AIM Concept Integration
3rd Year MBBS
Multisystem
Multisystem
Topic 17 — Molecular Basis of Cancer and Carcinogenesis
Connect the genetic basis of cancer, hallmarks of malignant cells, major carcinogenic mechanisms and the immediate approach to poisoning for rapid revision.
1. THE TOPIC IN ONE CONNECTED FLOW
Cancer develops when genetic damage alters the systems that normally control cellular growth, survival and genomic integrity. These abnormalities provide a selective advantage, allowing abnormal clones to expand, acquire further mutations and develop the biological capabilities required for malignant growth.
Initiating Factors
Inherited/acquired lesions, chemicals, radiation or microbes
→
Genetic Damage
Mutation, translocation, amplification or gene loss
→
Growth-Control Failure
Oncogene activation + tumor suppressor loss + impaired apoptosis/DNA repair
→
Clonal Expansion
Cells with a survival or growth advantage multiply
→
Additional Alterations
Subclones emerge and tumor heterogeneity increases
→
Cancer Hallmarks
Persistent growth, survival, angiogenesis, immortality and immune escape
→
Malignant Behavior
Progressive growth, invasion and metastasis
Two important carcinogenic routes:
Chemical or radiation exposure → DNA injury → mutation → abnormal clone → malignancy
Oncogenic infection → disturbed growth control or chronic inflammation → repeated proliferation/genetic injury → malignancy
Chemical or radiation exposure → DNA injury → mutation → abnormal clone → malignancy
Oncogenic infection → disturbed growth control or chronic inflammation → repeated proliferation/genetic injury → malignancy
2. KEY CLINICAL CONNECTIONS
p53 and DNA Damage
DNA damage
→
p53 activation
→
cell-cycle arrest for repair
→
p53 activation
→
cell-cycle arrest for repair
Irreparable damage
→
apoptosis or senescence
→
prevents propagation of abnormal DNA
→
apoptosis or senescence
→
prevents propagation of abnormal DNA
Chemical and Radiation Injury
Procarcinogen
→
metabolic activation
→
reactive metabolite
→
DNA mutation
→
metabolic activation
→
reactive metabolite
→
DNA mutation
UV/ionizing radiation
→
DNA lesions or strand breaks
→
mutation if repair fails
→
DNA lesions or strand breaks
→
mutation if repair fails
Microbial Carcinogenesis
High-risk HPV
→
E6/E7 effects
→
impaired p53/RB control
→
epithelial transformation
→
E6/E7 effects
→
impaired p53/RB control
→
epithelial transformation
HBV/HCV or H. pylori
→
chronic injury/inflammation
→
repeated regeneration
→
cancer risk
→
chronic injury/inflammation
→
repeated regeneration
→
cancer risk
Acute Poisoning Approach
Suspected poisoning
→
airway, breathing and circulation
→
stabilize first
→
airway, breathing and circulation
→
stabilize first
Stable patient
→
focused history/examination and monitoring
→
decontamination, antidote or supportive care when appropriate
→
focused history/examination and monitoring
→
decontamination, antidote or supportive care when appropriate
3. AIM HIGH-YIELD INTEGRATION REVIEW
⭐ Proto-oncogene activation → gain of growth-promoting function → persistent proliferative signaling; point mutation, translocation and amplification are important mechanisms.
⭐ p53 activation after DNA injury → cell-cycle arrest and repair; irreparable damage → apoptosis/senescence → reduced transmission of mutations.
DNA-repair failure → increased mutation accumulation → genomic instability → greater opportunity for oncogene activation and tumor-suppressor loss.
Initiation → permanent heritable genetic injury, whereas promotion → proliferation of initiated cells without directly producing the initiating mutation.
⭐ Indirect chemical carcinogen → metabolic activation → reactive electrophilic metabolite → DNA damage; direct-acting agents do not require this conversion.
UV radiation → pyrimidine DNA injury; ionizing radiation → strand breaks and reactive oxygen injury → mutations when repair is inadequate.
⭐ Oncogenic microbes → either direct interference with growth-control pathways or chronic inflammation/regeneration → progressive genetic abnormalities → malignancy.
Suspected poisoning → stabilize airway, breathing and circulation first → identify reversible threats and exposure → use decontamination, antidotes and supportive care according to the clinical situation.
AIM Exam Trap: An oncogene is the abnormally activated growth-promoting gene; an oncoprotein is its protein product. Do not confuse either with a normal proto-oncogene.