15 origins of carcinogenesis

Question 1

What is the sequence of molecular changes in cancer development?

Answer 1

Genome/Epigenome → Transcriptome → Proteome → Phenotypic changes

Question 2

What cellular changes occur due to cancer?

Answer 2

Loss of function, de-differentiation, ability to metastasise and invade.

Question 3

What determines cancer risk?

Answer 3

Constitutional and somatic genetics.

Question 4

How many bases are in the human genome?

Answer 4

3.2 billion bases.

Question 5

How many replication errors occur per cell division?

Answer 5

Approximately 120,000 mistakes.

Question 6

How many polymorphisms exist in the human genome?

Answer 6

Over 100 million (common, rare, unique).

Question 7

What are the main causes of somatic mutations in cancer?

Answer 7

Endogenous DNA damage (molecular oxygen), exogenous DNA damage (UV, ionising radiation, BPDE), and spontaneous DNA replication errors.

Question 8

What factors increase cancer risk?

Answer 8

Number of cell divisions and cumulative exposure to carcinogens

Question 9

What is the consequence of DNA mutations in tumour suppressor genes and proto-oncogenes?

Answer 9

Genetic instability and anti-apoptotic effects, leading to cancer.

Question 10

What are high-penetrance genetic variants?

Answer 10

Rare genetic variants that confer high lifetime cancer risk.

Question 11

How do high-penetrance variants contribute to cancer?

Answer 11

Typically, one defective allele is inherited, and the other is somatically mutated/silenced.

Question 12

What percentage of breast cancer cases are due to high-penetrance monogenic variants?

Answer 12

Only 1-2%.

Question 13

What is the post-mastectomy lifetime risk for hereditary breast/ovarian cancer?

Answer 13

Less than 5%.

Question 14

Is monogenic cancer susceptibility common in the population?

Answer 14

No, it is rare.

Question 15

What type of genetic risk is most common in cancer?

Answer 15

Polygenic risk.

Question 16

How do monogenic and polygenic diseases differ?

Answer 16

Monogenic: Low frequency, high penetrance.
Polygenic: High frequency, low penetrance.

Question 17

Example of a polygenic disease?

Answer 17

Chronic lymphocytic leukaemia (CLL).

Question 18

Which genome tolerates variation less: constitutional or somatic?

Answer 18

The constitutional genome.

Question 19

Examples of constitutional genetic disorders?

Answer 19

Patau syndrome (Trisomy 13), Edwards syndrome (Trisomy 18), Down syndrome (Trisomy 21).

Question 20

Examples of somatic genetic alterations in cancer?

Answer 20

Somatic hyperdiploidy in acute myeloid leukaemia.

Question 21

How common is pre-cancer?

Answer 21

Ubiquitous—everyone has cancer driver somatic mutations.

Question 22

How many somatic mutations are needed for cancer?

Answer 22

Between 1 to 10 mutations.

Question 23

Which major cancer genes are commonly mutated?

Answer 23

TP53 and MYC.

Question 24

Which cancers require the most mutations?

Answer 24

Liver cancer: ~4 mutations.
Colorectal cancer: Up to 10 mutations.

Question 25

What are the steps in haematopoietic cancer development?

Answer 25

Normal cells → Hyperplasia (increased cell number) Dysplasia (abnormal cells) Neoplasia (cancer)

Question 26

Where do haematopoietic cancers spread?

Answer 26

Blood and lymphatic systems.

Question 27

What is clonal haematopoiesis?

Answer 27

Clonal expansion of cells in blood and bone marrow with leukaemia-initiating mutations.§

Question 28

Which cancer is associated with clonal haematopoiesis?

Answer 28

Acute myeloid leukaemia (AML).

Question 29

What are potential diagnostic outcomes?

Answer 29

False positive → Unnecessary treatment. True positive → Cancer diagnosis. False negative → Missed cancer.

Question 30

Which cancer urgently needs better early detection methods?

Answer 30

Pancreatic cancer.

Question 31

What are cancer breath tests used for?

Answer 31

Detecting volatile organic compounds (VOCs) exhaled by cancer cells.

Question 32

Which cancers can breath tests detect?

Answer 32

Oesophageal, stomach, colon, pancreas, and liver cancer.

Question 33

What is PSA?

Answer 33

Prostate-specific antigen, a marker for prostate cancer.

Question 34

What percentage of prostate cancers are aggressive?

Answer 34

Only 10-15%.

Question 35

Why is PSA testing limited?

Answer 35

It does not differentiate well between aggressive and indolent prostate cancers.

Question 36

What are the stages of CLL progression?

Answer 36

Monoclonal B-cell lymphocytosis (asymptomatic). CLL diagnosis (asymptomatic or weak symptoms). Treatment required (heavily symptomatic).

Question 37

What percentage of CLL patients require treatment?

Answer 37

Approximately 40%.

Question 38

What are established prognostic markers in CLL?

Answer 38

Genetic: IGHV. Phenotypic: CD38.

Question 39

What are the major types of DNA damage that drive cancer?

Answer 39

Endogenous damage: Molecular oxygen. Exogenous damage: UV radiation, ionising radiation, BPDE. Spontaneous replication errors.

Question 40

What happens when tumour suppressor genes and proto-oncogenes mutate?

Answer 40

Genetic instability. Anti-apoptotic effects. Leads to cancer.

Question 41

How much of the heritable risk for CLL is accounted for by common genetic variants?

Answer 41

More than 45 loci contribute to about 25% of the heritable risk of CLL.

Question 42

Which chromosomes are associated with CLL progression?

Answer 42

Chromosome 6 (rs736456): Hazard ratio 1.98. Chromosome 10 (rs3778076): Hazard ratio 1.79.

Question 43

What is an example of epigenetic regulation in cancer?

Answer 43

TET2 regulates genomic methylation, which influences transcriptional repression.

Question 44

How does AML progress at the genetic level?

Answer 44

Initial diagnosis: TET2 and NPM1 mutations (3 genetic hits). Relapse: Additional mutation (4 genetic hits).

Question 45

What is the typical remission induction therapy for AML?

Answer 45

Daunorubicin / Ara-C.

Question 46

What happens if AML remission induction fails?

Answer 46

Patients may receive 5-azacitidine.

Question 47

What is a major challenge in distinguishing mutations in cancer?

Answer 47

Identifying driver mutations (causing cancer) from passenger mutations (non-functional).

Question 48

Why do we need better prostate cancer diagnostic markers?

Answer 48

To differentiate aggressive (lethal) from indolent (slow-growing) prostate cancers.

Question 49

Why is cancer considered an inevitable consequence of ageing?

Answer 49

Because genetic mutations accumulate over time, increasing cancer risk.

Question 50

What determines when someone develops cancer?

Answer 50

A complex interplay between genetics and exposure to carcinogens.

Question 51

What are the key stages in cancer development?

Answer 51

Normal cells: Functional, regulated growth. Hyperplasia: Increased cell number. Dysplasia: Abnormal cell morphology and function. Neoplasia: Uncontrolled cell growth (cancer).

Question 52

How do mutation numbers vary across cancers?

Answer 52

Leukaemia: 1 mutation can be sufficient. Liver cancer: ~4 mutations. Colorectal cancer: Up to 10 mutations.

Question 53

How common is pre-cancer in the human body?

Answer 53

Pre-cancer is ubiquitous—everyone has cancer-driving somatic mutations.

Question 54

What is an example of pre-cancer in the blood?

Answer 54

Clonal haematopoiesis—clonal expansion of cells in blood and bone marrow with leukaemia-initiating mutations.

Question 55

What are the key stages of CLL progression?

Answer 55

Monoclonal B-cell lymphocytosis: Asymptomatic. CLL diagnosis: May be asymptomatic or mildly symptomatic. Treatment phase: Heavily symptomatic, requiring intervention.

Question 56

Why do some CLL patients never need treatment?

Answer 56

Many are diagnosed at an early stage (Stage A) and die with CLL, not from it.

Question 57

What factors increase PSA levels?

Answer 57

Prostate cancer. Benign Prostatic Hyperplasia (BPH). Increasing age.

Question 58

What are the treatment steps for AML?

Answer 58

Initial diagnosis with peripheral blasts. Treatment: Daunorubicin / Ara-C remission induction. Day 15 marrow remission failure (37% blasts). Treatment: 5-azacitidine. Cytomorphological remission (bone marrow). Bone marrow relapse.

Question 59

What are cancer breath tests, and how do they work?

Answer 59

They detect volatile organic compounds (VOCs) exhaled in breath. Generated by cancer cells.

Question 60

What are the two major prognostic markers in CLL?

Answer 60

IGHV (Genetic marker). CD38 (Phenotypic marker).