SU5

Question 1

What is the fundamental definition of cancer as a disease of the genome?

Answer 1

It is a disease where the accumulation of somatic mutations and epigenetic dysregulation disrupts growth control, leading to malignant transformation.

Question 2

Cancer is described as a form of evolution occurring within the body; what does this mean?
See answer

Answer 2

Cells with dangerous mutations that provide a growth advantage multiply faster and outcompete healthy cells.

Question 3

What four key characteristics arise from the disruption of normal cell growth constraints in cancer?

Answer 3

Unregulated cell division, loss of tissue organisation, invasion of nearby tissues, and potential metastasis.

Question 4

What is the initial step in cancer progression, leading to clonal expansion?

Answer 4

A single cell acquires a driver mutation, giving it a small survival or growth advantage.

Question 5

The process where cancer cells spread to distant organs is known as _____.

Answer 5

metastasis

Question 6

What is the significance of clonal expansion in tumour evolution?

Answer 6

It increases the population of cells with a driver mutation, raising the probability that one will acquire the next required mutation.

Question 7

What is meant by the term ‘tumour heterogeneity’?

Answer 7

A tumour contains many subclones with different genetic and epigenetic profiles, leading to diverse properties.

Question 8

In normal tissues, a balance is maintained between proliferation and which other process?

Answer 8

Apoptosis, or programmed cell death.

Question 9

How does cancer disrupt the balance between cell proliferation and apoptosis?

Answer 9

It increases proliferation (accelerators on) and decreases apoptosis (brakes fail).

Question 10

Why does cancer risk increase significantly with age?

Answer 10

More time allows for more cell divisions, leading to the cumulative accumulation of the multiple driver mutations required for cancer.

Question 11

What are the ‘Hallmarks of Cancer’?

Answer 11

A shared set of acquired traits or capabilities, like evading growth suppression, that allow tumour cells to survive, grow, and spread.

Question 12

Therapies like anti-VEGF for angiogenesis and checkpoint inhibitors for immune evasion target what general aspect of cancer?

Answer 12

They target the specific ‘hallmark’ capabilities that tumours acquire.

Question 13

What are the two major classes of genes commonly altered in cancer?

Answer 13

Oncogenes and tumour suppressor genes.

Question 14

Using the car analogy, oncogenes are the _____ and tumour suppressor genes are the _____ of the cell cycle.

Answer 14

accelerators; brakes

Question 15

What is the normal, unmutated version of an oncogene called?

Answer 15

A proto-oncogene.

Question 16

What is the normal function of proto-oncogenes in a cell?

Answer 16

To promote normal cell growth, division, and survival.

Question 17

What is the normal function of tumour suppressor genes?

Answer 17

To prevent uncontrolled growth, repair DNA, or induce apoptosis if damage is too severe.

Question 18

Name one of the three primary mechanisms by which a proto-oncogene is converted into an oncogene.

Answer 18

Gene amplification, chromosomal translocation, or a gain-of-function point mutation.

Question 19

In the context of oncogene activation, what is gene amplification?

Answer 19

A process where tumour cells make hundreds of extra copies of a proto-oncogene, leading to excessive protein production.

Question 20

What are the two structural forms of gene amplification seen in cancer cells?

Answer 20

Double minutes (extrachromosomal) and homogeneously staining regions (intrachromosomal).

Question 21

Amplification of which proto-oncogene is a marker of poor prognosis in approximately 25% of neuroblastomas?

Answer 21

MYCN.

Question 22

Amplification of the ERBB2/HER2 gene is a defining feature of an aggressive subtype in which type of cancer?

Answer 22

Breast cancer (approximately 20-30% of cases).

Question 23

How does chromosomal translocation lead to oncogene activation?

Answer 23

By creating a hyperactive fusion gene or by placing a proto-oncogene under the control of a powerful enhancer from another location.

Question 24

The reciprocal translocation t(9;22) creates which specific chromosomal abnormality?

Answer 24

The Philadelphia chromosome.

Question 25

The Philadelphia chromosome results in the fusion of which two genes, causing Chronic Myeloid Leukaemia (CML)?

Answer 25

The BCR gene and the ABL1 gene.

Question 26

What is the molecular consequence of the BCR-ABL fusion protein?

Answer 26

It becomes a constitutively active tyrosine kinase that continuously signals for cell growth and survival.

Question 27

In Burkitt Lymphoma, the translocation t(8;14) places which gene under the control of a powerful immunoglobulin enhancer?

Answer 27

The MYC gene.

Question 28

What is the effect of gain-of-function point mutations in proto-oncogenes like RAS?

Answer 28

They can lock the resulting protein in a permanently 'on' state, leading to constant growth signalling.

Question 29

Mutations in the RAS gene are frequently found at which three specific 'hotspot' codons?

Answer 29

Codons 12, 13, or 61.

Question 30

Tumour suppressor genes that directly restrain cell division or promote apoptosis are known as _____.

Answer 30

gatekeepers

Question 31

Tumour suppressor genes that maintain genome integrity, such as DNA repair genes, are known as _____.

Answer 31

caretakers

Question 32

According to Knudson's two-hit hypothesis, how many inactivating 'hits' are typically required for a tumour suppressor gene to lose its function?

Answer 32

Two hits, one for each allele of the gene.

Question 33

In hereditary cancer syndromes, how does the 'first hit' in Knudson's model occur?

Answer 33

It is inherited via the germline, meaning it is present in every cell of the body from birth.

Question 34

Why do hereditary cancers associated with tumour suppressor genes typically have an earlier onset than sporadic cases?

Answer 34

Because the first 'hit' is already inherited, only one additional somatic mutation is needed to initiate a tumour.

Question 35

At the cellular level, a mutation in a tumour suppressor gene like RB1 is considered _____, whereas in a family pedigree, the cancer predisposition is inherited as a _____ trait. See answe

Answer 35

recessive; dominant

Question 36

The loss of the normal, wild-type allele in a cell that already has one mutated tumour suppressor allele is known as _____

Answer 36

loss of heterozygosity (LOH)

Question 37

Inherited mutations in the RB1 gene cause which type of cancer?

Answer 37

Retinoblastoma.

Question 38

What is the primary function of the p53 protein, often called the 'guardian of the genome'?

Answer 38

It monitors for DNA damage and can halt the cell cycle for repair or induce apoptosis if the damage is too severe.

Question 39

A germline mutation in the TP53 gene is associated with which hereditary cancer syndrome?

Answer 39

Li-Fraumeni syndrome.

Question 40

Li-Fraumeni syndrome is characterised by a broad spectrum of early-onset cancers, often abbreviated as SBLA. What does SBLA stand for?

Answer 40

Sarcomas, Breast, Leukaemia, and Adrenocortical carcinoma

Question 41

What is the normal function of the APC gene product?

Answer 41

It controls cell proliferation by promoting the degradation of β-catenin.

Question 42

Inherited mutations in the APC gene lead to which syndrome, characterised by the development of hundreds of colon polyps?

Answer 42

Familial Adenomatous Polyposis (FAP).

Question 43

What is the primary function of the BRCA1 and BRCA2 proteins?

Answer 43

They are involved in the homologous recombination repair of double-strand DNA breaks.

Question 44

Germline mutations in the BRCA1 and BRCA2 genes are primarily associated with an increased risk for which two types of cancer?

Answer 44

Hereditary breast and ovarian cancer.

Question 45

What is meant by 'genomic instability' in the context of cancer?

Answer 45

A persistent state where the genome of a cancer cell cannot maintain its stability, leading to an increased rate of mutations and chromosomal errors.

Question 46

What are the two major types of genomic instability found in cancer cells?

Answer 46

Chromosomal Instability (CIN) and Microsatellite Instability (MIN).

Question 47

Chromosomal Instability (CIN) is characterised by errors in chromosome _____ or _____.

Answer 47

number (aneuploidy); structure (rearrangements)

Question 48

What is Microsatellite Instability (MIN)?

Answer 48

The expansion or contraction of short, repetitive DNA sequences (microsatellites) due to a defective DNA mismatch repair (MMR) system.

Question 49

Defects in the mismatch repair (MMR) genes, such as MLH1 and MSH2, are the cause of which hereditary cancer syndrome?

Answer 49

Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer, HNPCC).

Question 50

What is the lifetime risk of colorectal cancer for individuals with Lynch syndrome?

Answer 50

Approximately 70-90%, with an early age of onset around 45 years.

Question 51

The multi-step progression model for colorectal cancer often involves the sequential loss of _____, activation of _____, and loss of _____.

Answer 51

APC; KRAS; p53

Question 52

What is epigenetic silencing in the context of cancer?

Answer 52

A heritable change, such as DNA methylation in a promoter region, that switches off a gene's expression without altering the DNA sequence itself.

Question 53

How can epigenetic silencing contribute to cancer development?

Answer 53

By inactivating tumour suppressor genes, acting as a functional equivalent to a mutational 'hit'.

Question 54

The phenomenon where a tumour becomes highly dependent on a single activated oncogene for its survival is known as _____.

Answer 54

oncogene addiction

Question 55

The targeted therapy drug imatinib (Gleevec) is designed to inhibit which specific oncogenic fusion protein?

Answer 55

The BCR-ABL tyrosine kinase found in Chronic Myeloid Leukaemia (CML).

Question 56

The targeted therapy drug trastuzumab (Herceptin) is effective against breast cancers that have amplification of which gene?

Answer 56

HER2 (also known as ERBB2).

Question 57

What is the principle of 'synthetic lethality' in cancer therapy?

Answer 57

It involves exploiting a tumour's existing DNA repair defect by inhibiting a backup repair pathway, leading to cell death specifically in cancer cells.

Question 58

PARP inhibitors are a form of targeted therapy based on synthetic lethality, specifically for tumours with mutations in which genes?

Answer 58

BRCA1 or BRCA2.

Question 59

Why are tumours with mismatch repair deficiency, such as those in Lynch syndrome, often responsive to immunotherapy?

Answer 59

Their high mutation load makes them more visible to the immune system, so they respond well to checkpoint inhibitors.

Question 60

What is a potential unintended consequence of genetic testing where a genetic variant is identified, but its clinical significance is unknown?

Answer 60

The identification of a Variant of Uncertain Significance (VUS).

Question 61

The term _____ describes the situation where not everyone with a high-risk genetic mutation, like in BRCA1, will develop cancer.

Answer 61

incomplete penetrance

Question 62

When assessing a family for possible inherited susceptibility to cancer, what features would you look for as proof?

Answer 62

- Common cancer in close blood relatives - Uncommon cancers in two or more close blood relatives - Early age at diagnosis/ onset - Multifocal / bilateral origin of tumours

Question 63

Deleterious mutations between codons 867 and 1114 of the APC tumour suppressor gene in familial adenomatous polyposis (FAP) affect the β-catenin binding domain within the APC protein. What is the role of beta-catenin and how does a deletion of its binding domain within the APC protein contribute to FAP development?

Answer 63

Beta catenin drives cell division. If the binding domain within the APC protein is deleted, this would lead to beta catenin being constitutively active, making the cell grow uncontrollably.

Question 64

What are gatekeeper tumour suppressors and how do they differ from caretaker and Landscaper tumour suppressor genes?

Answer 64

Gatekeepers directly restrain division / promote apoptosis. Caretakers maintain genome integrity. Landscapers shape tumour microenvironment

Question 65

What is the difference between driver and passenger mutations

Answer 65

Driver mutations provide a growth advantage that drives cancer development, while passenger mutations are neutral alterations that accumulate during a tumor's evolution but do not directly contribute to its growth

Question 66

Unintended consequences

Answer 66

Incomplete penetrance → a positive test ≠ certain cancer. * Variants of uncertain significance (VUS) → unclear results, hard to act on. * Psychological impact → anxiety, guilt, survivor’s guilt. * Social/ethical risks → insurance or employment discrimination. * Incidental findings → discovering unrelated disease risks.