This document includes the notes of both the book and the given lectures during the Oncology course. There are also practice questions in between the notes, which may be asked during the real exam as well. Some sentences are highlighted in red to make you think more in depth about the subjects
EXAM 1 MATERIAL
Book, chapter 1
A tumor is both clonal and heterogeneous.
Therapeutic index is the part between 50% effect and 50% toxic effect.
Therapeutic window: what dose can I give.
Lecture 1, notes:
The incidence of cancer is defined to be the number of new cases that is registered within a certain
period (mostly 1 year), usually expressed per 100.000 persons/ year.
The prevalence of cancer means all persons who somewhere in time have been diagnosed with
cancer and are still living at a certain date (so also cured people).
Mortality is the number of people who died per year, survival is the patients that are still alive (in
percentage).
Only when a tumor is metastasizing and invasive you can call it cancer.
Carcinomas arise from epithelia (~85% of all cancers).
Adenocarcinomas arise from glandular tissues (e.g. breast).
Sarcomas arise from mesodermal tissues (e.g. bone, muscle).
Lymphomas arise from (progenitors of) white blood cells.
Epithelial cells are most exposed to carcinogens (= anything that causes cancer).
Cancer is not inheritable. However, some inherited germline mutations can increase the chance to
develop cancer and can be passed on to the next generation of offspring.
Why does the risk to develop cancer increase at older age?
- An accumulation of mutations in the DNA is needed for the development of cancer.
- It is a matter of chance and time (exposure to carcinogens).
- The incidence of cancer is increasing due to longer life expectancy.
What are the hallmarks of cancer?
- Resisting cell death
- Enabling replicative immortality
- Evading growth suppressors
- Activating invasion and metastasis
- Sustaining proliferative signalling
- Inducing angiogenesis
- Deregulating cellular energetics
- Genome instability and mutation
- Avoiding immune destruction
- Tumor-promoting inflammation
What are the characteristics of cancer cells?
- Different morphology
- Can grow in low serum culture media
- No/decreased contact inhibition
- Can grow without substrate for attachment
The therapeutic index/window of most chemotherapeutics is relatively small. The TI is the
difference between maximum tolerated dose (MTD) and the minimum dose needed to exert anti-
cancer activity.
,STUDY:
Difference between incidence and prevalence; and between survival and mortality.
Clinical definition of cancer, types, why it is life threatening.
Causes of cancer, carcinogens, life-style effects.
Oncogenesis process, clonality, heterogeneity, tumor complexity.
Hallmarks of cancer (10).
Identification of cancer cells and oncogenes (in the laboratory).
Classical treatments and their limitations.
Targeted treatment concept.
Book, chapter 2: No notes.
Lecture 2 part 1, notes
TP53 and RB1 are important targets of DNA tumor viruses.
A single strand brake can become a double strand break, this brings risk for deletions and large
chromosomal rearrangements > extremely toxic.
Exogenous causes of DNA aberrations: smoking, drinking, sun, radiation etc.
Endogenous causes: DNA replication mistakes and ROS (produced by oxidative phosphorylation in
the mitochondria).
Genetic alterations induced by DNA-damaging agents
8-oxoguanine is potentially mutagenic because DNA polymerase reads it as a thymine.
- ROS causes oxidation/ ionization of G-base by adding O.
- OxoG has a new way to bind to bases such as A.
- So, there is a G to T transversion (so acts like a T and binds to A).
DNA repair mechanisms:
Damaged base = base excision repair.
o Primary way of removing nucleotides damaged by intracellular processes such as
- free radical oxidation (8-oxoguanine)
- deamination (cytosine to uracil).
o You have an altered sequence.
o DNA glycosylase recognizes damaged base, leaving an AP (apurinic/apyrimidinic) site
o An AP endonuclease cleaves the deoxyribosephosphate chain 5’ to the damaged
base to create a 3’ hydroxyl group.
o The 3’ hydroxyl group is used by DNA polymerase to replace one base.
Bulky adduct = nucleotide excision repair.
o Removes both small oxidative DNA damages and gross DNA distortions.
o A stretch of 25-30 nucleotides is removed.
, Mismatch error = mismatch repair.
o For repair in the newly synthesized daughter strand (post-replication repair).
o DNA sequence with a mismatch in the new strand.
o Mutations of crucial repair proteins (e.g. HNPCC or Lynch syndrome).
Strand breaks = homologous recombination repair (HR) and non-homologous end joining
(NHEJ) (e.g. Fanconi anemia).
o ATM is activated by the double strand break.
o 5’-3’ exonuclease activity of RAD50/MRE11/NBS1 complex digests damaged strands
to expose ss regions.
o RAD proteins facilitate strand exchange (RAD51).
o DNA polymerase, ligases and resolvases restore the four strands.
Cross-links = complex repair, coordinated by the FA pathway (e.g. BRCA1 AND BRCA2).
Fanconi/ BRCA pathway: DNA breaks and cross-links (signalling/ recognition damage, removal and
repair).
Treatment for BRCA1-tumors:
BRCA1 loss > defect in HR: cannot repair breaks > sensitive to DNA cross-linkers as Cisplatin.
Treatment for biallelic mutations in HR gene:
Tumors are sensitive to cisplatin, but all normal cells too > Cisplatin cannot be used.
Synthetic lethality: mutations in 2 genes, e.g. BRCA1 defect + PARP inhibitor > lethal (1 is not
enough to be lethal, for example: no PARP is no problem as long as you still have a functioning
BRCA1).
Lecture 2 part 2, notes
PRACTICE QUESTION
The induction of pyrimidine dimers in DNA is typical after:
1. X-rays
2. Oxidative damage
3. UV radiation
4. Polycyclic aromatic hydrocarbons (PAH)
Ionising radiation/ radiotherapy
Ionizing radiation = high frequency electromagnetic radiation.
Gray (Gy): absorbed dose in tissue, used in radiotherapy.
o 1 Gy = energy deposit of 1 Joule/ kg tissue
Sievert (Sv): Equivalent dose, unit for biological damage, used in radiation protection and
radiation risk estimates
o = absorbed dose in Gy multiplied by the radiation quality factor (= 1 for photons, 20
for neutrons).
Linear Energy Transfer (LET) radiation = the rate of energy loss (deposit) along the track of an
ionizing particle [keV/ μm].
Low LET radiation: X-rays, gamma rays, protons.
o Diffuse ionization track.
High LET radiation: a-particles, neutrons, carbon-ions.
o Dense ionization track.
o More non-repairable DNA damage.
, The higher the LET of radiation, the higher the energy deposit over short distance, the lower the
penetration dept in material/ tissue.
Carcinogenesis is a multi-step process: initiation, promotion, progression.
Information about carcinogenic effects of radiation is obtained via epidemiological studies of
exposed population.
- Victims of nuclear accidents/ activities
- Patients treated with radiotherapy
- Radiation workers
Requirements for carcinogenic risk estimation:
Large radiation exposed population
Non-exposed control group
Long follow-up time
Individual dosimetry data
o Leukemia is the most frequent ionizing radiation-induced cancer.
o Risk of solid cancer increases with dose in a linear fashion.
o Age at exposure is important: children are the most sensitive to radiation.
Latent period tumour induction = the mean time period between exposure to radiation and
manifestation of a tumour.
Risk period tumour induction = the time period between the minimal and maximal latent period.
Most important genotoxic DNA-damage inducing carcinogens:
Polycyclic Aromatic Hydrocarbons (PAHs)
Aromatic amines
Nitrosamines
Alkylating drugs
Most important genotoxic DNA-damage inducing carcinogens
Working mechanism genotoxic carcinogens
Timing: DNA synthesis
Mechanism: DNA adduct formation: An electron deficient group binds covalently to an
electron rich group of the DNA (e.g. amino, hydroxyl, sulfhydryl group).
Effect: DNA adducts disturb the DNA structure and replication (mostly after enzymatic
activation by cytochrome P450-dependant enzymes such as CYP1A1, which act as
catalysator)
Result: in case of un-sufficient DNA damage repair: carcinogen specific mutation
The source of ROS is oxidative phosphorylation (ATP production). Protection by glutathione, vitamins
A, C and E inactivating ROS.
Chemotherapy
Alkylating agents: form DNA adducts via alkyl group
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