impaired receptor degradation/accumulation of MET and increases downstream signaling. This will lead to oncogenic transformation, often seen in lung cancer

Question 20

Describe the Philadelphia chromosome

Answer 20

A fusion gene resulting from translocation between chromosomes 9 and 22 that encodes BCR-ABL1 fusions. BCR-ABL1 is a tyrosine kinase, and this mutation causes enhanced activation of the kinase and increased downstrea signalling. This is often seen in CML.

Question 21

Describe MYC

Answer 21

A proto-oncogene that gets translocated upstream of immunoglobulin heavy chain locus. This results in strong constitutive promotion and drives MYC expression. MYC encodes a protein involved in many processes, and ultimately leads to increased proliferation. This is often seen in Burkitt lymphoma

Question 22

Describe the rationale behind targeted therapies

Answer 22

It is thought that some tumors rely on a single dominant oncogene for growth and survival, known as oncogene addiction. The thought is that if we can target the specific oncogene, the tumor will shrink. However, this does not hold up in all cancers.

Question 23

The most inherited variants that contribute to familial syndromes are __ genes

Answer 23

tumor suppressor

Question 24

What are denovo mutations

Answer 24

New mutations occurring during the formation of germ cells. This results in unaffected siblings and an absence of mutation in maternal tissues. You would not see a family history.

Question 25

What is the two-hit hypothesis

Answer 25

Cancer requires two genetic events to initiate oncogenic transformation. The inherited mutation is the first event, and the second event often occurs early in life.

Question 26

Describe loss of heterozygosity in terms of oncogenic transformation

Answer 26

After inherited mutation, an issue forming a defective copy of the second (non-mutated) allele at some point after birth is necessary for tumor development.

Question 27

Name the ways we can develop loss of heterozygosity

Answer 27

Chromosome loss, deletion, unbalanced translocation, loss and replication, mitotic recombination, point mutation, methylation

Question 28

What is the typical age of onset for familial cancers

Answer 28

early age of onset

Question 29

What pattern is seen in paired organs in familial cancer

Answer 29

Bilateral distribution

Question 30

What is the typical inheritance pattern seen in familial cancer syndromes

Answer 30

Autosomal dominant

Question 31

What distribution among the family is used to classify familial cancers

Answer 31

Same cancer in two or more close relatives on the same side of the family

Question 32

If an individual gets two rare cancers back to back, what does this mean

Answer 32

They likely have a familial cancer syndrome

Question 33

Evidence of autosomal dominant transmission of a cancer indicates what?

Answer 33

familial cancer syndromes