1. CENETICS OF CANCER
Salwa Hassan Teama
M.D. Clinical Pathology and Oncology
National Cancer Institute/ Cairo/ Egypt
2. Cancer is one of the most common and severe problems of clinical medicine.
Statistics sow that cancer in some form strikes more than one third of the
population, account for more than 20% of all deaths, and, in developed countries,
is responsible for more than 10% of the total cost of medical care.
Cancer is a complex disease that result from the same basic process of
uncontrolled growth. Cell proliferation results in a mass that invades neighboring
tissues and may metastasize to more distant sites. The growth is autonomous,
increasingly malignant, if untreated, invariably fatal. Some cancers, however,
such as blood cancers, do not form tumors.
Tumor formation is a multistep process involving many of genetic changes in the
evolving tumor cell population. Tumors are classified by site, tissue type and
degree of malignancy.
Most cancer are disorders of later life, but some are affect childhood.
3. A tumor is composed of a
parenchyma of proliferating cells,
with a stroma of connective tissue
and blood vessels.
Three main form:
 Sarcoma: Tumor arise from
 Carcinoma: Tumor originate from
 Hematopoietic and lymphoid
malignancies: leukemia and
Different Types of Cancer
4. Nearly all cancers are caused by abnormalities in the genetic material of
the transformed cell.
In order for a normal cell to transform into a cancer cell, genes which
regulate cell growth and differentiation must be altered. When normal
regulation is altered, uncontrolled growth is initiated and a malignant tumor
Genetic changes can occur at many levels, from gain or loss of entire
chromosomes to a mutation affecting a single DNA nucleotide.
New aspects of the genetics of cancer pathogenesis, such as DNA
methylation and microRNAs are increasingly recognized.
The Genetic Nature of Cancer
5.  Cancer is a genetic disorder in which the normal control of cell growth is
lost. The basic mechanism in all cancer is mutation. Carcinogenic agents are
involved through causing mutation.
 The mutation affects genes responsible for cell proliferation, cell development
and other cellular activities.
 Initiation of cancer; cells undergoing a series of genetic mutation or alteration
which result in their instability to respond normally to intracellular/extracellular
signals that control proliferation, differentiation and death.
6. Germline mutations are responsible for 5% to 10% of cancer cases. This
is also called familial cancer. These mutations are present in every cell of
the body and are passed from parent to child.
Sporadic cancer or somatic mutation are caused by tobacco, over-exposure
to UV radiation, and other toxins and chemicals. These mutations are not in
every cell of the body and are not passed from parent to child.
7. Randomly acquired through errors in
Inherited and thus present in all cells
from birth. The heritability of cancers
are usually affected by complex
interactions between carcinogens and
the host's genome.
Carcinogens, such as tobacco smoke,
radiation, chemicals, or infectious
agents (Viruses are involved in
Causes of Cancer
8. There is strong evidence that a tumor is a clone of cells derived from a single ancestral
cell in which the initiating events has taken place. However the clonal origin of tumor
does not imply homogeneity among cancer cells, since further genetic change and
microenviromental influences occur during tumor growth lead to heterogeneity in a wide
variety of the properties of the individual tumor growth.
The Clonal Nature of Cancer
9. Many aspects of cell function are controlled by a balance of positive and
negative signals from inside and outside the cell. In normal tissues, there is a
balance between cell proliferation and cell death. In tumor, this balance is lost
because of genetic defect that lead to faulty cell signaling or to imbalance of
molecules that stimulate (cyclin and cyclin dependent kinases) or inhibit
(cyclin dependent kinases inhibitors) the movement of cells around the cell
10.  The risk of cancer shows significant variation among different
population in different environment. The risk must depend on
exposure to carcinogens in the environment.
e.g. Industrial cancer which result from prolonged exposure to
carcinogenic chemicals as cancer of the skin in tar workers,
cancer of the bladder in aniline dye workers,…..
Cancer and the Environment
11. Source: Wikipedia
Source: National Cancer Institu
12. Cancer develops when several genes in a cell
become mutated in a way that overrides the
checks and balances of the cell. However, many
cancers cannot be tied to a specific gene, and
some genes may interact in unpredictable ways
with other genes or factors in the environment to
13. Oncogenes are known by three letter abbreviation which reflect their origin
or the type of tumor with which they are associated.
Cancer-promoting oncogenes: If oncogene is altered or overexpressed, either
as a result of a mutation in the gene itself or by altered external control, the
cell in which the change occurred can undergo uncontrolled growth,
eventually malignant. Most oncogenes are mutated forms of normal genes,
14.  Oncogenes were identified initially in cancer causing viruses (DNA/RNA
 The first confirmed oncogene was discovered in 1970 and was termed src.
Src was in fact first discovered as an oncogene in a chicken retrovirus.
Experiments performed by Dr. G. Steve Martin of the University of
California, Berkeley demonstrated that the Src was indeed the oncogene
of the virus. The first nucleotide sequence of v-src was sequenced in 1980
by A.P. Czernilofsky et al. Many of the viral oncogenes (v-onc) have
homologous cellular counterparts (c-onc) known as proto-oncogenes.
 The study of retroviral oncogene functions has provided insights into the
role of cellular proto-oncogenes.
15. Proto-oncogene is a normal gene that can become an oncogene due to
mutations or increased expression.
Proto-oncogenes code for proteins that help to regulate cell growth and
differentiation. Proto-oncogenes are often involved in signal transduction and
execution of mitogenic signals, usually through its protein product.
Types of Proto-oncogenes
Cellular oncogenes (c- oncogenes): proto-oncogene which have been to
mutate in any individual.
Normal oncogene (n- oncogene): proto-oncogenes that have not been found
16.  These are typical cellular genes with typical control sequences. As
 Most have introns.
 They are always at same place in genome.
 No LTR sequences.
 They show normal Mendelian inheritance because they are normal
genes, essential to the functions of the cell
 Cellular oncogenes are expressed by the cell at some period in the life of
the cell, often when the cell is growing, replicating and differentiating
normally. They are usually proteins that are involved in growth control
 Cellular oncogenes are highly conserved.
Characteristic of Cellular Proto-oncogene
17. Point mutations
 Deletions, or insertions that lead to hyperactive gene product.
 Deletions, or insertions in the promoter region of a proto-oncogene that
lead to increased transcription.
Gene amplification events leading to extra chromosomal copies of a proto-
oncogene lead to normal protein greatly overproduced. Amplified segments
of DNA are often detected as two types of cytogenetic change, double
minute and homogeneously staining regions.
 Relocation of a proto-oncogene to a new chromosomal site that leads to
 Fusion between a proto-oncogene and a second gene, which produces a
fusion protein with oncogenic activity.
Activation of Proto-oncogene
19. Oncogene can be classified according to their cellular location and function
of their encoded oncoproteins in the signal transduction pathway:
 Growth factors
 Growth factor receptors
 GTP binding proteins
 Post receptor tyrosine kinase
 Cytoplasmic oncogenes
 Nuclear oncogenes
 Apoptotic oncogenes
Types of Oncogenes
20. Most oncogenes are dominant mutations; a
single copy of this gene is sufficient for
expression of the growth trait.
This is also a "gain of function" mutation
because the cells with the mutant form of
the protein have gained a new function not
present in cells with the normal gene.
21. Tumor suppressor gene or anti oncogene: Normal genes implicated in the
control of cell cycle, repair DNA mistakes, and tell cells when to die (apoptosis
or programmed cell death). The product of tumor suppressor genes normally
block abnormal growth and malignant transformation and lead to malignancy
when the function of both alleles is lost. When tumor suppressor genes don’t
work properly, cells can grow out of control, which can lead to cancer.
In contrast to mutations in proto-oncogene, which are dominant in their action,
most mutation in tumor suppressor genes are recessive.
Tumor Suppressor Gene
22.  Genes that control cell division Some tumor suppressor genes help control cell growth
and reproduction. e.g. retinoblastoma gene (RB1). Abnormalities of the RB1 gene can
lead to a type of eye cancer (retinoblastoma) in infants, as well as to other cancers
 DNA repair genes: These are genes that fix any mistakes made when DNA is replicated
(copied). Mistakes that aren't fixed become mutations, which may eventually lead
cancer. e.g. Genes responsible for HNPCC (hereditary nonpolyposis colon cancer).
When these genes do not repair the errors in DNA, HNPCC can result.
 Cell "suicide" genes e.g. p53.
23. p53 located human chromosome 17,
gene with tumor suppressor activities.
 p53 protein contains 393 amino acids and
a single amino acid substitution can lead to
loss of function of the gene. Mutations at
amino acids 175, 248, and 273 can lead to
loss of function and changes at 273 (13%)
are the most common.
 About 50% of human cancers can be
associated with a p53 mutation including
cancers of the bladder, breast, cervix,
colon, lung, liver, prostate, and skin
 p53 related cancers are also more
aggressive and have a higher degree of
 These all act as recessive mutations.
24. Inherited Abnormalities of Tumor Suppressor Genes have been found in several cancers that
tend to run in families.
 Mutations in p53, RB1, and the genes involved in HNPCC, .
 A defective APC gene causes familial polyposis a condition in which people develop
hundreds or thousands of colon polyps, some of which may eventually acquire several
sporadic mutations and turn into colon cancer.
 Abnormalities of the BRCA genes account for 5% to 10% of breast cancers.
Non-inherited mutations of tumor suppressor genes
 Acquired mutations of the p53 gene appear to be involved in a wide range of cancers,
including lung, colorectal, and breast cancer, as well as many others.
 Acquired changes in many other tumor suppressor genes also contribute to the development
of sporadic (not inherited) cancers
25.  Several close (first or second degree) relatives with a common cancer.
 Several close relatives with related cancers. e.g. breast and ovary or
bowel and endometrial cancer.
 Two family members with the same rare cancer
 An unusually early age of onset
 Bilateral tumors in paired organs
 Synchronous or successive tumors
 Tumors in two different organ systems in one individual
Feature Suggestive of an Inherited Cancer Susceptibility Syndrome in Families
26.  The heritability of cancers are usually affected by complex interactions between
carcinogens and the host's genome
 The level of risk for persons with a family history of one of the common cancers
such as bowel or breast cancer depends on a number of factors. These include
the number of person at risk to the affected individuals and the age at which
the affected family members develop cancers,…
 The presence of an oncogene in a germ line cell (egg or sperm) results in
an inherited predisposition for tumors in the offspring. However, a single
oncogene is not usually sufficient to cause cancer, so inheritance of an
oncogene does not necessarily result in cancer.
 Persons at risk of an inherited cancer susceptibility can be screened for
associated features of a familial cancer predisposing syndrome or for
Inherited Susceptibility for the Common Cancers
27. Cancer is Multistep Process
Cancer is multistep process
28.  The gene defective in the chromosome instability syndrome may be viewed as cancer
genes. The enzymes defective in these syndromes must be intimately involved in DNA
repair and maintenance of chromosome integrity.
 Chromosome instability syndromes are a group of inherited conditions associated
with chromosomal instability and breakage. They often lead to an increased tendency to
develop certain types of malignancies.
The following chromosome instability syndromes are known:
 Ataxia telangiectasia
 Ataxia telangiectasia-like disorder
 Bloom syndrome
 Fanconi anaemia
 Nijmegen breakage syndrome
Chromosome Instability Syndrome
Many viruses infect humans but only a few viruses are known to promote
human cancer. These include both DNA viruses and retroviruses, a type of
Viruses associated with cancer include human papillomavirus (genital
carcinomas), hepatitis B (liver carcinoma), Epstein-Barr virus (Burkitt's
lymphoma and nasopharyngeal carcinoma), human T-cell leukemia virus (T-
cell lymphoma); and, probably, a herpes virus called KSHV (Kaposi's sarcoma
and some B cell lymphomas).
Virus and Cancer
30. Viruses can also contribute to cancer by inserting their DNA into a
chromosome in a host cell.
 Insertion of the virus DNA directly into a proto-oncogene may
mutate the gene into an oncogene, resulting in a tumor cell.
 Insertion of the virus DNA near a gene in the chromosome that
regulates cell growth and division can increase transcription of that
gene, also resulting in a tumor cell.
 Human papillomavirus makes proteins that bind to two tumor
suppressors, p53 protein and RB protein, transforming these cells
into tumor cells.
DNA Tumor Viruses
31. Source: Wikipedia
Cancer is a genetic disorder in which the
normal control of cell growth is lost. The basic
mechanism in all cancer is mutation, either in
the germ line or much more frequently, in
somatic cells. Cancer is multi-factorial diseases,
much remains to be learned about the genetic
processes of carcinogenesis and about he
environmental factors that alter DNA and thus
lead to malignancy.