CARCINOGENESIS

MUTAGENESIS
Dr. Rasha Fadhel

Cancer
• Cancer is a disease characterized by mutation,
modified gene expression, cell proliferation, and
abnormal cell growth.
• Multiple causes of cancer
1. infectious agents
2. Physical
3. Chemicals
• Estimates suggest that 70% to 90% of all human
cancers have a linkage to environmental, dietary,
and behavioral factors.

Proportions of human cancer deaths attributed to various

factors
 Terminology
• Neoplasia :New growth or autonomous growth of
tissue
• Neoplasm: The lesion resulting from the neoplasia
• Benign: Lesions characterized by expansive
growth, frequently exhibiting slow rates of
proliferation that do not invade surrounding
tissues.
• Malignant: Lesions demonstrating invasive
growth, capable of metastases to other tissues
and organs
 Terminology
• Metastases: Secondary growths derived from
a primary malignant neoplasm.

• Tumor: Lesion characterized by swelling or

increase in size, may or may not be neoplastic

• Cancer: Malignant neoplasm

Terminology
• Carcinogen : A physical or chemical agent that
causes or induces neoplasia.

• Genotoxic carcinogen: Carcinogens that

interact with DNA resulting in mutation.

• Nongenotoxic carcinogen: Carcinogens that

modify gene expression but do not damage
DNA.
 Genotoxic carcinogens

Genotoxic carcinogens are those agents that

interact with DNA to damage or change its
structure, they are frequently mutagenic

Nongenotoxic carcinogens.
Non-genotoxic carcinogens are the agents that
do not directly interact with nuclear DNA.
❖Non-genotoxic carcinogens may:
. Change gene expression
. Modify normal cell function
. Increase the number of cells in the target
tissue

• CHEMICAL CARCINOGENS

Aromatic hydrocarbons
Present in coal tar derivatives and cigarette
smoke Cause lung and skin cancer
Aromatic amines
They are present in aniline dye rubber and cable
industries Responsible for 25% of urinary
bladder cancer

Nitrosamines
Nitrates is present in food as food derivatives
which is converted to nitrosamines by nitrate
reducing bacteria to nitrosamines which causes
UB carcinoma .
Nitrosamines may be present in food and causes
stomach carcinoma.

Asbestos fibers
It can be inhaled and causes bronchogenic
carcinoma . it also can cause mesothelioma of
the pleura
 Arsenic compounds
On chronic exposure may cause skin
cancer

Alkylating agent
(Anti cancer)
Alkylating agents are antineoplastic drugs that
work by inhibiting the transcription of DNA to
RN by alkylation. Alkylation is the process of
adding an alkyl group ( CH3) to DNA. This
process prevents the DNA from being used in
protein synthesis and the production of new
cells, including cancer cells.
Aflatoxins
They are cancerous agent produced by Aspergillus
fungi in grains and nuts which cause hepatocellular
carcinoma

Vinyl chloride
The most important cause of hepatic
angiosarcoma
Hormones and neoplasia
• Individuals with higher circulating estrogen
levels and those with exposure to the potent
estrogenic agent diethylstilbestrol (DES) are at
increased risk of cancer development.

• Like adenocarcinomas of the vagina and cervix in

daughters of women treated with the hormone
during pregnancy.

Hormone dependent neoplasms

• Prostatic cancer : always dependent on

androgens
• Breast cancer is usually dependent(not always )
on hormones
• Well differentiated thyroid cancer is dependent
constantly on TSH
 Proto-oncogenes
An oncogene encodes a protein that is capable of
transforming cells in culture or inducing cancer in
animals.
Activation of proto-oncogenes to oncogenes arises
through mutational events occurring within
proto-oncogenes.

Proto-oncogenes and Tumor-

suppressor Genes
Mutations in both Proto-oncogenes and tumor
suppressor genes contribute to the
progressive development of human cancers.
 Proto-oncogenes and Tumor-
suppressor Genes
✓Retinoblastoma (Rb) Gene—Loss or mutational
inactivation of Rb contributes to the development
of a wide variety of human cancers.

✓p53 Gene—The p53 protein is a tumor-suppressor

gene that promote apoptosis, and therefore would
prevent proliferation of cells that are likely to
accumulate multiple mutations.

✓ BRCA1 Gene -a breast cancer -suppressor gene.

✓ p16 Gene—cyclin-kinase inhibitors proteins play

an important role in cell cycle regulation.
deletions of the p16 gene are common in several
human cancers including a high percentage of
melanomas.

Multistage Carcinogenesis
• The carcinogenesis process involves a series of
definable and reproducible stages.
1. initiation
2. promotion
3. progression
Multistage model of carcinogenesis

Initiation

• The first stage of the cancer process involves

initiation, a process that is defined as a stable,
heritable change.
• This stage is a rapid, irreversible process that
results in a carcinogen-induced mutational
event.
• Chemical and physical agents that interact with
cellular components at this stage are referred to
as initiators or initiating agents.

Initiation
• Initiating agents lead to genetic changes
including mutations and deletions.
• Chemical carcinogens that covalently bind to
DNA that result in mutations are initiating
agents.
 Promotion
• The second stage of the carcinogenesis process
involves the selective clonal expansion of
initiated cells to produce a preneoplastic lesion.

• Following initiation, the initiated cells undergo

promotion, a stage characterized by the
stimulation of cell proliferation. This occurs
through the exposure to promoters, which are
agents that promote the growth and survival of
initiated cells. Promoters may include hormones,
growth factors, and chronic inflammation

Promotion
Tumor promoters
are not mutagenic and generally are not able to
induce tumors by themselves; rather they act
through several mechanisms involving gene
expression changes that result in sustained cell
proliferation through increases in cell
proliferation and/or the inhibition of apoptosis.

Progression
• Progression involves the conversion of benign
preneoplastic lesions into neoplastic cancer.
• In this stage, due to an increase in DNA
synthesis and cell proliferation in the
preneoplastic lesions, additional genotoxic
events may occur, resulting in further DNA
damage including chromosomal aberrations
and translocations.
• The progression stage is irreversible in that
neoplasm formation.
 Mutation
• Mutation is the change in DNA sequence
of a gene can.
• Gene mutations have varying effects on
health, depending on where they occur
and whether they alter the function of
essential proteins.
• The types of mutations include:
• Missense mutation This type of mutation is a
change in one DNA base pair that results in
the substitution of one amino acid for another
in the protein made by a gene.

Mutation
• Nonsense mutation : is also a change in one
DNA base pair. Instead of substituting one
amino acid for another, however, the altered
DNA sequence prematurely signals the cell to
stop building a protein. This type of mutation
results in a shortened protein that may
function improperly or not at all.
 Mutation
• Insertion: changes the number of DNA bases in a gene
by adding a piece of DNA. As a result, the protein
made by the gene may not function properly.

• Deletion: changes the number of DNA bases by

removing a piece of DNA. Small deletions may remove
one or a few base pairs within a gene, while larger
deletions can remove an entire gene or several
neighboring genes. The deleted DNA may alter the
function of the resulting protein(s).

Mutation
• Duplication: consists of a piece of DNA that is
abnormally copied one or more times. This type of
mutation may alter the function of the resulting
protein.
• Frame shift mutation This type of mutation occurs
when the addition or loss of DNA bases changes a
gene's reading frame. A reading frame consists of
groups of 3 bases that each code for one amino acid.
The resulting protein is usually nonfunctional.
Insertions, deletions, and duplications can all be
frame shift mutations.
Mutation