Genetic basis of Cancer

Question 1

Define Oncogene and Tumour Suppressor

Answer 1

oncogene - mutated form of cellular genes involved in cell proliferation. Results in Dominant gain in function Tumour suppressor: gene whose normal function is to stop proliferation. mutation results in recessive loss of function

Question 2

Why are tumour suppressor mutations recessive loss of function?

Answer 2

Because they are very important so it requires both alleles to be defective

Question 3

what are the different kinds of oncogene?

Answer 3

• Growth factors, regulatory genes involved in the control of cell multiplication. - Protein kinases, add phosphate groups to target proteins, important in signal transduction pathways

Question 4

What is a Proto-oncogene?

Answer 4

Normal form of the gene that is involved in positive regulation of the cell cycle

Question 5

Tumour suppressor genes - what do they do and give an example protein (not p53)

Answer 5

• Normally inhibit cell growth e.g. RB, p53, APC, PTEN Retinoblastoma (RB) protein normally blocks a transcription factor, E2F. mutated Rb is constitutively phosphorylated which doesn’t block E2F (a transcription factor) leading to a loss of function

Question 6

Facts about p53

Answer 6

• Detects DNA damage - The “Last Gatekeeper” > Involved in ~50% of cancers >Often not malignant despite other cancer-causing mutations until p53 is inactivated by mutation - Two possible responses to DNA damage: 1) Acts as a Transcription Factor to activate expression of p21, which inhibits CDK2/G1 cyclins to halt the cell cycle; then activates DNA repair 2) Triggers Apoptosis (programmed cell death) if damage can’t be repaired - Not usually one of the first mutated genes

Question 7

UC reduced cell death slide RELISTEN

Question 8

What are Mutator genes?

Answer 8

•Genes that are involved in DNA repair as they have the potential to propagate mutation by not being able to repair mutations.

•Many environmental factors (carcinogens) also cause DNA damage or mutations, that can lead to cancer

Question 9

DNA methylation

Answer 9

A section of DNA that is hypermethylated is less likely to be transcribed

Question 10

DNA translocation implications

Answer 10

if you move a gene from one chtomosomal position to another you risk putting it next to an active promoter or into a repressed region which effects the transcription. if the gene is cut in the middle then it causes many problems as it is a non-functional gene and causes disruption in the target locus.

Question 11

Histone modification RELISTEN

Question 12

Telomeres and breast cancer prognosis

Answer 12

Telomeres that are longer tend to be associated with better prognosis

Question 13

Explain the colorectal cancer multi-step model

Answer 13

(1) The clonal origin of tumours: each individual cancer is a clone that arises from a single cell.

The progeny have a growth (or survival) advantage over the surrounding normal cells

(2) Cancer development is a multi-step process. Multiple mutations accumulated over periods of many years “multi-hit” model.

Question 14

Why are there so many treatments for Haematological cancers?

Answer 14

Haem cancers are much more accessible due to it being in the blood. You can easily repeat biopsies to confirm treatment of cancer

Question 15

Pathogenesis of Chronic Myeloid leukaemia

Answer 15

—CML

–Cancer of the haematopoietic stem cell

–Well-characterized molecular pathogenesis

—Philadelphia (Ph) chromosome (9;22 translocation)

–First abnormality associated with cancer

–Chronic phase (typical duration ~4 years)

–Blast crisis

—Bcr-Abl tyrosine kinase

–A single molecular abnormality that causes transformation of a haematopoietic progenitor into a malignant clone