Mutations are changes in genetic material that can be caused by errors in DNA replication or by exposure to mutagens. There are several types of mutations including substitutions, insertions, deletions, and chromosomal mutations. Mutations can have varying effects, from being harmless to causing genetic disorders or cancer. Carcinogenesis is the process by which normal cells are transformed into cancer cells through a series of mutations that disrupt the balance between cell proliferation and cell death.

1. An Introduction to “Mutations”
and “Carcinogenesis”
Presented By:
Jay Prakash Soni (MC-PhD/2017/03)
Department of Med. Chem. NIPER Hyderabad
MC-PhD/2017/03 1

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 The sequence of bases in DNA are like the letters of a coded message
 What would happen if a few of those letters changed accidentally? altering the original
message?
 What effects we can predict if such changes happen to on a genes and the polypeptides for
which they code?
 The cells make mistakes in
copying their own DNA:
Inserting the wrong base or
skipping a base as a strand
putting together
 These variations are called
mutations; Latin word “mutare”
meaning “to change”
 Mutations are heritable
changes in genetic information
“Mutations”

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“Mutations-Types”
 Those that produce changes in a single gene are known as gene mutations
 That produce changes in whole chromosomes are known as chromosomal mutations
 GENE MUTATIONS: Substitution, Insertion and Deletion (Point and Frameshift Mutation)
 Mutations that involve changes in one or a few nucleotides are known as point
mutations; They occur during replication at any single point in the DNA sequence
 If a gene in one cell is altered, the alteration passed on to every cell that develops from
the original one

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 SUBSTITUTIONS: usually affect single amino acid and sometimes they don’t have any effect
 INSERTIONS AND DELETIONS: If a nucleotide is added or deleted, the bases are still read in
groups of three, but now those grouping shift in every codon that follows the mutation
 They are also called Frameshift Mutations; they shift the “reading frame” of the genetic
message
 Frameshift mutations can change every amino acid that follows the point of the mutation
and can alter a protein so much that it is unable to perform its normal functions
“Gene Mutations”

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Chromosomal Mutations involve changes in the number or structure of chromosomes
 These mutations can change the location of genes on chromosomes and can even change
the number of copies of some genes
 Deletion, Duplication, Inversion and Translocation
 Deletion involves the loss of all or part of a chromosome
 Duplication produces an extra copy of all or part of a chromosome
 Inversion reverses the direction of parts of a chromosome
 Translocation occurs when part of one chromosome breaks off and attaches to another
“Chromosomal Mutations”

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“Nondisjunction”
 Failure of chromosomes to separate during meiosis; Causes gamete to have too many or
too few chromosomes

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“Causes for Mutations or Mutagens”
 Physical mutagens include some forms of electromagnetic radiation, such as ionizing
radiation X-rays produces oxidative damage and non-ionizing radiation ultraviolet light
produces dimerization of base pairs
 Chemical mutagens include alkylating agents, nitrogen base analogs, nitrous acid,
pesticides, a few natural plant alkaloids, tobacco smoke and organic solvents
(formaldehyde, benzene, carbon tetrachloride)
 Error in cell division includes DNA replication or Nondisjunction

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“Mutations-Effects”
 The effects of mutations on genes vary widely; some have little or no effect, some produce
beneficial variations, some even can negatively disrupt gene function
 Mutations are often thought of as negative because they disrupt the normal function of
genes; However, without mutations, organisms cannot evolve, because mutations are the
source of genetic variability in a species
 Harmful effects: Harmful mutations are those that dramatically change protein structure or
gene activity; The defective proteins produced by these mutations can disrupt normal
biological activities and result in genetic disorders
 Beneficial effects: Some of the variation produced by mutations can be highly
advantageous to an organism or species; Mutations often produce proteins with new
or altered functions that can be useful to organisms in different or changing environments;
For example, mutations have helped many insects resist chemical pesticides, Some
mutations have enabled microorganisms to adapted to new chemicals in the environment

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“Mutations of Haemoglobin”
 Haemoglobin is a tetramer unit consisting of 2-α and 2-β polypeptides chains
 The β-chain gene is found on chromosome 11 and α-chain gene is found on chromosome 16
 Several inherited mutations occur on the β-chain (146 amino acids)
Sickle Cell HaemoglobinNormal Cell Haemoglobin

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Mutation Codon
Change to DNA
sense strand
Change in
Amino Acid
S (Sickle Cell) 6 GAG to GTG Glu to Val
C (Cooleys
Syndrome)
6 GAG to AAG Glu to Lys
GSan Jose 7 GAG to GGG Glu to Gly
E 26 GAG to AAG Glu to Lys
MSaskatoon 63 CAT to TAT His to Tyr
MMilwauki 67 GTG to GAG Val to Glu
OArabia 121 GAA to GTA Glu to Val
Mutations on the β-chain of Haemoglobin (146 amino acids)

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 Sickle cell disease is a disorder associated with changes in the shape of red blood cells
from round shape to long and pointed cells with symptoms like anemia, severe pain,
frequent infections, and stunted growth
 Disease is caused by a point mutation in one of the polypeptides found in hemoglobin
Blood smear (normal) Sickle cell anaemia
Codon: GAG to GTG
AA: Glu to Val
 Cystic fibrosis is a life-threatening disease caused by genetic defect that causes a thick
buildup of mucus in/around the lungs, pancreas, and other internal organs
 In the lungs the mucus clogs the airways making it difficult to breathe

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 Double eyelashes is caused by a transcription error on the
16th chromosome; This trait is considered dominant so if one
of the parents have this mutation then there is a 75% chance
the offspring will also have Double eyelashes
 Down syndrome also called trisomy 21; Is genetic disorder
caused by the presence of all of a part of a third copy of the
21st chromosome
 Duchenne muscular dystrophy is caused by a defect on a
specific gene on the X chromosome, which affects the
production of a certain protein called dystrophin; lower levels
of dystrophin production cause muscle cells to become fragile
and easily damaged
 Plant and animal breeders often make use of “good”
mutations; when a complete set of chromosomes fails to
separate during meiosis, the gametes that result may produce
triploid (3N) or tetraploid (4N) organisms (Polyploidy); which
are often larger and stronger than diploid plants; ex. Banana
and limes
Double eyelashes
Duchenne muscular
dystrophy

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 Color Blindness an partial or inability to see all colors;
The variation of a gene on the X-chromosome is
responsible for disorder
 In most cases the miscoded gene prevents the proper
development of the structures in the eye called cones;
which transmit color information to the optic nerve

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“Carcinogenesis/Oncogenesis/tumorigenesis”
 Carcinogenesis is the process by which a normal cell is transformed
into a malignant cell and repeatedly divides to become a cancer
 Cancers or tumors may also caused by a series of mutations; Each
mutation alters the behavior of the cell somewhat
 Normally the balance between proliferation and programmed cell
death (apoptosis) is maintained to ensure the integrity of tissues and
organs
 Upsetting the normal balance between proliferation and cell death
results in uncontrolled cell division and the evolution of those cells by
natural selection in the body (Mutations)
 Certain mutations lead to cancer whereas the others do not
 Chemicals which initiate the process are called chemical carcinogens
while the chemicals which increase the effectiveness of carcinogens
is called co-carcinogens

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 Cancer is a disease of regulation of tissue growth; alteration of genes that regulate cell
growth and differentiation may results in a transform of normal cell to a cancer cell
 Oncogenes may be normal genes that are expressed at inappropriately high levels or
expression of altered genes that have novel properties promotes the malignant phenotype
of cancer cells
 Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of
cancer cells; which are often disabled by cancer-promoting genetic changes
 Mutations or changes in the nucleotide sequence of genomic DNA
 Epigenetic changes that alter the genes expression
 Aneuploidy is the presence of an abnormal number of chromosomes (either gain or loss of
one or more chromosomes)
 Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small
chromosomal region containing one or more oncogenes and adjacent genetic material
 Translocation occurs when two separate chromosomal regions become abnormally fused
often at a characteristic location
Causes for Generation of Cancer Cells

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DNA damage is considered to be the primary cause of cancer
 It may be due to endogenous cellular processes or
can be arise from exposure to exogenous agents
 Example: Tobacco smoke causes lung cancer
due to increased DNA damage; UV light
causes melanoma; H. pylori infection
produces high levels of reactive oxygen
species that contributes to gastric cancer; The
Aspergillus metabolite i.e. aflatoxin is a DNA
damaging agent causing liver cancer;
Macrophages and neutrophils in colonic
epithelium produces ROS which initiate
colonic tumorigenesis; High levels of bile
acids in the colons damage DNA and
contribute to colon cancer

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Biological properties of a cancer cell
 Acquisition of self-suficiency in growth signals,
leading to unchecked growth
 Loss of sensitivity to anti-growth signals, also
leading to unchecked growth
 Loss of capacity for apoptosis, in order to allow
growth despite genetic errors and external
anti-growth signals
 Loss of capacity for senescence, leading to
limitless replicative potential (immortality)
 Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of
passive nutrient diffusion
 Acquisition of ability to invade neighboring tissues, the defining property of invasive
carcinoma
 Acquisition of ability to build metastases at distant sites, the classical property of malignant
tumors (carcinomas or others)
 Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic
instability), thus accelerating all the other changes

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Carcinogen
Inactive productReactive intermediate
DNA adduct DNA mutation Cancer
Error free DNA
DNA repair
Metabolism
Carcinogenesis - Mechanism

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Risk factors for cancer
 There are many risk factors for cancer: age, family history, viruses and bacteria, lifestyle,
contact with harmful substances/chemicals found in everyday items such as foods,
personal products, packaging, prescription drugs, and household
 Asbestos, Arsenic, Benzene, Beryllium, Vinyl chloride, Nitrogen mustard,
Nitrosomethylurea, Benzyl chloride Chloroform and DDT are well known chemical
carcinogens
Cells Respond to Chemical Injuries

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Chemical or Drug Associated Neoplasms
Alkylating agents (cyclophosphamide, melphalan) Bladder, leukemia
Inorganic arsenicals Skin, liver
Azathioprine (Immunosuppressive drug) Lymphoma, reticulum cell sarcoma
Chlornaphazine Bladder
Chloramphenicol Leukemia
Diethylstibesterol Vagina (clear cell carcinoma)
Estrogens
Premenopausal
Postmenopausal
Liver cell adenoma
Endometrium
Methoxypsoralen with ultaviolet light Skin
Oxymetholone Liver
Phenacetin Renal pelvis (carcinoma)
Phenytoin Lymphoma, neuroblastoma
Chemicals or Drugs Associated with Cancer