Full overview of MOD2
All of the learning objectives are explained
Useful guide and what to learn with explanation
A lot of subjects are repeated, because repetition = learning!
LEARNING OBJECTIVES MOD2
THEME 1A: CANCER BIOLOGY & GENETICS
Explain the processes that initiate and influence cancer development
and relate these processes to the phenotypical characteristics of cancer, patient
clinical
outcomes, and the impact on treatment strategies.
Processes that Initiate and Influence Cancer Development
o Genetic Mutations
Initiating events
Mutation of DNA in cell
Inherited: germline
Acquired: somatic
Environmental exposure: smoking, UV
Errors in DNA replication
Viral infections, e.g., HPV
Types of genetic changes
Oncogenes
Mutated forms of normal genes, proto-
oncogenes, which drive uncontrolled cell
proliferation
E.g., HER2 in breast cancer
Tumor suppressor genes
Normally inhibit cell growth or induce apoptosis
Mutated form cannot inhibit anymore
Loss-of-function mutations
p53
DNA repair genes
Mutations lead to impaired ability to repair
damaged DNA, leads to further mutations
BRCA1/2
o Epigenetic Mutations
DNA methylation & histone modification
Alter expression without DNA modifying
Hypermethylation in tumor suppressor promoters can
lead to silencing, contributing to cancer
o Cellular Microenvironment
Tumor microenvironment
Comprises surrounding stromal cells, immune cells,
blood vessels, and signaling molecules
Interaction between tumor and TME supports tumor
growth, angiogenesis, and immune evasion
Chronic inflammation
Persistent inflammatory response can promote
carcinogenesis by generating reactive oxygen species
(ROS)
ROS damage DNA and create a pro-tumorigenic
environment
o Clonal Evolution &
Heterogeneity
Clonal selection &
competition
1
Figure 1: Clonal cooperation
, MVD
Mutations accumulate some cells acquire selective
advantages dominate tumor mass
Intertumoral heterogeneity
Genetic diversity within tumor allows for adaptation to
environmental pressures therapy resistance
Phenotypical Characteristics of Cancer
o Uncontrolled Proliferation
Cause
Activation of oncogenes
Loss of tumor suppressor gene function
Clinical implication
Rapid tumor growth
Potential spread: metastasis
o Resistance to Cell Death
Cause
Mutations in genes regulating
apoptosis
Expression of anti-apoptotic
proteins
Clinical implication
Tumors can persist despite the
body’s natural mechanisms to
eliminate abnormal cells
o Sustained Angiogenesis
Cause Figure 2: Resistance to Cell Death
Pro-angiogenic factors (e.g.,
VGEF) secreted by tumors
Ensure adequate blood supply
Clinical implication
Facilitates tumor growth
Facilitates metastasis
Angiogenesis inhibitors can be used as treatment
o Tissue Invasion & Metastasis
Cause
Epithelial-mesenchymal transition (Weinberg), cancer
cells acquire ability to migrate and invade other tissues
Table 1: Characteristics
Epithelial Mesenchymal
Cell polarity No cell polarity
Cell adhesion: to Loss of cell adhesion
each other and ECM
Stationary Ability to migrate and
invade
High level of E- Low level of E-cadherin
cadherin
Low level of N- High level of N-
cadherin cadherin
Clinical implication
Metastasis
o Genomic Instability
Cause
Impaired DNA repair mechanisms
Clinical implication
2
, MVD
Genetic diversity within tumor
Drives evolution and resistance to therapy
o Evasion of Immune Surveillance
Cause
Cancer cells can evade immune system by
downregulating antigen presentation or expressing
immune checkpoint proteins (e.g., PD-L1)
Clinical implication
Immunotherapies can block checkpoints helps
restore immune activity against cancer
Relation to Clinical Outcome
o Aggressiveness of the Tumor
High proliferative rates and metastatic potential worsen
prognosis
Genomic instability and tumor heterogeneity poor
responses to standard treatments
o Biomarkers & Predictive Factors
Genetic mutations or protein expression levels can be used to
predict the likely course of the disease and guide targeted
therapy
o Stage at Diagnosis
Early-stage detection has generally better outcome than
advanced stage detection
Impact on Treatment Strategies
o Targeted Therapies
Action
Target specific molecular alterations
Challenges
Resistance may develop
o Immunotherapies
Action
Utilize the body’s immune system to recognize and kill
cancer cells
Immune checkpoint inhibitors
Challenges
Not all patients respond
Immune-related side effects
o Chemotherapy & Radiation
Action
Target rapidly dividing cells
Induce DNA damage
Challenges
Nonselective
Effects normal cells, causing side effects
Tumors with DNA repair defects may be more sensitive
o Epigenetic Therapies
Action
Reverse abnormal epigenetic changes in cancer cells
Challenges
Still in development
Variable efficacy
o Combination Therapy
Rationale
Distinguish the roles of genetic and environmental factors in increasing cancer
risk, associate specific etiological factors (e.g., gene defects, oncogenic viruses)
with the
development of specific cancer types, and propose preventive strategies for
specific at-
risk populations.
Roles of Genetic & Environmental Factors in Cancer Risk
o Genetic Factors
Germline mutations (inherited)
Present in every cell from birth
Can be passed on to offspring
5-10% of all cancers
Examples
BRCA
MLH1, MSH2, MSH6, PMS2 Lynch
Family history
Strong family history of cancer suggests a higher risk to
develop cancer due to shared genetic mutations or
family-wide exposure to carcinogens
Genetic syndromes
Certain hereditary syndromes predispose individuals for
the development of cancer
Examples
Lynch syndrome
Li-Fraumeni syndrome
o Environmental Factors
Lifestyle choices
Smoking
UV
Alcohol consumption
Poor diet
Physical inactivity
Obesity
Carcinogens
Chemical exposure
Asbestos, benzine, etc.
Radiation
UV, radon, etc.
Air pollution
Infectious agents
Oncogenic viruses
HPV
Hep B/C
Hormones
Association of Specific Etiological Factors with Cancer Types
o Gene Defects
BRCA1/2 mutations
Associated cancers
Breast
4
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