Wk1 - Cancer

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What is the definition of cancer in terms of clonal evolution?

Cancer is a disease where one cell acquires a mutation conferring a growth advantage, and its progeny accumulate further mutations through Darwinian selection.

What are the four stages of multi-step carcinogenesis?

( \text{Initiation} \longrightarrow \text{Promotion} \longrightarrow \text{Progression} \longrightarrow \text{Invasion} )

How long does it typically take for multi-step carcinogenesis to progress to cancer?

It takes years to decades.

What are the three defining properties of malignant cells?

1. Proliferate without external signals and ignore inhibitory signals.
   2. Resist programmed cell death (apoptosis).
   3. Invade local tissue and colonise distant organs (metastasis).

What is the primary cause of patient mortality in cancer?

Invasion of local tissue and colonisation of distant organs (metastasis).

Cancer is not a single disease; it consists of over how many distinct conditions?

Over 200 distinct conditions unified by shared molecular biology.

What is the key functional difference between benign and malignant tumours?

Benign tumours proliferate clonally but do not invade local tissues or metastasise.

Why does cancer incidence rise steeply with age?

Because older patients have accumulated more somatic mutations over time.

In the context of cancer, what is the definition of screening?

Detecting cancer or precancerous lesions in asymptomatic individuals at a population or high-risk level.

What is the name of the criteria used to define a valid screening programme?

Wilson-Jungner Criteria.

List the six Wilson-Jungner Criteria for screening programmes.

1. Important health problem.
   2. Acceptable treatment exists.
   3. Detectable latent stage.
   4. Reliable and acceptable test.
   5. Cost-effective.
   6. Continuous process.

What is the current protocol for Cervical Screening in the UK?

HPV primary testing for ages 25–64; colposcopy is performed for HPV-positive or abnormal results.

What percentage of cervical cancers can be prevented when screening is combined with vaccination?

Approximately 70%.

What is the Breast Screening protocol in the UK?

Mammography every 3 years for ages 50–70 (currently expanding to 47–73).

What are the benefits of the Breast Screening programme?

It detects ~50% more cancers and reduces breast cancer mortality by ~20%.

What test is used for Bowel Screening and for which age group?

The Faecal Immunochemical Test (FIT); performed every 2 years for ages 50–74.

What does a positive FIT result trigger in bowel screening?

A referral for a colonoscopy to detect colorectal cancer (CRC) or adenomas.

Who is eligible for Lung Cancer Screening (NHSE 2023 rollout)?

Individuals aged 55–74 with a ( \ge 30 ) pack-year smoking history.

What imaging modality is used for Lung Cancer Screening?

Low-dose CT (LDCT).

What is the surveillance protocol for BRCA1/2 carriers?

Annual breast MRI from age 25–30 and biannual pelvic ultrasound (USS) + CA125 testing.

What is the surveillance protocol for Lynch Syndrome?

Colonoscopy every 1–2 years starting at age 25, and endometrial ultrasound/biopsy annually starting at age 35.

How often should a patient with Barrett's Oesophagus undergo surveillance endoscopy?

Every 2–5 years, depending on the histological grade.

What is the surveillance protocol for Familial CRC (Non-Lynch)?

Colonoscopy every 5 years starting from age 40, or 5 years before the youngest affected relative was diagnosed.

What is the name of the 9-valent vaccine used for HPV prevention?

Gardasil 9.

Which HPV types does Gardasil 9 target?

Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Besides cervical cancer, what other cancers does the HPV vaccine prevent?

Oropharyngeal, anal, and penile cancers.

The HBV vaccination is primarily aimed at preventing which type of cancer?

Hepatocellular carcinoma (HCC).

How does H. pylori eradication impact cancer risk?

It reduces gastric cancer risk in infected individuals.

Which drug has been shown to reduce colorectal cancer (CRC) risk by 63% in Lynch syndrome patients (CaPP2 trial)?

Aspirin.

Which chemoprevention agents are used for breast cancer risk reduction in high-risk women or BRCA2 carriers?

Tamoxifen or Raloxifene.

Approximately what percentage of cancers are attributable to modifiable risk factors?

Approximately 42%.

What is the definition of a carcinogen?

Any agent that causes initiating DNA damage or promotes the clonal expansion of mutated cells.

Match the WHO/IARC Classification to its definition: Group 1, Group 2A, Group 2B.

Group 1: Definite human carcinogen.
Group 2A: Probable human carcinogen.
Group 2B: Possible human carcinogen.

Which chemical carcinogens are found in tobacco smoke?

Polycyclic aromatic hydrocarbons (PAHs), nitrosamines, and benzene (among >70 others).

How does alcohol drive carcinogenesis?

Its metabolite, acetaldehyde, causes DNA adducts and crosslinks.

Which carcinogen is produced by Aspergillus contamination in food?

Aflatoxin B1.

What specific mutation is associated with Aflatoxin B1 exposure?

A ( TP53 ) codon 249 hotspot mutation, leading to hepatocellular carcinoma.

Which occupational leukaemogen is associated with Acute Myeloid Leukaemia (AML) and MDS?

Benzene.

How does asbestos interact with smoking in the development of lung cancer?

They act synergistically (the combined risk is much higher than the sum of individual risks).

Where are nitrosamines commonly found and what cancers are they linked to?

Found in processed meats; linked to gastric and colorectal cancer.

How does UV-B radiation (280–315 nm) cause skin cancer?

It induces pyrimidine dimers; if nucleotide excision repair (NER) fails, it leads to ( BRAF ) V600E and ( NRAS ) mutations.

Which cancers are associated with UV-B induced DNA damage?

Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC).

What is the mechanism by which HPV 16/18 causes cancer?

The E6 protein degrades p53, and the E7 protein inactivates Rb (Retinoblastoma protein).

Which cancers are linked to the Epstein-Barr Virus (EBV)?

Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disorder (PTLD).

Which specific strains of H. pylori induce gastric adenocarcinoma?

\( CagA+ \) strains.

Which viruses drive hepatocellular carcinoma via chronic inflammation and cirrhosis?

HBV and HCV (Hepatitis B and C).

Which cancer is caused by HTLV-1?

Adult T-cell leukaemia/lymphoma.

Give an example of chronic inflammation driving cancer.

Inflammatory Bowel Disease (IBD) driving CRC or Barrett's oesophagus driving oesophageal adenocarcinoma.

Who defined the 8 Hallmarks of Cancer?

Hanahan & Weinberg.

What are the 8 Hallmarks of Cancer?

1. Sustaining proliferative signalling.
   2. Evading growth suppressors.
   3. Resisting cell death.
   4. Enabling replicative immortality.
   5. Inducing angiogenesis.
   6. Activating invasion & metastasis.
   7. Reprogramming energy metabolism.
   8. Evading immune destruction.

"What is the hallmark ""Sustaining proliferative signalling""? "

Uncontrolled cellular replication via autonomous growth signals.

"What is the hallmark ""Reprogramming energy metabolism""? "

Shifting metabolic pathways to support rapid growth, such as aerobic glycolysis (the Warburg effect).

"What is the hallmark ""Enabling replicative immortality""? "

Maintaining telomeric length to avoid senescence.

What are proto-oncogenes?

Normal, unmutated genes that code for growth factors, receptors, signal transducers, or transcription factors to drive physiological cell growth.

What is an oncogene?

A mutated proto-oncogene that is constitutively active (permanently 'on'), driving cellular proliferation.

Are oncogenes genetically dominant or recessive?

Dominant; a mutation in just one allele is sufficient to drive the phenotype.

What are the three primary mechanisms of oncogene activation?

1. Point mutation.
   2. Gene amplification.
   3. Chromosomal translocation.

What percentage of all human cancers involve RAS mutations?

30%.

What is the normal function of RAS GTPases?

They cycle between an inactive (GDP-bound) state and an active (GTP-bound) state.

What is the RAS Gly12Val point mutation?

A substitution of glycine with valine at position 12, which blocks intrinsic GTPase activity, locking RAS in the 'on' state.

Which two major signalling cascades are activated by permanently active RAS?

1. ( \text{RAF} \rightarrow \text{MEK} \rightarrow \text{ERK} )
   2. ( \text{PI3K} \rightarrow \text{AKT} )

In which cancer type is KRAS mutation most prevalent (~90%)?

Pancreatic cancer.

What is Gene Amplification in the context of cancer?

Structural chromosome changes leading to 20–50 copies of a gene within a single cell, instead of the standard 2.

What is HER2 (ERBB2)?

A receptor tyrosine kinase belonging to the epidermal growth factor receptor (EGFR) family.

How is HER2 status clinically tested?

Via Immunohistochemistry (IHC); scores of 2+ require Fluorescent In Situ Hybridisation (FISH) for confirmation.

"How is ""HER2-low"" defined? "

An IHC score of 1+, or 2+ with a negative FISH result.

What is the mechanism of the BCR-ABL translocation?

A segment of chromosome 9 (ABL) fuses with chromosome 22 (BCR), known as the Philadelphia Chromosome, ( t(9;22) ).

The BCR-ABL fusion protein functions as a constitutively active what?

Tyrosine kinase.

BCR-ABL is identifiable in ~95% of which cancer cases?

Chronic Myeloid Leukaemia (CML).

What are Tumour Suppressor Genes (TSGs)?

Genes that code for proteins that exert negative regulatory control over the cell cycle and survival.

Are TSGs genetically dominant or recessive?

Recessive; both alleles must be inactivated (Biallelic loss of function) before malignancy is driven.

Explain Knudson's Two-Hit Hypothesis using Retinoblastoma.

Hereditary cases inherit one defective allele (1st hit) and only need one somatic mutation (2nd hit) for a tumour. Sporadic cases require two rare, independent somatic hits.

Which TSG is associated with FAP (Familial Adenomatous Polyposis)?

\( APC \).

What phenotype results from Mismatch Repair (MMR) gene loss in Lynch Syndrome?

Microsatellite Instability-High (MSI-H).

Loss of the remaining BRCA1/2 allele results in what cellular phenotype?

Homologous recombination-deficient (HRD), which is highly sensitive to PARP inhibitors.

What syndrome is caused by a germline mutation in ( TP53 )?

Li-Fraumeni Syndrome.

"Why is ( TP53 ) called the ""Guardian of the Genome""? "

It is the most frequently mutated TSG (in >50% of cancers) and coordinates the cell's response to DNA damage and stress.

What are the three possible outcomes of p53 activation?

1. G1 Cell Cycle Arrest (via p21).
   2. DNA Repair Activation.
   3. Apoptosis Induction (via BAX/PUMA if damage is irreparable).

What is the pathophysiological consequence of losing ( TP53 ) function?

Cells with damaged genomes accumulate mutations unchecked, driving rapid clonal evolution and treatment resistance.```

What is the normal physiological function of the RB1 (Retinoblastoma Protein)?

It restrains E2F transcription factors at the G1/S checkpoint. Unphosphorylated Rb binds E2F, blocking S-phase gene transcription.

How do CDK4/6-Cyclin D complexes affect the RB1 protein?

They phosphorylate Rb, causing the release of E2F and subsequent S-phase entry.

What is the molecular pathophysiology of RB1 loss?

Loss of Rb removes the G1 brake, leading to continuous, unregulatable entry into S-phase and autonomous replication.

Which clinical syndromes and tumor types are associated with RB1 mutations?

1. Retinoblastoma (paediatric)
   2. Osteosarcoma
   3. Small Cell Lung Cancer (SCLC)

What is the therapeutic application of CDK4/6 inhibitors (e.g., palbociclib) in cancer?

They are used to restore the Rb-mediated pathway brake in Hormone Receptor-positive (HR+) breast cancer.

What is the normal physiological function of the APC (Adenomatous Polyposis Coli) protein?

It acts as a negative regulator of the Wnt/(\beta)-catenin pathway by forming a destruction complex that degrades cytoplasmic (\beta)-catenin.

What happens molecularly upon the biallelic loss of APC?

(\beta)-catenin degradation is prevented; it translocates to the nucleus, causing constitutive transcription of Wnt target genes like MYC and Cyclin D1.

In what percentage of sporadic colorectal cancers (CRC) is biallelic somatic loss of APC found?

>80%

What condition is caused by germline mutations in the APC gene, and what is the associated risk?

Familial Adenomatous Polyposis (FAP), which carries a 100% CRC risk by age 40.

What are the clinical signs of the Gardner variant of FAP?

1. Desmoid tumours
   2. Osteomas
   3. Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) on fundoscopy.

What clinical management is required for patients with FAP?

Prophylactic colectomy and strict surveillance.

What is the normal physiological function of PTEN (Phosphatase & Tensin Homologue)?

It acts as a lipid phosphatase that dephosphorylates ( \text{PIP}_3 ) to ( \text{PIP}_2 ), antagonising the PI3K signaling cascade.

What is the molecular result of PTEN loss?

Accumulation of ( \text{PIP}_3 ), leading to constitutive activation of the AKT and mTOR pathways, driving growth and protein synthesis.

What are the common tumor types associated with PTEN loss?

Breast (~30%), Endometrial (~50%), Thyroid, Prostate, and Glioblastoma (GBM).

What are the clinical features of Cowden Syndrome (germline PTEN mutation)?

1. Macrocephaly
   2. Facial trichilemmomas
   3. Mucocutaneous lesions

How does PTEN loss impact therapeutic targeting of the PI3K pathway?

It predicts resistance to upstream PI3K inhibitors due to paradoxical downstream activation.

What is the normal physiological function of the VHL (Von Hippel-Lindau) protein?

It functions as an E3 ubiquitin ligase substrate adapter that targets hydroxylated HIF-1(\alpha) for rapid proteasomal degradation under normoxic conditions.

What happens molecularly in the absence of VHL?

HIF-1\(\alpha\) is stabilised regardless of oxygen levels and induces transcription of VEGF-A, PDGF, EPO, and GLUT1.

In what percentage of sporadic clear cell Renal Cell Carcinoma (RCC) is biallelic somatic loss of VHL seen?

>90%