15 origins of carcinogenesis Flashcards
What is the sequence of molecular changes in cancer development?
Genome/Epigenome → Transcriptome → Proteome → Phenotypic changes
What cellular changes occur due to cancer?
Loss of function, de-differentiation, ability to metastasise and invade.
What determines cancer risk?
Constitutional and somatic genetics.
How many bases are in the human genome?
3.2 billion bases.
How many replication errors occur per cell division?
Approximately 120,000 mistakes.
How many polymorphisms exist in the human genome?
Over 100 million (common, rare, unique).
What are the main causes of somatic mutations in cancer?
Endogenous DNA damage (molecular oxygen), exogenous DNA damage (UV, ionising radiation, BPDE), and spontaneous DNA replication errors.
What factors increase cancer risk?
Number of cell divisions and cumulative exposure to carcinogens
What is the consequence of DNA mutations in tumour suppressor genes and proto-oncogenes?
Genetic instability and anti-apoptotic effects, leading to cancer.
What are high-penetrance genetic variants?
Rare genetic variants that confer high lifetime cancer risk.
How do high-penetrance variants contribute to cancer?
Typically, one defective allele is inherited, and the other is somatically mutated/silenced.
What percentage of breast cancer cases are due to high-penetrance monogenic variants?
Only 1-2%.
What is the post-mastectomy lifetime risk for hereditary breast/ovarian cancer?
Less than 5%.
Is monogenic cancer susceptibility common in the population?
No, it is rare.
What type of genetic risk is most common in cancer?
Polygenic risk.
How do monogenic and polygenic diseases differ?
Monogenic: Low frequency, high penetrance.
Polygenic: High frequency, low penetrance.
Example of a polygenic disease?
Chronic lymphocytic leukaemia (CLL).
Which genome tolerates variation less: constitutional or somatic?
The constitutional genome.
Examples of constitutional genetic disorders?
Patau syndrome (Trisomy 13), Edwards syndrome (Trisomy 18), Down syndrome (Trisomy 21).
Examples of somatic genetic alterations in cancer?
Somatic hyperdiploidy in acute myeloid leukaemia.
How common is pre-cancer?
Ubiquitous—everyone has cancer driver somatic mutations.
How many somatic mutations are needed for cancer?
Between 1 to 10 mutations.
Which major cancer genes are commonly mutated?
TP53 and MYC.
Which cancers require the most mutations?
Liver cancer: ~4 mutations.
Colorectal cancer: Up to 10 mutations.
What are the steps in haematopoietic cancer development?
Normal cells → Hyperplasia (increased cell number)
Dysplasia (abnormal cells)
Neoplasia (cancer)
Where do haematopoietic cancers spread?
Blood and lymphatic systems.
What is clonal haematopoiesis?
Clonal expansion of cells in blood and bone marrow with leukaemia-initiating mutations.§
Which cancer is associated with clonal haematopoiesis?
Acute myeloid leukaemia (AML).
What are potential diagnostic outcomes?
False positive → Unnecessary treatment.
True positive → Cancer diagnosis.
False negative → Missed cancer.
Which cancer urgently needs better early detection methods?
Pancreatic cancer.
What are cancer breath tests used for?
Detecting volatile organic compounds (VOCs) exhaled by cancer cells.
Which cancers can breath tests detect?
Oesophageal, stomach, colon, pancreas, and liver cancer.
What is PSA?
Prostate-specific antigen, a marker for prostate cancer.
What percentage of prostate cancers are aggressive?
Only 10-15%.
Why is PSA testing limited?
It does not differentiate well between aggressive and indolent prostate cancers.
What are the stages of CLL progression?
Monoclonal B-cell lymphocytosis (asymptomatic).
CLL diagnosis (asymptomatic or weak symptoms).
Treatment required (heavily symptomatic).
What percentage of CLL patients require treatment?
Approximately 40%.
What are established prognostic markers in CLL?
Genetic: IGHV.
Phenotypic: CD38.
What are the major types of DNA damage that drive cancer?
Endogenous damage: Molecular oxygen.
Exogenous damage: UV radiation, ionising radiation, BPDE.
Spontaneous replication errors.
What happens when tumour suppressor genes and proto-oncogenes mutate?
Genetic instability.
Anti-apoptotic effects.
Leads to cancer.
How much of the heritable risk for CLL is accounted for by common genetic variants?
More than 45 loci contribute to about 25% of the heritable risk of CLL.
Which chromosomes are associated with CLL progression?
Chromosome 6 (rs736456): Hazard ratio 1.98.
Chromosome 10 (rs3778076): Hazard ratio 1.79.
What is an example of epigenetic regulation in cancer?
TET2 regulates genomic methylation, which influences transcriptional repression.
How does AML progress at the genetic level?
Initial diagnosis: TET2 and NPM1 mutations (3 genetic hits).
Relapse: Additional mutation (4 genetic hits).
What is the typical remission induction therapy for AML?
Daunorubicin / Ara-C.
What happens if AML remission induction fails?
Patients may receive 5-azacitidine.
What is a major challenge in distinguishing mutations in cancer?
Identifying driver mutations (causing cancer) from passenger mutations (non-functional).
Why do we need better prostate cancer diagnostic markers?
To differentiate aggressive (lethal) from indolent (slow-growing) prostate cancers.
Why is cancer considered an inevitable consequence of ageing?
Because genetic mutations accumulate over time, increasing cancer risk.
What determines when someone develops cancer?
A complex interplay between genetics and exposure to carcinogens.
What are the key stages in cancer development?
Normal cells: Functional, regulated growth.
Hyperplasia: Increased cell number.
Dysplasia: Abnormal cell morphology and function.
Neoplasia: Uncontrolled cell growth (cancer).
How do mutation numbers vary across cancers?
Leukaemia: 1 mutation can be sufficient.
Liver cancer: ~4 mutations.
Colorectal cancer: Up to 10 mutations.
How common is pre-cancer in the human body?
Pre-cancer is ubiquitous—everyone has cancer-driving somatic mutations.
What is an example of pre-cancer in the blood?
Clonal haematopoiesis—clonal expansion of cells in blood and bone marrow with leukaemia-initiating mutations.
What are the key stages of CLL progression?
Monoclonal B-cell lymphocytosis: Asymptomatic.
CLL diagnosis: May be asymptomatic or mildly symptomatic.
Treatment phase: Heavily symptomatic, requiring intervention.
Why do some CLL patients never need treatment?
Many are diagnosed at an early stage (Stage A) and die with CLL, not from it.
What factors increase PSA levels?
Prostate cancer.
Benign Prostatic Hyperplasia (BPH).
Increasing age.
What are the treatment steps for AML?
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.
What are cancer breath tests, and how do they work?
They detect volatile organic compounds (VOCs) exhaled in breath.
Generated by cancer cells.
What are the two major prognostic markers in CLL?
IGHV (Genetic marker).
CD38 (Phenotypic marker).
