ONCOGENESIS

Case No. 1
Melai N. Oma, 25 year old housewife, consulted a physician because of a brownish black irregular mole on
her forearm. Her physician is concerned that the mole might be a malignant melanoma and so he performed
an excision biopsy.
Questions:
1. What is Melanoma?
A melanoma is a tumor produced by the malignant transformation of melanocytes. Melanocytes are
derived from the neural crest. Melanomas, although they usually occur on the skin can arise in other
locations where neural crest cells migrate, such as the gastrointestinal tract and brain.
Signs and Symptoms
The characteristics of melanoma (known by the acronym ABCDE) include the following:

A: Asymmetry
B: Irregular border
C: Color variations: Especially red, white, and blue tones in a brown or black lesion
D: Diameter greater than 6 mm
E: Elevated surface

In addition, melanomas may itch, bleed, ulcerate, or develop satellites. Patients who present with
metastatic disease or with primary sites other than the skin have signs and symptoms related to the
affected organ system(s).
2. What are the risk factors of developing malignant melanomas?
a. Ultraviolet Light Exposure
The nature of the UV exposure may play a role in melanoma development. For example, the
development of melanoma on the trunk (chest and back) and legs has been linked to
frequent sunburns (especially in childhood). This might also have something to do with the
fact that these areas are not constantly exposed to UV light. Some experts think that
melanomas that start in these areas are different from those on the face, neck, and arms,
where the sun exposure is more constant. And different from either of these are melanomas
that develop on the palms of the hands, soles of the feet, under the nails, or on internal
surfaces such as the mouth and vagina, where there has been little or no sun exposure.
b. Moles
A mole (also known as a nevus) is a benign (non-cancerous) pigmented tumor. Babies are not
usually born with moles; they often begin to appear in children and young adults. Most moles
will never cause any problems, but a person who has many moles is more likely to develop
melanoma.
c. Fair skin, freckling and light hair
The risk of melanoma is much higher for whites than for African Americans. Whites with red
or blond hair, blue or green eyes, or fair skin that freckles or burns easily are at increased
risk.
d. Family history of melanoma
The increased risk might be because of a shared family lifestyle of frequent sun exposure, a
family tendency to have fair skin, certain gene changes (mutations) that run in a family, or a
combination of factors.
Most experts do not recommend that people with a family history of melanoma have genetic
testing to look for mutations, as its not yet clear how helpful this is. Rather, experts advise
that they do the following:

Have regular skin exams by a dermatologist

Thoroughly examine their own skin once a month
Be particularly careful about sun protection and avoiding artificial UV rays (such as
those from tanning booths)
e. Personal history of melanoma

f.

A person who has already had melanoma has a higher risk of getting melanoma again. About
5% of people with melanoma will develop a second one at some point. People who have had
basal or squamous cell skin cancers are also at increased risk of getting melanoma.
Weakened immune system
A persons immune system helps fight cancers of the skin and other organs. People with
weakened immune systems (from certain diseases or medical treatments) are more likely to
develop many types of skin cancer, including melanoma.
For example, people who get organ transplants are usually given medicines that weaken their
immune system to help prevent them from rejecting the new organ. This increases their risk
of developing melanoma.

People infected with HIV, the virus that causes AIDS, often have weakened immune systems
and are also at increased risk for melanoma.
g. Older age
Melanoma is more likely to occur in older people, but it is also found in younger people. In
fact, melanoma is one of the most common cancers in people younger than 30 (especially
younger women). Melanoma that runs in families may occur at a younger age.
h. Male gender
i. Xeroderma Pigmentosum
Xeroderma pigmentosum (XP) is a rare, inherited condition that affects skin cells ability to
repair damage to their DNA. People with XP have a high risk of developing melanoma and
other skin cancers when they are young, especially on sun-exposed areas of their skin.
3. Several mutations involving the following are implicated in the development of malignant
melanomas. Explain how these can result to malignancy.
a. Ras
In the majority of cases, these mutations are missense mutations which introduce an amino
acid substitution at positions 12, 13, or 61. The result of these mutations is constitutive
activation of NRAS signaling pathways. NRAS mutations are found in all melanoma subtypes,
but may be slightly more common in melanomas derived from chronic sun-damaged (CSD)
skin
b. P53

c. P16 and CDK 4

d. Cadherin/-Catenin regulation

4. What are the clinical warning signs that Melai N. Oma should observe and preventive measures that
she should follow?
The characteristics of melanoma (known by the acronym ABCDE) include the following:
A: Asymmetry
B: Irregular border
C: Color variations: Especially red, white, and blue tones in a brown or black lesion
D: Diameter greater than 6 mm
E: Elevated surface
In addition, melanomas may itch, bleed, ulcerate, or develop satellites. Patients who present with
metastatic disease or with primary sites other than the skin have signs and symptoms related to the
affected organ system(s).
Close follow-up care is essential to monitor for new primary lesions, recurrence, or metastases.
History and physical examination are the cornerstones, with further testing (eg, chest radiography,
blood chemistries) if suggestive findings are encountered. Most practitioners observe patients every
3-6 months initially and then eventually decrease the frequency, although no consensus exists.
Physicians observe patients with thicker tumors more frequently than patients with thinner lesions.
Follow-up care with a dermatologist is strongly recommended. Educate patients on self-examination

for detection of new or recurrent lesions and for recognition of the signs and symptoms of metastatic
disease because the risk of developing a second melanoma or having recurrence is well recognized.

Case No. 2
Luke E. Miyah, a 45 year old male, consulted a hematologist, Dr. J because of abdominal enlargement
and early satiety. He complained of malaise on other days. He also informed his doctor that he had lost
weight significantly. A complete blood count , peripheral smear and bone marrow analysis sent for
Fluorescence in situ hybridization (FISH) (BCR-ABL) were done and revealed the following:
Refer to SGD Questions handout.

Questions:
1. What type of mutationis involved in the development of CML?
Translocation - chromosome mutations in which chromosome segments, and the genes they contain,
change positions. Translocations can occur within a chromosome (intrachromosomal) or between
chromosomes (interchromosomal).
Most cases of CML start when a "swapping" of chromosomal material (DNA) occurs between
chromosomes 9 and 22 during cell division. Part of chromosome 9 goes to 22 and part of 22 goes to 9.
This is known as a translocation and gives rise to a chromosome 22 that is shorter than normal. This new
abnormal chromosome is known as the Philadelphia chromosome. The Philadelphia chromosome is found
in the leukemia cells of almost all patients with CML.
The swapping of DNA between the chromosomes leads to the formation of a new gene (an oncogene)
called BCR-ABL. This gene then produces the BCR-ABL protein, which is the type of protein called a
tyrosine kinase. This protein causes CML cells to grow and reproduce out of control.
2. How is CML different from Burkitts Lymphoma?
Both leukemia and lymphoma result from problems with white blood cells.
In leukemia, bone marrow produces too many white blood cells that dont naturally die off in the way
that normal aging blood cells do. Instead, they keep dividing and ultimately take over healthy red blood
cells, which your body depends on for normal oxygen and nutrient transport. Leukemia also may start in
the lymph nodes.
Lymphoma often begins in the lymph nodes, which are small tissues that help in your bodys fight
against infection. Certain types of lymphoma also may occur due to the spread of abnormal white blood
cells in other parts of the body.
3. The chemotherapeutic drugs used for CML are Imatinib and Nilotinib and a newly developed called
Gleevec. Discuss their MOA.
a. Imatinib
Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine
kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome
abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis
in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome
positive chronic myeloid leukemia. Imatinib also inhibits the receptor tyrosine kinases for
platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Imatinib was
identified in the late 1990s by Dr Brian J. Druker. Its development is an excellent example of
rational drug design. Soon after identification of the bcr-abl target, the search for an inhibitor
began. Chemists used a high-throughput screen of chemical libraries to identify the molecule
2-phenylaminopyrimidine. This lead compound was then tested and modified by the

introduction of methyl and benzamide groups to give it enhanced binding properties,

resulting in imatinib.
b. Nilotinib
Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits
the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of
the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by
mutations.
c. Gleevec (Imatinib mesylate)
Gleevec (imatinib mesylate) is a protein-tyrosine kinase inhibitor that blocks the constitutive
abnormal tyrosine kinase, Bcr-Abl tyrosine kinase, that is created by the Philadelphia
chromosome abnormality found in CML. The drug inhibits proliferation and induces apoptosis
in Bcr-Abl positive cells and in fresh leukemic cells.

XENOBIOTICS AND CYTOCHROME P450

CP is a 45 year old Female diagnosed case of Rheumatic Heart Disease and being maintained on IM Penicillin,
once a month, and warfarin daily (INR of 2.5) suddenly came in because of right sided weakness. She was
rushed to the hospital where MRI of the brain showed ischemic stroke. Warfarin was continued. However, the
following day, patient suddenly developed a seizure and was given Phenobarbital. A week after Phenobarbital
was given repeat INR was requested and showed a level of 0.8 1.0.
Questions:
1. What is RHD and why did she developed stroke and seizure.
Rheumatic heart disease is a condition in which permanent damage to heart valves is caused by
rheumatic fever. The heart valve is damaged by a disease process that generally begins with a strep
throat caused by bacteria called Streptococcus, and may eventually cause rheumatic fever. The patient
suffered stroke as a complication of RHD. Complications include heart failure, which means the heart is
unable to pump blood effectively. The strain causes the heart to enlarge. Other complications of RHD
include infection of damaged heart valves (infective endocarditis) and stroke due to clots forming in the
enlarged heart or on damaged valves. These clots then break off (embolise) and cause blockage in blood
vessels in the brain and stroke.
2. What is warfarin and why do you need to check INR?
Warfarin is an anticoagulant (blood thinner). Warfarin reduces the formation of blood clots.
Warfarin is used to treat or prevent blood clots in veins or arteries, which can reduce the risk of stroke,
heart attack, or other serious conditions. Warfarin acts by inhibiting the synthesis of vitamin K-dependent
clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S.
Your INR results need to stay within a certain range. This range is called the target INR. The target INR
ranges from 2 to 3 for people taking warfarin. However, some people will need to have a lower or slightly
higher target INR.
If your INR is too high your risk of bleeding increases. And if your INR is too low, your blood is more likely
to form a blood clot. Monitoring your INR and keeping it in the target range will help you to avoid side
effects.
The target INR helps doctors to adjust your warfarin dose, which can differ from person to person, and
from time to time.
3. Why did the patients INR decreased when she was started with phenobarbital?
Phenobarbital is a broad-spectrum cytochrome P450 inducer that can impact the enzymatic activity of
the CYP1A2, CYP2C9, CYP2C19, and CYP3A4 subfamilies.[9] Phenobarbital decreases INR and the
anticoagulant effects of warfarin by increasing its clearance through induction of the cytochrome P450
isoenzymes by which warfarin is metabolized. Phenobarbital and other antiepileptic drugs induce the
cytochrome P450 system by binding to hepatic cell receptors and signaling transcription factors to
increase production of CYP enzymes.

4. Is there a need to adjust medication dose or change medicines?

Yes, since Phenobarbital would decrease the patients INR, blood clots are more likely to occur. Warfarin
dose may be increased until the desired activity is obtained. Consider alternative drugs to phenobarbital
such as the benzodiazepines that are not likely to react with warfarin.

DNA MUTATION, DAMAGE AND REPAIR

1. Why do cells exposed to visible light following irradiation with ultraviolet light have a greater survival
rate than kept in dark after irradiation with ultraviolet
Ultravioloet (UV) light can damage DNA by causing dimerization of thymidylate residues. One
mechanism for repairing thymine dimers is enzymatic photoreactivation, catalyzed by DNA photolase.
This enzyme uses energy from visible light to cleave the dimer and repair DNA. Thus cells that are
exposed to visible light following UV irradation are better able to repair DNA than cells kept in the dark.