Oncology

ONCOLOGY
CH1: Molecular biology of Cancer
Incidence: a number defined to be the number of new cases that is registered in a year
(usually 1), often in a certain region. If you want to compare different regions, often the
number is given per 100.000 inhabitants in a certain period.
Prevalence: number, all the people who have been diagnosed with cancer in a certain
period before and are still alive at that moment, still active cancer, healed, and some people
are cured very well and they can live for many years so that will influence the data so we
only talk about 5-year prevalence.
Mortality: a number of patients that have died as a result of cancer, leaving out cases that
didn’t die because of cancer but because of other reasons, so you always need to correct
the number for any chance of dying anyhow, mostly in one year.
Survival: percentage of patients still living after diagnoses, corrected for the expected death
within a comparable population, if they were really dying of cancer.
Cancer incidence: Netherlands incidence in 2023 = 129 '000, 1/140 people in the
Netherlands were diagnosed with cancer last year, and if you multiply it by the years you will
live (x85), that’s around 61% chance you will be diagnosed with cancer during your life.
From the 1990 the incidence has increased every year, until the last years, where it’s
leveling off, meaning that we’re doing something good, and a down peak, when we had
covid and less people could go to the gp and cannot be diagnosed, and we would expect a
peak in the following years but there wasn’t, so they might have died because of
undiagnosed cancer.
Cancer prevalence and mortality: mortality didn’t increase, around 46 ‘000 per year.
Survival in time: as a function of time after diagnosis, per decade.
There are different numbers for every tumor type, also differences between men and
women, and low-middle income countries and high income countries. Some types of cancer
have very bad prognosis, such as colon and liver cancer, red bar is almost the same as the
blue one, but also the opposite, thyroid cancer for instance has almost no red bar, so can be
treated very well. In LMICs there is less screening, and more deaths for other reasons.
Dark blue countries, cancer is the first cause of death, and in the light blue is the second
because the first is cardiovascular diseases, while in red countries, cancer is the 6-7th
reason, because they are more viral diseases, and other causes which are not treated as
well as in the other more developed countries.
Cancer mortality trends 2010 vs 2000 for different types of cancer, looking at 10-year
survival, more bars on the left so less dying in 2010, but still some bars on the right, women
started smoking so their numbers are catching up with the men’s. Melanoma is increasing in
both sexes, because a long time ago it was fashionable to be pale while now they’re
exposed to a lot of sun.

Cancer: collection of groups of different diseases that have some things in common but also
not, more than 100 cancer types can be distinguished, based on the tissue of origin, and
they all have in common that there is uncontrolled cell proliferation, invasive and
metastases, not tumor, which is just a growing mass, and if this is non invasive it’s benign,
while if it’s invasive is called malignant, and called cancer.
A malignant tumor is threatening because it takes resources from other parts of the body,
they compete with normal cells for nutrients and oxygen, in the entire body; it invades organs
disturbing their function; and it can cause obstructions, due to its solid mass, such as they
can close a blood vessels, breath vessels, lymph vessels, gallbladder as well.

,Carcinomas: epithelial cells, most cancers are carcinomas (85%); usually in direct contact
with the outside and in the inside they also are exposed to environment agents, to
carcinogens; they also replicate more than other cells in the body.
Adenocarcinoma: glandular cells;
Sarcomas: from mesoderm cells, either muscle or bone for example;
Lymphoma/leukemia: blood cells.
Carcinogen: any agent that causes cancer, compounds, radiations, UV, etc, and they cause
alterations in the DNA, whose accumulation contribute step-wise to the development of
cancer, carcinogenesis/oncogenesis. There are steps, premalignant cells with some
mutations, but not invasive and metastasizing yet, then after many years other mutations
might have accumulated. It all starts with one cell getting the first mutation, and some of the
tumor cells get other mutations, heterogeneously, so with many types of cells.
Disease of the genome: it’s not inheritable, they develop in somatic cells, because if it
developed in a germline cell you would just get a tumor mass and not a baby, but what can
happen is genes that are prone to being oncogenic can be pass to the next generation, so
some germline mutations can be inherited, increasing the chance. Some germline mutations
can cause an increased risk of developing cancer but are rarely involved in causing cancer
immediately. Older age individuals are more at risk, because they are more prone to get
mutations, because it takes time to get this accumulation, it is all a matter of chance and
time, and can be partly avoidable with healthy lifestyles. The Hallmark of cancer: they
proposed that acquiring the capability for autonomous
growth signals, evasion of growth inhibitory signals, evasion
of apoptotic cell death, unlimited replicative potential,
angiogenesis (the formation of new blood vessels), and
invasion and metastasis are essential for carcinogenesis.
More recently, they have modified their concept to include
two enabling characteristics, genome instability and
tumor-promoting inflammation, that are crucial for acquiring
the six hallmarks of cancer, and they highlight two emerging
hallmarks, reprogramming energy metabolism and avoiding
immune destruction.
We now appreciate that cancer is not just a cell-autonomous process but is also dependent
on interactions between tumor cells, with the tumor microenvironment, and with
long-distance systemic signaling. A tumor is not just a mass of cells, there are other types of
cells, the tumor microenvironment, with stroma giving structure, vessels going there, immune
cells, in order to signal with each other, a small ecosystem. It is generally assumed that only
one of the 1014 cells in the body needs to be transformed in order to create a tumor.
However, cancer cells continue to change their behavior as they progress. The progressive
changes of a cell, resulting from an accumulation of additional mutations that confer a
growth advantage over its neighbors, proceed in a fashion analogous to Darwinian evolution:
chance events give rise to mutations that confer changes in phenotype and allow adaptation
to the environment, resulting in sub clonal selection and an advantage in fitness.Thus, clonal
evolution explains the heterogeneous population of cells within a tumor; primary tumors
become composed of subclones.
Dedifferentiation, differentiation, proliferation and apoptosis, and in cancer the
differentiation and apoptosis are blocked. There are three important processes that
contribute to the overall net cell number in an individual. First, cell proliferation (cell division,
cell growth) is the most obvious. Cell division results in two daughter cells. Second, the

,elimination of cells by programmed cell death also affects the net cell number. Last, during
the process of differentiation, cells can enter an inactive phase of cell growth, and thus
differentiation can affect net cell numbers. DNA mutations that alter the function of normal
genes involved in growth, apoptosis, or differentiation can affect the balance of cell numbers
in the body and lead to unregulated growth. However, if apoptosis is blocked in one cell and
that cell divides instead, the total number of cells will increase to 11. Similarly, if
differentiation of a stem or precursor cell is blocked and that cell divides, as is the case in
some leukemias, the number of cells will also increase.
Oncogenes drive cancer, and tumor suppressor genes try to avoid it. Normal genes that
can be activated by mutation to be oncogenic are called proto-oncogenes. Protooncogenes
play functional roles in normal cells. The term reminds us that all normal cells have genes
that have the potential to become oncogenic. A general description of an oncogene is a
gene mutated such that its protein product is produced in higher quantities or has increased
activity and therefore acts in a dominant manner to initiate tumor formation. “Dominant”
refers to the characteristic that a mutation in only one allele is sufficient for an effect. Tumor
suppressor genes code for proteins that play a role in inhibiting both growth and tumor
formation. Loss of growth inhibition occurs when mutations cause a loss of function of these
genes. Consequently, growth is permitted. Tumor suppressor mutations are mainly recessive
in nature because one intact allele is usually sufficient to inhibit growth; thus both alleles of
the gene must be mutated before the loss of function is actually seen phenotypically.
Patients that inherit one mutated tumor suppressor allele may acquire a second somatic
mutation over time, leading to predisposition to an increased risk of cancer. towards a cancer
phenotype in the race for accumulation of mutations. Recent evidence suggests there is an
alternative mechanism for particular tumor suppressor genes, called haploinsufficiency,
whereby only one mutated allele can lead to the cancer phenotype. As the term suggests,
one normal allele produces half (“haplo-”) of the quantity of protein produced by normal cells,
and this is not enough to suppress tumor formation in these cases.
Recognize cancer cells: differentiation loss, low-serum concentration growth, no/decreased
contact inhibition, they grow without substrate for attachment, they don’t need ECM such as
leukemia, but epithelial do.
Factors: environment (asbestos, sun light), diet and exercise (diet is one of the most
influential factors, while, for instance, the risk of breast cancer can be reduced by at least
25% by more physical activity in women from the onset of menarche throughout the
perimenopausal years), alcohol (there is convincing evidence that chronic alcohol drinking
increases the risk of cancer of the mouth, esophagus, and breast, and probable evidence for
increased risk of liver cancer), smoking (at least 81 carcinogens have been identified in
cigarette smoke, 40% of all cancer deaths, including implications in pancreatic, bladder,
kidney, mouth, stomach, and liver cancer, and above all lung cancer), reproduction,
contraception, hormone replacement therapy /these are all related to hormones and include
especially breast cancer in women), viruses (sexual transmissable, cervical cancer). In
addition to lifestyle factors, there are risk factors inherent in our own physiology. By-products
of our metabolism and errors that occur during DNA replication contribute to carcinogenesis.
Mostly your own metabolism and for this you cannot do much, you can try to lower the
chance with a healthy lifestyle but you cannot stop your metabolism.
Treatment: surgery is very localized, relatively easy in some types of cancer and impossible
in other types; radiotherapy or chemotherapy when it’s not localized anymore, but are used
to inhibit or eradicate metastasized cells. There are limitations, they also affect healthy
tissues, adverse effects. The objectives of cancer therapies are to prevent proliferation

, (cytostatic effect) and to kill the cancer cells (cytotoxic effect). The aim
with all drugs is to achieve an effective result with the minimum side
effects. This is indicated by the therapeutic index. Therapeutic
index/window is the difference between maximum tolerated dose and
the minimum dose needed to exert anti-cancer activity. The further from
each other, the larger the therapeutic index, and ideally you would have
100% effects before you get the side effects, but in reality this is not the
case. You don’t wanna exceed the upper limit of the window but you
want 100% effect so you want to get as close as possible to that. The
larger the value, the safer the drug.
Conventional chemotherapy uses chemicals that target DNA, RNA, and protein to disrupt
the cell cycle in rapidly dividing cancer cells and thus has broad specificity. The ultimate goal
of cytotoxic chemotherapy is to cause severe DNA damage and to trigger apoptosis in the
rapidly dividing cancer cells. The side effects of chemotherapy, which we are all too aware
of, such as alopecia (loss of hair), ulcers, and anemia, are due to the fact that hair follicles,
stomach epithelium, and hematopoietic cells are also rapidly dividing, and therefore they too
are greatly affected by these drugs.
Clinical trials: testing of new drugs in humans must progress through staged clinical trials.
Phase I trials examine dose responses for assessing drug safety, using a small number
(20–80) of healthy volunteers or patients. About 70% of drugs tested in Phase I will progress
to Phase II studies. Phase II trials are designed to examine efficacy in a larger group of
people (100–300). Phase II trials should not be initiated prior to knowing the effective drug
dosage. Phase III trials are large-scale studies (1000–3000 people) to confirm drug
effectiveness, to monitor side effects, and also to compare the efficacy of the new drug with
conventional treatments. Only terminally ill patients may be recruited for clinical trials, by law,
in many countries. In order to reduce the risk of bias, trials can be randomized. In addition,
the trial may be conducted as a single-blind study, whereby patients do not know which
group they are in, or as a double-blind study, whereby neither patients nor investigators
know who has received the treatment or placebo until after a code is broken that identifies
the people in the two groups.
Targeted drugs: drugs based on our knowledge on how cancer cells are different from
normal cells, some therapeutic compounds inhibit the hallmarks. For some of the therapies,
we still don’t have good results, with an effectiveness, not only meaning curing but reducing
effects or prolonging lives as well, of 15%, which sounds bad but for other diseases there
are also people that don’t benefit from therapy, but anyways cancer is still lower compared to
them. This is different between individuals, because we metabolize drugs in different ways,
and also cancer cells are developing from heterogenous cells which change between
individuals, and this is why the main task is to create a targeted therapy or personalized
medicine, so to understand which patients will benefit from it and which ones will not.

CH2: Radiation and chemical carcinogenesis
DNA structure: nucleic acids make chains, which coil in histones in chromatin fibers, and
the reason why it’s so heavily folded is because there is a lot of DNA, 2 m in length and it
needs to fit the nucleus, 4 micrometers. It consists of two strains, the sugar ribose connected
to the next with a phosphate group, and each ribose is connected to a base, pyrimidine with
one ring and purine with two rings. The two strands have opposite orientations, 3’ or 5’,
depending on the carbon on the ribose structure that’s attached to the phosphorus at the
end, and in one strand it’ll be 5’ → 3’ and the other 3’ → 5’. Adenine with thymine and