Genetics of Cancer

Course:
Biochemistry and Medical Genetics
Prepared by: Dr. Alisa Chebotarova, MD, PhD
Modified by: Dr. I. Vyshnytska, MSc, PhD
 INTENDED LEARNING OBJECTIVES
By the end of the lecture students must be able to:
1. Outline the current state of knowledge about the biochemical and molecular basis of cancer
2. Describe the Main Forms of Cancer
3. Explain the main difference between Benign and Malignant Tumors
4. List hallmarks of Cancer
5. List Cancer-causing agents
6. Describe Proto-oncogenes and Oncogenes
7. Explain Mechanisms of activation of Oncogenes
8. Describe Tumor Suppressors – definition, functions, classification (Gatekeepers, Caretakers)
9. List Mutations in Tumor suppressors
10. Explain Loss of Heterozygosity

Dr. Alisa Chebotarova, MD, PhD

 High-Yield Terms
• Carcinogen ✮ : any substance, such as a chemical, or any type of radiation that is directly
involved in causing cancer
• Neoplasm: any abnormal mass of tissue, medically synonymous with the term tumor
• Malignancy: medically describes any condition that becomes progressively more severe,
with respect to cancers the term characterizes invasiveness and the tendency to metastasize
• Metastasis: refers to the spread of cancer from a site of origin to a new organ or another
part of the body
• Proto-oncogene ✮ : any normal gene that can become an oncogene due to gene mutation
or abnormal expression
• Oncogene ✮ : any gene that has the potential to cause cancer, in tumor cells, these genes
are often mutated or expressed at high levels
• Tumor suppressor ✮ : any gene that prevents the unregulated growth of cells, loss of
function of this class of gene can result in cancer, also called antioncogene
Dr. Alisa Chebotarova, MD, PhD
 Cancer genetics

Transformation of a cell is due to the action of one or more “oncogenes”

(gain of function) and/or due to the loss of one or more “tumor suppressor
genes” (loss of function).
Dr. Alisa Chebotarova, MD, PhD
 Basics of Cancer Biology ✮
• Tumors or Neoplasms
• a disease process characterized by uncontrolled cellular proliferation leading to a
mass formation
• Benign tumor
• does not metastasize
• grows in a confined local area
• Malignant tumor
• Uncontrolled growth
• capable of invading neighboring tissues or spreading (metastasizing)
• Cancer: a general term for a malignant tumor

Dr. Alisa Chebotarova, MD, PhD

 Benign vs. Malignant ✮
Benign Malignant
• Slow growing • Fast growing
• Capsulated • Non capsulated
• Non-invasive • Invasive and Infiltrate
• Do not metastasize • Metastasize
• Well differentiated • Poorly differentiated
• Suffix ‘oma’ eg., Fibroma • Suffix “Carcinoma” or
“Sarcoma”

Dr. Alisa Chebotarova, MD, PhD

 Benign to Malignant
• Cancer arises from a loss of normal growth control. In normal tissues,
the rates of new cell growth and old cell death are kept in balance.
• In cancer, this balance is disrupted.
• This disruption can result from uncontrolled cell growth or loss of a
cell's ability to undergo cell suicide by a process called "apoptosis"
• In normal tissues, apoptosis, or "cell suicide," is the mechanism by
which old or damaged cells normally self-destruct.

Dr. Alisa Chebotarova, MD, PhD

 Three Main Forms of Cancer
• Carcinomas
– originate in epithelial tissues
– Account for 90% of all cancers
• Sarcomas
– originating in mesenchymal tissue (bone, cartilage,
fat, connective tissue, muscle, nervous tissue)
• Leukemias and lymphomas
– cancer cells reside and proliferate mainly in the
bloodstream, lymphatic system and bone marrow

Dr. Alisa Chebotarova, MD, PhD

 Biochemical Characteristics of Cancer
Cells:
1. Increased synthesis of DNA and RNA.
2. Increased rate of glycolysis both aerobic and anaerobic. ✮
3. Alterations of permeability and surface charge.
4. Changes in composition of glycoproteins and glycosphingolipids on cell surfaces (alterations of the
oligosaccharide chains).
5. Increased activity of ribonucleotide reductase and decreased catabolism of pyrimidines ✮
6. Secretion of certain proteases and protein kinases.
7. Alterations of isoenzyme patterns often to a fetal pattern and synthesis of fetal proteins, ✮ e.g.
carcinoembryonic antigen (CEA), α-fetoprotein (AFP), etc.
8. Appearance of new antigens and loss of certain antigens.
9. Inappropriate synthesis of certain hormones and growth factors.
10. Cancer cells continue to express telomerase activity which prevents telomere shortening.
*Hallmarks of Cancer: The Next Generation, 2011;
https://www.cell.com/fulltext/S0092-8674(11)00127-9
Dr. Alisa Chebotarova, MD, PhD
Cancer Causing Agents
 Carcinogens
• Carcinogens are cancer-causing agents
• Ionizing Radiation
• Chemical Carcinogens
– Asbestos and lung cancer
– Alcohol and liver cancer
– Smoking and lung cancer
• Biological agents
– Aflatoxin B1 and liver cancer
– Hepatitis B (HBV) and hepatocellular cancer
– Human Papilloma Virus (HPV) and cervical cancer
– Human immunodeficiency virus (HIV) and Kaposi
sarcoma
– Helicobacter pylori and stomach cancer
– Schistosomiasis
Dr. Alisa Chebotarova, MD, PhD and bladder cancer
 Radiation and Cancer
• Ionizing and ultraviolet radiation
• DNA mutations that lead to cancer
• Risk is age dependent
- under 10 and elderly
• Significant risk for individuals with inborn
defects of DNA repair

Dr. Alisa Chebotarova, MD, PhD

 Radiation and Cancer
1. Exposure to ultraviolet radiation in the form of
sunlight is related to the frequency of skin
cancers, such as squamous cell and basal cell
carcinomas and melanomas.
The process is thought to act by inducing
dimer formation between neighboring thymine
pairs in DNA. In most cases, such dimers are
successfully repaired by enzymatically mediated
mechanisms (excision endonuclease).
• xeroderma pigmentosum, an AR disorder
characterized by failure of DNA excision repair
mechanisms.
2. Ionizing radiation is a classic cause of cancer,
exemplified by the increased incidence of cancers
in those exposed to radiation.
Dr. Alisa Chebotarova, MD, PhD
 Chemical Carcinogens
• When chemical carcinogens are internalized by cells, they are often metabolized,
and the resulting metabolic products are either excreted or retained by the cell.

• Inside the cell, carcinogens or their metabolic products can either directly or
indirectly affect the regulation and expression of genes involved in cell-cycle
control, DNA repair, cell differentiation or apoptosis.
• For example, carcinogenic ions or compounds of nickel, arsenic and cadmium can induce
structural and numerical chromosome aberrations.

• Together genotoxic and non-genotoxic mechanisms can alter signal-transduction

pathways that finally result in hypermutability, genomic instability, loss of
proliferation control, and resistance to apoptosis — some of the characteristic
features of cancer cells.
Dr. Alisa Chebotarova, MD, PhD
Oncogenes
 Oncogenesis ✮
• Oncogenes are abnormal (mutated) versions of “Proto-oncogenes” that are part
of normal cellular function. ✮
• The process of activation of proto-oncogenes to oncogenes can include retroviral
transduction or retroviral integration, point mutations, insertion mutations, gene
amplification, chromosomal translocation, and/or protein-protein interactions.
• Retroviruses: RNA viruses that synthesize DNA as the replicative form and cause insertion
of DNA into the host DNA. This DNA carries a mutant form of the genes.
• Modification of the structure and/or level of expression of a protooncogene may
convert it into an oncogene.
• Oncogene formation is usually an autosomal dominant mutation (gain of
function mutation)
Dr. Alisa Chebotarova, MD, PhD
 Oncogenes
Oncogenes arise from the mutation of proto-
oncogenes.
They resemble proto-oncogenes in that they code
for the production of proteins involved in growth
control.
However, oncogenes code for an altered version (or
excessive quantities) of these growth-control
proteins, thereby disrupting a cell's growth-
signaling pathway
By producing abnormal versions or quantities of
cellular growth-control proteins, oncogenes cause
a cell's growth-signaling pathway to become
hyperactive.
Dr. Alisa Chebotarova, MD, PhD
 GF signaling in norm

Dr. Alisa Chebotarova, MD, PhD *MAP - the mitogen-activated protein kinase
 GROWTH FACTORS
Action at Molecular Level
1. Most of the growth factors have high affinity protein receptors on the membranes
of target cells.
2. Genes for receptors of EGF and IGF have been extensively studied. Structurally
they are found to have short membrane spanning segments and external and
cytoplasmic domains of varying lengths.
3. Most of the receptors, e.g. of PDGF, EGF, etc. have been found to exhibit protein
tyrosine kinase activity which is located in cytoplasmic domain.
4. The kinase activity brings about autophosphorylation of the receptor protein and
also phosphorylation of other proteins of target cells.
5. Growth factors interact with the specific membrane receptor and transmits the
message across the plasma membrane to the interior of the cells by transmembrane
signal transduction, which finally affect one or more processes involved in mitosis of
the
Dr. Alisacells.
Chebotarova, MD, PhD
 Growth Factor signaling: key players
• Growth Factors: ligands that stimulate cell proliferation

• Growth Factor Receptors: a mutated receptor may remain constitutively active in

the absence of a ligand: c-erbB2, ret

• Plasma membrane G proteins: ras

• Nonreceptor Protein Kinases: Abl

• Transcription factors
• Myc → Altered gene expression.

• Cell cycle or cell-death regulators

• Chebotarova,
Dr. Alisa Cdk4, cyclin D, Bcl-2
MD, PhD
 Growth Factors (Mitogens)

• Are usually polypeptides.

• Play a major role in regulating differentiation of stem cells to form various types
of mature cells.
• Products of several oncogenes are either growth factors or parts of receptors for
growth factors.
• Chronic exposure of target cells to increased amounts of a growth factor or to
decreased amounts of a growth inhibitory factor may alter the balance of cellular
growth (growth autonomy).

Dr. Alisa Chebotarova, MD, PhD

 Growth Factors

• Growth factors may act in the following 3 ways:

• Endocrine action: Similar to hormone action. May be synthesized in one place
and then carried by bloodstream to target cells where they exert their effects.
• Autocrine action: Synthesized and act on the same cells.
• Paracrine action: Synthesized in certain cells and secreted from them to affect the
neighbouring cells.

Dr. Alisa Chebotarova, MD, PhD

 Growth Factors

Dr. Alisa Chebotarova, MD, PhD

 Growth Factors: A modified receptor

Under normal circumstances
membrane-bound receptors require the
binding of their ligand to be in an
activated state.
Dr. Alisa Chebotarova, MD, PhD
In contrast, receptors
encoded by oncogenes do
not require the regulatory
step of ligand binding to be
active (constitutively active
receptores).
 RET proto-oncogene ✮
• A point mutation in RET gene makes it active oncogene

• Encodes for a Receptor tyrosine kinase (RTK)

• RET autophosphorylation and intracellular signaling: phosphorylated tyrosines

become docking sites for intracellular signaling proteins

• Abnormal gene product: Mutations in codons in the cysteine-rich extracellular

domain results in Ligand-independent RET
• Constitutive activation (i.e., gain of function) of tyrosine kinase

Dr. Alisa Chebotarova, MD, PhD

 RET and Multiple Endocrine Neoplasia
type 2
• Autosomal Dominant
• Associated with RET gene mutations (10q11.2)
• Receptor tyrosine kinase

• MEN 2A:
• Medullary thyroid carcinoma (secretes calcitonin)
• Pheochromocytoma
• Parathyroid hyperplasia
• MEN 2B:
• Medullary thyroid carcinoma (secretes calcitonin)
• Pheochromocytoma
• Oral/intestinal ganglioneuromatosis (mucosal neuromas).
• Associated
Dr. Alisa Chebotarova, MD,with
PhD marfanoid habitus.
 RAS proto-oncogene ✮
• A point mutation in RAS gene makes it active
oncogene

• One of the first oncogenes discovered was a

mutant RAS gene that encoded a large family of
small GTP binding (G) proteins.
• Point mutations in the RAS gene result in the ras
protein that is locked in its active, GTP-bound
form.
• Transfection of normal cells with RAS (and other
oncogenes) causes these cells to grow in
uncontrolled fashion (transformation).
• RAS has been found to be associated with a large
number of cancers (colon, lung, pancreatic)
Dr. Alisa Chebotarova, MD, PhD
 HER2 / neu ✮
• HER2 is a protein receptor that in humans is
encoded by c-erbB2 gene, a known proto-
oncogene located at the long arm of human
chromosome 17
• Amplification of the c-erbB2 leads to
addition the extra copies of chromosomal
regions containing proto - oncogenes.
• The up to 200-fold amplification of proto-
oncogene products like HER2/neu-human
epidermal growth factor receptor (in
breast cancer in older females, ovarian,
and gastric carcinomas) can be found.
Dr. Alisa Chebotarova, MD, PhD
HER2 gene status
identified by FISH.

• Chromosome 17 centromere
(CEP17) gain is frequently
observed in breast cancer
by FISH. Red signals
represent HER2 gene, green
signals represent CEP17.
• A: HER2 gene negative case;
• B: HER2 gene positive case,
HER2/CEP17 ratio of higher
than 2.0;
• C: HER2 gene positive case,
HER2 signals are clustered;
• D: HER2 gene with CEP17
gain.
Dr. Alisa Chebotarova, MD, PhD
 Chromosomal Translocation
• A proto-oncogene may also be activated in some instances by a chromosomal
mutation, most usually, a translocation.
• Three important examples:
• Chronic myelogenous leukemia (CML):
• translocation between chromosomes 9 and 22.
• Burkitt lymphoma:
• translocation between chromosomes 8 and 14.
• B-cell lymphoma:
• Translocation involving chromosomes 18 and 14 leads to over-expression of the anti-
apoptotic gene bcl-2.

Dr. Alisa Chebotarova, MD, PhD

 Chronic myelogenous leukemia (CML) and
Philadelphia chromosome ✮
• A reciprocal translocation of the long arms of
chromosomes 9 and 22, termed the Philadelphia
chromosome.
• This translocation alters the activity of the abl proto-
oncogene (chr 9)
• The BCR locus was originally identified as a region of
frequent chromosomal breakage and thus, termed the
breakpoint cluster region, BCR (chr 22)

The chimeric BCR-ABL fusion gene on the Philadelphia

chromosome encodes a membrane-associated protein
tyrosine kinase that remains constitutively active
Dr. Alisa Chebotarova, MD, PhD
 Chromosomal translocation and Burkitt
Lymphoma ✮
• Translocation between chromosome 8 and 14
occurs in Burkitt lymphoma.
• The gene for the transcription factor c-myc (from
8) comes under the influence of strong
promotors of the heavy immunoglobulin chains
(14).
• rare form of cancer
• B-cell lymphoma
• predominantly affecting young children in Central
Africa
– associated with Epstein Barr virus infection
– pathogenic mechanism involves EBV-induced latent
membrane
Dr. Alisa Chebotarova, protein (LMP-1)
MD, PhD
 Chromosomal translocation and B-cell
Lymphoma ✮
• Translocation involving chromosome 14 and 18 in
B-cell lymphoma (Follicular and undifferentiated
lymphomas).
• Translocation places bcl-2 (from 18) near the
strong promoter for immunoglobulin heavy chain
gene (14)
• Thus leading to over-expression of the anti-
apoptotic gene BCL2.
• Damaged cells may then escape apoptosis

Dr. Alisa Chebotarova, MD, PhD

Tumor Suppressors
 Tumor Suppressors
• Tumor suppressor genes are genes that regulate the growth of cells and when
these genes are functioning properly, they can prevent and inhibit the growth of
tumors.
• There are 3 main classes of tumor suppressor genes:
• These include genes that encode proteins that tell cells to stop growing and
dividing.
• Another class encodes proteins responsible for repairing DNA damage prior to
allowing cells to complete the cell cycle.
• The third class encodes proteins that are involved in regulating cell death
processes, called apoptosis.

Dr. Alisa Chebotarova, MD, PhD

 Mutations in Tumor suppressors can cause
cancer ✮

• Tumor suppressor proteins arrest cell cycle at checkpoints and keep cell division
in control
• Mutations in tumor suppressor genes cause a loss of function of these proteins
• Both copies of tumor suppressor genes need to be mutated for development of
cancers

Dr. Alisa Chebotarova, MD, PhD

 Oncogenes vs. Tumor suppressors

Dr. Alisa Chebotarova, MD, PhD

 The two-hit model of cancer ✮
• Tumor-Suppressor Genes
• Both alleles of the tumor suppressor gene
need to be mutated
• 1st hit can be inherited
• 2nd hit can arise spontaneously
• By mutation
• Epigenetic origin
• gene silencing
• X inactivation
• imprinting

Dr. Alisa Chebotarova, MD, PhD

 The two-hit model of cancer ✮
• Tumor-Suppressor Gene: Retinoblastoma gene, RB1
• In hereditary retinoblastoma, mutations in the RB1 gene appear to be inherited in
an autosomal dominant pattern (means that one copy of the altered gene in
each cell is sufficient to increase the risk of cancer).
• 1st hit: A person with hereditary retinoblastoma may inherit an altered copy of
the RB1 gene from one parent, or the altered gene may be the result of a new
mutation that occurs in an egg or sperm cell or just after fertilization.
• 2d hit: For retinoblastoma to develop, a mutation involving the other copy of the
RB1 gene must occur in retinal cells during the person's lifetime. This second
mutation usually occurs in childhood, typically leading to the development of
retinoblastoma in both eyes (bilateral).

Dr. Alisa Chebotarova, MD, PhD

 Loss of Heterozygosity - LOH ✮
• When normal tumor suppressor genes are absent or nonfunctional
due to LOH, the cell may begin to divide abnormally and become
cancerous.
• If a patient 1) inherits or develops a mutation in a tumor suppressor
gene, 2) the complementary allele must be deleted/mutated before
cancer develops.
• In case of Retinoblastoma:
• One RB1 allele is mutant
• The remaining normal RB1 allele is lost in heterozygotes (LOH)

Dr. Alisa Chebotarova, MD, PhD

 Loss of function mutations in proteins
that can lead to carcinogenesis

1. Proteins that regulate a particular phase of the cell cycle or monitor

checkpoints to arrest cell cycle (e.g., Rb, p53 block G1→S phase)
2. Proteins that are components of growth-inhibitory signaling pathways (APC
protein)
3. Proteins that promote apoptosis (Fas, Bax)
4. Proteins that participate in DNA damage repair (NER proteins implicated in
Xeroderma pigmentosum, BRCA1, BRCA2)

Dr. Alisa Chebotarova, MD, PhD

 Checkpoints and Cell Cycle Regulation

•The processes that drive a cell through the cell cycle must be highly regulated so
as to ensure that the resultant daughter cells are viable and each contains the
complement of DNA found in the original parental cell.

•Many important genes involved in the regulation of cell cycle transit have been
identified and are referred to as cell division cycle genes (or cdc genes). Many of
these genes encode proteins that control progression through the phases of a cell
cycle at specific points called checkpoints or restriction points.

Dr. Alisa Chebotarova, MD, PhD

 Checkpoints and Cell Cycle Regulation

•The heart of this timing control is the responsibility of a family of

protein kinases that are called cyclin-dependent kinases, CDK.
•Different CDK operate at different points in the cell cycle.
•The kinase activity of these enzymes rises and falls as the cell progresses
through a cell cycle.
•Constitutively expressed but inactive when not bound to cyclin.

Dr. Alisa Chebotarova, MD, PhD

 Checkpoints and Cell Cycle Regulation

•The cyclical activity of each CDK is controlled by the proteins cyclins

• Regulatory proteins that control cell cycle events;
• phase specific;
• activate CDKs.
•Four different classes of cyclins have been defined on the basis of the stage of the
cell cycle in which they bind and activate CDKs:
• G1-cyclins,
• G1/S-cyclins,
• S-cyclins,
• M-cyclins.
Dr. Alisa Chebotarova, MD, PhD
 Checkpoints and Cell Cycle Regulation

• Cyclin-CDK complexes:
• Phosphorylate other proteins to coordinate cell cycle progression;
• must be activated and inactivated at appropriate times for cell cycle to progress.

• p21 is CDK inhibitory proteins (CIP): protein that binds to and inhibits cyclin-CDK
complexes
• and there are other CIP: p27, p57, p15, p16, p18, and p19 in mammalian cells.
Dr. Alisa Chebotarova, MD, PhD
 Checkpoints and Cell Cycle Regulation

Rb

Dr. Alisa Chebotarova, MD, PhD

 Retinoblastoma protein
• The retinoblastoma protein (protein name abbreviated pRb; gene name
abbreviated RB or RB1) is a tumor suppressor protein that is dysfunctional in
several major cancers.
• This protein acts as a tumor suppressor, which means that it regulates cell growth
and keeps cells from dividing too fast or in an uncontrolled way. 
• One function of pRb is to prevent excessive cell growth by inhibiting cell
cycle progression (G1→S) until a cell is ready to divide.
•  The Rb protein is present in one of two forms:
• Active – hypophosphorylated
• Inactive – hyperphosphorylated
• The resting cell in G0 phase contain active – hypophosphorylated Rb protein
Dr. Alisa Chebotarova, MD, PhD
 Role of Retinoblastoma protein
• Active: Early in G1/G0, Rb is in its hypophosphorylated active form, and it binds to
and inhibits the E2F family of transcription factors, preventing transcription of
cyclin E.
• The initiation of DNA replication (S phase) requires the activity of cyclin E/CDK2
complexes.

• Inactive: Growth factor signaling (or mitogenic signaling) leads to cyclin D

expression and activation of cyclin D–CDK4/6 complexes. These complexes
phosphorylate Rb, inactivating the protein and releasing E2F to induce target
genes such as cyclin E gene.
• Expression of cyclin E then stimulates DNA replication and progression through
the cell cycle.
Dr. Alisa Chebotarova, MD, PhD
 Retinoblastoma ✮

• A rare type of eye cancer that forms in

immature cells of the retina and most often
manifest in early childhood prior to the age
of 5.
• Diagnosis of retinoblastoma after the age of 6 is
extremely rare due to the terminal differentiation of
retinal epithelial cells.

• Autosomal dominant

• Mutation in the Rb tumor suppressor gene

• microdeletions in chromosome 13 in
affected individuals, in the RB gene
Dr. Alisa Chebotarova, MD, PhD
 Retinoblastoma ✮
• Two forms:
• sporadic-always unilateral - 60% of the total cases
• Requires two somatic “hits"
• Two mutations in same cell
• Often a single tumor
• Occurs at a later age

• familial-autosomal dominant - 40% of the total cases ( 80%

bilateral, 15% unilateral, 5% asymptomatic)
• One gene mutated in all cells at birth (germline
mutation)
• Second somatic mutation “hit"
• Frequent, multiple tumors
• Tumors at younger age
• high risk of other primary tumors (osteosarcoma)
Dr. Alisa Chebotarova, MD, PhD
 Retinoblastoma ✮
• Tumors develop due to unchecked division of precursor cells in the immature
retina.
• In the non-hereditary form, typically only one eye is affected and there is no
family history of the disease. Affected individuals are born with two normal
copies of the RB1 gene. Then, usually in early childhood, both copies of the RB1
gene in certain retinal cells acquire mutations. People with non-hereditary
retinoblastoma are not at risk of passing these RB1 gene mutations to their
children.
• In the hereditary form of the disease, one copy of the Rb gene is mutated in
every cell and the cells become predisposed to become cancerous. When the
good second copy of the gene is damaged due to a somatic mutation, the cells
lose the control of G1-S checkpoint.
Dr. Alisa Chebotarova, MD, PhD
 p53 is an important tumor suppressor protein
and is induced during DNA damage ✮
• The p53 tumor suppressor protein is encoded by the TP53 gene, located in
chromosome 17

• Expression of p53 is very low in normal cells. p53 is stimulated by cellular stress
like ionizing radiation, hypoxia, carcinogens, and oxidative stress.

• The p53 gene is the most common genetic alteration in cancer, and patients who
inherit a mutated copy of the p53 gene have an increased predisposition to soft
tissue neoplasms, leukemias, central nervous system tumors, and breast cancer.

Dr. Alisa Chebotarova, MD, PhD

 The p53 tumor suppressor gene acts as the
‘Guardian of the Genome’ ✮
• The p53 has three major effects:
1. p53-mediated cell cycle arrest. It occurs late in
the G1 phase and is caused mainly by p53-
dependent transcription of the CDK inhibitory
proteins gene (p21). The p21 protein inhibits
cyclin–CDK complexes and prevents
phosphorylation of Rb, thereby arresting cells in
the G1 phase.
2. p53-induced senescence is a permanent cell
cycle arrest
3. p53-induced apoptosis of cells with irreversible
DNA damage
Dr. Alisa Chebotarova, MD, PhD
 p53 Tumor Suppressor and Cancer
• More than 50% of all human cancers exhibit mutations in the TP53 gene.
• Examples of cancers in which p53 fails to activate include Li-Fraumeni syndrome
and Ataxia telangiectasia.
• Metabolic activation of benzo(a)pyrene, which is present in cigarette smoke and
charbroiled meat, produces a potent mutagen.
• Activated benzo(a)pyrene causes mutations in genes such as TP53 by G→T
transversions.
• Aflatoxin, a fungal metabolite that is present as a contaminant in moldy grain and
peanuts also induces G→T transversions in TP53 gene.
• Both benzo(a)pyrene and aflatoxin are the carcinogens because the mutations they cause
lead to cancer.

Dr. Alisa Chebotarova, MD, PhD

 Li - Fraumeni Syndrome ✮
• Li-Fraumeni syndrome is a rare autosomal
dominant disorder that greatly increases the risk of
developing several types of cancer.
• Is a familial DNA repair syndrome caused by
mutation in the tumor-suppressor gene p53.
• The cancers most often associated with Li-Fraumeni
syndrome include breast cancer, a form of bone
cancer (osteosarcoma), and cancers of soft tissues
(such as muscle) called soft tissue sarcomas.
• Other cancers commonly seen in this syndrome include
brain tumors, cancers of blood-forming tissues
(leukemias), and a cancer called adrenocortical
carcinoma that affects the outer layer of the adrenal
glands.
Dr. Alisa Chebotarova, MD, PhD
 Li - Fraumeni Syndrome ✮
• A 23-year-oldwoman develops a tumor of the soft tissue of her arm (sarcoma)
and is being evaluated by an oncologist. The physician learns that her older
brother had leukemia when he was 12 years old, her grandmother died of a brain
tumor, and her aunt has breast cancer. With this clustering of tumors, the
oncologist suspects Li-Fraumeni syndrome and orders molecular studies on the
patient’s tumor for which of the following genes?
a. p53
b. RET
c. WT-1
d. Rb
e. TNF
Dr. Alisa Chebotarova, MD, PhD
 BRCA1, BRCA2 and breast and ovarian cancer ✮
• BRCA1:
• Tumor-suppressor gene, BRCA-1, has been identified at the chromosomal locus
17q21.
• Functions of BRCA-1 gene product
• This gene encodes a zinc finger protein and the product therefore may function
as a transcription factor.
• The gene product also appears to be involved in Double Strand Break repair.

• BRCA1 gene mutations – autosomal dominant! - do not always result in breast or ovarian
cancer – Incomplete penetrance

Dr. Alisa Chebotarova, MD, PhD

 About 5% to 10% of breast and 10% to 15% of
ovarian cancers are hereditary.
• BRCA1:
• Women who inherit a mutated allele of this gene from either parent have at
least a 60-80% lifetime chance of developing breast cancer and about a 33%
chance of developing ovarian cancer.
• Men who carry a mutant allele of the gene have an increased incidence of
prostate cancer and breast cancer.
• family history of breast cancer, often at a young age.
• BRCA2:
• This gene has been localized to chromosome 13q12; it is also associated with an
increased incidence of breast cancer in men and women.

Dr. Alisa Chebotarova, MD, PhD

 APC gene and Familial Adenomatous
Polyposis ✮
• Familial Adenomatous Polyposis (FAP) is an
inherited disorder characterized by a highly elevated
risk of developing colorectal carcinoma. FAP is
associated with germline mutations in the
adenomatous polyposis coli (APC) gene.
• FAP adenomas appear as a result of loss of function
mutations to the APC gene which characterizes the
gene as a tumor suppressor
• Multiple colonic polyp development, within the first
decades of life, is characteristic of FAP. These polyps
become malignant carcinomas and adenomas later in
life.
• Colectomy (removal of colon) prevents development of malignancies
Dr. Alisa Chebotarova, MD, PhD
 NF 1 gene ✮
• NF-1 is a tumor suppressor gene on the
chromosome 17
• NF1 gene encodes a GTP ase-activating protein (GAP)
that accelerates GTP hydrolysis of active GTP-Ras to
inactive GDP-Ras.
• Ras is a signal transducer protein that is active when
bound to GTP. Active Ras promotes cell proliferation.
• Loss of NF1 function (due to mutation) allows ras to
remain in its activated GTP-bound state for an
extended period.

Dr. Alisa Chebotarova, MD, PhD

 Neurofibromatosis 1 (von Recklinghausen
disease)✮

• Neurofibromatosis type 1 is an autosomal dominant disorder, though some

cases result from spontaneous new mutations (no prior family members with the
mutation).
• NF-1 exhibits variable expressivity, because the manifestations (location and
types of neoplasms) are not the same in all patients:
• changes in skin coloring (pigmentation): 6 or more café au lait spots
• 2 or more neurofibromas: the growth of tumors along nerves in the skin, brain, and other
parts of the body.
• Axillary or inguinal freckling
• Optic glioma

Dr. Alisa Chebotarova, MD, PhD

 WT genes
• The WT1 gene provides instructions for making a protein that is necessary for the
development of the kidneys and gonads (ovaries in females and testes in males).
• chromosome 11p13
• The WT1 protein plays a role in cell growth and in apoptosis. To carry out these
functions, the WT1 protein regulates the activity of other genes by binding to
specific regions of DNA. On the basis of this action, the WT1 protein is a
transcription factor.

Dr. Alisa Chebotarova, MD, PhD

 Wilms' tumor ✮
• aka. Nephroblastoma

•  Most common renal malignancy of early childhood

(ages 2–4). Contains embryonic glomerular structures.
Presents with large, palpable, unilateral flank mass
and/or hematuria.

• “Loss of function” mutations of tumor suppressor

genes WT1  or WT2 

Dr. Alisa Chebotarova, MD, PhD

Important oncogenes and associated
tumors

Dr. Alisa Chebotarova, MD, PhD