Oncology
Table of Contents
Ch 1 .................................................................................................................................. 1
Ch 2: Mutations versus repair ........................................................................................... 3
CH 4: Growth factor signaling and oncogenes. ................................................................ 11
Ch 3: Regulation of gene expression ................................................................................ 17
Ch 5: The cell cycle .......................................................................................................... 24
Ch 6: Growth inhibition and tumor suppressor genes ...................................................... 29
Molecular diagnostics in Pathology-NGS-based mutation analysis .................................. 34
Practicum uitleg: .................................................................................................................... 35
Ch 1
Definitions:
- Incidence: The incidence of cancer is defined to be the number of new cases that is
registered within a certain period (mostly 1 year). To be able to follow the incidence
in time, or to enable comparison between regions, the incidence is mostly expressed
as the number of new cases per 100.000 inhabitants/persons each year: the crude
incidence rate.
o Netherlands 2023: 129.000
- Prevalence: The prevalence of cancer comprises all persons who somewhere in time
have been diagnosed with cancer; and are still living at a certain date. Hence, this is a
diverse group, ranging from persons who have been cured from cancer in the past to
persons who just have been diagnosed with cancer. The period can be unlimited, but
also defined. As an example: the 5-year prevalence on January 1st , 2020, comprises
all still living people who have been diagnosed with cancer since January 1st , 2015.
o Netherlands: 413.000
- Mortality: The mortality of cancer comprises the number of patients who died as a
result of cancer within a certain period (mostly 1 year).
o Mortality: 46.000
- Survival: Survival is the percentage of patients still living at a certain period after
diagnosis. The presented survival is a relative survival that approaches the “cancer-
specific survival”. This means that the survival observed is corrected for the expected
death within a comparable population (with respect to country/region, gender, age
and calender year).
o 5-year survival improved ~30% since 1980
Cancer:
- Cancer is a group of diseases.
1
, - More than 100 cancer types can be distinguished (or even every tumor is different?).
- Uncontrolled cell growth.
- Invasive and forming metastases.
- Only malignant tumors are cancer
o Invasion of organs disturbs organ function.
o Cancer cells compete with normal cells for nutrients and oxygen.
o Growing tumors can cause obstructions.
- Carcinomas arise from epithelia (~85% of all cancers).
o Epithelial cells are most exposed to carcinogens
- 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.
Carcinogens:
- A carcinogen is an agent causing
cancer (compound, radiation, etc.).
- A carcinogen causes alterations in the
DNA of a cell. (chapter 2)
- Cancer cells contain many alterations
in the DNA.
- The accumulation of mutations in the
DNA of a cell causes stepwise
development of cancer (oncogenesis,
carcinogenesis).
Main characteristics of cancer → hallmarks of cancer
The growth of a tumor:
- Disturbed balance between proliferation, cell
death and differentiation
- Oncogenes and suppressor genes
Is it possible to recognize cancer cells in tissue culture?
- Cancer cells have a different morphology.
- Cancer cells can grow at low serum concentration.
- Cancer cells show no/decreased contact inhibition.
- Cancer cells can grow without substrate for
attachment.
Factors playing a role in development of cancer:
- Environment (soot, sunlight, asbestos).
- Diet (fruit and vegetables, fish) and exercise.
- Alcohol (head and neck, breast).
- Smoking (>80 carcinogens; 40% of all cancer deaths).
- Reproduction, contraception, hormone replacement therapy.
- Viruses (sexual transmittable).
- Own metabolism (by-products of metabolism and errors in DNA replication).
2
,Cancer treatments:
- Surgery
- Radiotherapy
- Chemotherapy
- Prevention of cell division (cytostatic effect)
- Killing of cancer cells (cytotoxic effect)
Limitations of conventional chemotherapy?
- Adverse events/toxicity on normal tissues.
- The therapeutic index/window of most chemotherapeutics is relatively small.
o The therapeutic index (book)/window (correct) is the difference between
maximum tolerated dose (MTD) and the minimum dose needed to exert anti-
cancer activity.
- Efficacy of current drugs
➢ Every hallmark is a potential target for selective therapy
Therapeutic targets:
How do you know whether a patient might be a suitable candidate for treatment with a
particular targeted drug?
- Diagnostics.
o Genetics.
o Imaging.
o Immunohisto chemistry
- Link profiles to treatment succes
- Develop biomarker for prediction.
Ch 2: Mutations versus repair
Part 1: DNA structure, mutations and carcinogenic agents
DNA structure
3
, Folded to fit in nucleus
CG binding stronger
Small DNA changes
- Base pair substitution → amino acid change/ stop codon
- Insertion/ Deletion → frame shift/ stop codon
Large DNA changes
- Aneuplopidy: whole chromosome gain or loss
- Chromosome rearrangements (translocations)
- Amplifications
- Intra-chromosomal
- Extra-chromosomal
- Deletions
Genetic stability/ instability
Causes of DNA aberrations:
Endogenous:
DNA replication errors.
Reactive oxygen species (ROS)
• Oxidative phosphorylation in the mitochondria produces ROS
Exogenous:
• Smoking (Polycyclic aromatic hydrocarbons; PAH)
• Alcohol
4
Table of Contents
Ch 1 .................................................................................................................................. 1
Ch 2: Mutations versus repair ........................................................................................... 3
CH 4: Growth factor signaling and oncogenes. ................................................................ 11
Ch 3: Regulation of gene expression ................................................................................ 17
Ch 5: The cell cycle .......................................................................................................... 24
Ch 6: Growth inhibition and tumor suppressor genes ...................................................... 29
Molecular diagnostics in Pathology-NGS-based mutation analysis .................................. 34
Practicum uitleg: .................................................................................................................... 35
Ch 1
Definitions:
- Incidence: The incidence of cancer is defined to be the number of new cases that is
registered within a certain period (mostly 1 year). To be able to follow the incidence
in time, or to enable comparison between regions, the incidence is mostly expressed
as the number of new cases per 100.000 inhabitants/persons each year: the crude
incidence rate.
o Netherlands 2023: 129.000
- Prevalence: The prevalence of cancer comprises all persons who somewhere in time
have been diagnosed with cancer; and are still living at a certain date. Hence, this is a
diverse group, ranging from persons who have been cured from cancer in the past to
persons who just have been diagnosed with cancer. The period can be unlimited, but
also defined. As an example: the 5-year prevalence on January 1st , 2020, comprises
all still living people who have been diagnosed with cancer since January 1st , 2015.
o Netherlands: 413.000
- Mortality: The mortality of cancer comprises the number of patients who died as a
result of cancer within a certain period (mostly 1 year).
o Mortality: 46.000
- Survival: Survival is the percentage of patients still living at a certain period after
diagnosis. The presented survival is a relative survival that approaches the “cancer-
specific survival”. This means that the survival observed is corrected for the expected
death within a comparable population (with respect to country/region, gender, age
and calender year).
o 5-year survival improved ~30% since 1980
Cancer:
- Cancer is a group of diseases.
1
, - More than 100 cancer types can be distinguished (or even every tumor is different?).
- Uncontrolled cell growth.
- Invasive and forming metastases.
- Only malignant tumors are cancer
o Invasion of organs disturbs organ function.
o Cancer cells compete with normal cells for nutrients and oxygen.
o Growing tumors can cause obstructions.
- Carcinomas arise from epithelia (~85% of all cancers).
o Epithelial cells are most exposed to carcinogens
- 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.
Carcinogens:
- A carcinogen is an agent causing
cancer (compound, radiation, etc.).
- A carcinogen causes alterations in the
DNA of a cell. (chapter 2)
- Cancer cells contain many alterations
in the DNA.
- The accumulation of mutations in the
DNA of a cell causes stepwise
development of cancer (oncogenesis,
carcinogenesis).
Main characteristics of cancer → hallmarks of cancer
The growth of a tumor:
- Disturbed balance between proliferation, cell
death and differentiation
- Oncogenes and suppressor genes
Is it possible to recognize cancer cells in tissue culture?
- Cancer cells have a different morphology.
- Cancer cells can grow at low serum concentration.
- Cancer cells show no/decreased contact inhibition.
- Cancer cells can grow without substrate for
attachment.
Factors playing a role in development of cancer:
- Environment (soot, sunlight, asbestos).
- Diet (fruit and vegetables, fish) and exercise.
- Alcohol (head and neck, breast).
- Smoking (>80 carcinogens; 40% of all cancer deaths).
- Reproduction, contraception, hormone replacement therapy.
- Viruses (sexual transmittable).
- Own metabolism (by-products of metabolism and errors in DNA replication).
2
,Cancer treatments:
- Surgery
- Radiotherapy
- Chemotherapy
- Prevention of cell division (cytostatic effect)
- Killing of cancer cells (cytotoxic effect)
Limitations of conventional chemotherapy?
- Adverse events/toxicity on normal tissues.
- The therapeutic index/window of most chemotherapeutics is relatively small.
o The therapeutic index (book)/window (correct) is the difference between
maximum tolerated dose (MTD) and the minimum dose needed to exert anti-
cancer activity.
- Efficacy of current drugs
➢ Every hallmark is a potential target for selective therapy
Therapeutic targets:
How do you know whether a patient might be a suitable candidate for treatment with a
particular targeted drug?
- Diagnostics.
o Genetics.
o Imaging.
o Immunohisto chemistry
- Link profiles to treatment succes
- Develop biomarker for prediction.
Ch 2: Mutations versus repair
Part 1: DNA structure, mutations and carcinogenic agents
DNA structure
3
, Folded to fit in nucleus
CG binding stronger
Small DNA changes
- Base pair substitution → amino acid change/ stop codon
- Insertion/ Deletion → frame shift/ stop codon
Large DNA changes
- Aneuplopidy: whole chromosome gain or loss
- Chromosome rearrangements (translocations)
- Amplifications
- Intra-chromosomal
- Extra-chromosomal
- Deletions
Genetic stability/ instability
Causes of DNA aberrations:
Endogenous:
DNA replication errors.
Reactive oxygen species (ROS)
• Oxidative phosphorylation in the mitochondria produces ROS
Exogenous:
• Smoking (Polycyclic aromatic hydrocarbons; PAH)
• Alcohol
4
