Oncology summary (exam 1+2)
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,Ch1 | Introduction: The Nature of Cancer 3
Ch2a | DNA Structure and Stability: Mutations vs. Repair 6
Ch2b | Radiation and Chemical Carcinogenesis 11
Ch3 | Regulation of Gene Expression 16
Ch4 | Growth Factor Signaling and Oncogenes 22
Ch5 | The Cell Cycle 28
Ch6 | Growth Inhibition and Tumor Suppressor Genes 33
Molecular Diagnostics in Pathology 39
Ch7 | Apoptosis 42
Ch8 | Stem cells and di erentiation 49
Ch9 | Metastasis 54
Ch14 | Technology, and drug and diagnostics development 59
Ch10 | Angiogenesis 62
Ch11 | Nutrients, hormones, and gene interactions 65
Ch12/13 | In ammation, immunotherapy, and cancer 70
Ch13 | Infectious agents and cancer 76
BMW seminar 1 | Proteomics, global analysis of the functionally relevant
OME in cancer 81
BMW seminar 2 | Let’s kill the tumor vasculature 85
BMW seminar 3 | MicroRNA from trash to treasure 87
BMW seminar 4 | Functional oncogenomics 89
BMW seminar 5 | History of sequencing 91
BMW seminar 6 | Advances in pancreatic cancer translational research 94
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, Ch1 | Introduction: The Nature of Cancer
CANCER EPIDEMIOLOGY: DEFINITIONS & TRENDS
- Incidence of cancer: the number of new cases diagnosed with cancer 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
- Cancer incidence in the Netherlands in 2021: ~124,000 (i.e. 1/137)
- ~1/3 chance to get cancer someday
- Trend: increase in cancer incidence over time, except for 2020 (due to covid)
- Prevalence of cancer: 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 de ned: e.g. the 5-year prevalence on January 1st,
2010, comprises all still living people who have been diagnosed with cancer during the
previous 5 years
- 5-year cancer prevalence in the Netherlands in 2021: ~380,000
- Trend: cancer mortality slightly increased over time (but not as steep as the incidence), but
has not increased in the last 4 years
- Cancer incidence increases, while the mortality levels o
- Mortality of cancer: the number of patients who died as a result of cancer within a certain
period (mostly 1 year)
- Are not necessarily the same cases that were diagnosed that year: incidence vs. mortality
- Cancer mortality in the Netherlands in 2021: ~46,000
- In the Western world, cancer mortality is 1st/2nd cause of premature death: top ranking of
cancer as leading cause of premature death partly re ects marked declines in mortality
rates of stroke and coronary heart disease in many countries
- Regional di erences in cancer mortality: the cancer mortality in Southern (and South-
Eastern) countries is not as high as in the Western world, due to other leading causes
of death (infectious diseases, etc.)
- Trends (2010 vs. 2000): relative mortality due to cancer decreases, but there are some
striking di erences (e.g. increase in lung cancer among women due to increased smoking,
and increase in melanoma)
- Survival of cancer: the percentage of patients still living at a certain period after diagnosis
- The presented survival is a relative survival that approaches the ‘cancer-speci c
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 calendar year)
- Trend of survival in time as function of time after diagnosis: 5-year survival improved ~30%
since 1980
CHARACTERISTICS OF CANCER
- Clinical de nition of cancer:
- Cancer is a group of diseases
- More than 100 cancer types can be distinguished (or even every tumor is di erent?)
- Uncontrolled cell growth
- Invasive and forming metastases
- A patient with a tumor does not always have cancer:
- A tumor is a mass of cells
- Not every tumor is invasive and metastasizing
- Benign tumors are no cancer, only malignant tumors are cancer
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, - Why is a malignant tumor life-threatening?
- Invasion of organs disturbs organ function
- Cancer cells compete with normal cells for nutrients and oxygen
- Growing tumors can cause obstructions (e.g. in blood vessels)
- (Some benign tumors can also be life-threatening because of their location)
- The di erence between carcinoma, adenocarcinoma, sarcoma and lymphoma:
- Carcinomas arise from epithelial cells (85% of all cancers)
- Incidence of carcinomas is much higher than of other cancers, because: carcinomas
are derived from epithelial cells, which align our body (inside and outside), and are
most exposed to carcinogens (e.g. gut, lungs, etc.)
- 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
- Cancer is a disease of the genome:
- What is a carcinogen?
- A carcinogen is an agent causing cancer (compound, radiation, etc.)
- A carcinogen causes alterations in the DNA of a cell: most carcinogens are mutagens
- 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
- Development of cancer (oncogenesis):
- Genetic progression model: progression model based on gene expression
- Normal epithelium -> hyperplasia -> dysplasia -> carcinoma in situ -> invasive
carcinoma -> lymph node and distant metastases
- Because oncogenesis is the stepwise accumulation of mutations in di erent parts of
the genome over time, a tumor is always clonal and heterogeneous
- Clonal: oncogenesis always starts with a rst mutation, and all cancer cells later
on are daughter cells of this one cell
- Heterogeneous: during growth, di erent daughter cells can get other di erent
mutations, resulting in sub-clones with more mutations accumulated
- This classi es the mechanism of cancer as a complex Darwinian adaptive
system, with sub-clonal selection and survival of the ttest
- Is cancer inheritable?
- No: almost all of the mutations develop in somatic cells and will not be passed to the
next generation of o spring
- However: some inherited germ-line mutations can increase the chance to develop
cancer and can be passed on to the next generation of o spring
- These mutations are rarely involved in causing cancer immediately
- 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
- The main characteristics of cancer are described in the 6 ‘Hallmarks of Cancer’, de ned by
Hanahan and Weinberg: sustaining proliferative signaling, evading growth suppressors,
resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating
invasion and metastasis
- Renewed and 4 extra ones added:
- Enabling characteristics: genome instability and mutation, and tumor-promoting
in ammation
- Emerging hallmarks: reprogramming energy metabolism, and avoiding immune
destruction
- In 2022, renewed and 4 extra ones added: ‘New dimensions’ by Hanahan
- Unlocking phenotypic plasticity, senescent cells, polymorphic microbiomes, and non-
mutational epigenetic reprogramming
- All these hallmarks distinguish a cancer cell from a normal healthy cell, and are potential
target pathways for the design of new therapeutics
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