Genomic instability can occur at both the chromosomal and nucleotide levels and plays an important role in cancer development. Chromosomal instability results in gains and losses of whole chromosomes and structural changes, while instability at the nucleotide level is caused by defects in DNA repair pathways like mismatch repair and base excision repair. Many mechanisms help maintain genomic stability during cell division, including DNA repair pathways, epigenetic modifications, telomere protection, and proteins like ATM, ATR, BRCA1 and BRCA2. Cancer arises through a multi-step process as mutations accumulate in single cells, allowing their uncontrolled growth and proliferation into malignant tumor masses.

1. GENETICIN STABILITY AND ITS ROLE IN CANCER
ARUN PATEL
M.Sc Biotechology
MD UNIVERSITY(Rohtak)

2. Genomic instability
• Genomic instability is defined as a process prone to genomic changes or an increased
propensity for genomic alterations.
• This term encompasses diverse genetic changes, which can be classified in a variety
of ways. For simplicity we will categorize them into two major groups, instability
occurring at the chromosomal level and at the nucleotide level.
• Instability at the nucleotide level occurs due to faulty DNA repair pathways such as
base excision repair and nucleotide excision repair and includes instability of
microsatellite repeat sequences (MSI) caused by defects in the mismatch repair
pathway.
• The second form or chromosomal instability (CIN), defines the existence of
accelerated rate of chromosomal alterations, which result in gains or losses of whole
chromosomes as well as inversions, deletions, duplications and translocations of large
chromosomal segments.
• During cell division, genomic instability is associated with the failure of parental
cells to accurately duplicate the genome and precisely distribute the genomic material
among the daughter cells.

3. Major mechanisms to maintain genomic stability during
the cell cycle

4. • What is chromosomal instability?
• A state of continuous formation of novel chromosome
mutations, at a rate higher than in normal cells.
• Result in gains or losses of whole chromosomes as
well as inversions, deletions, duplications and
translocations of large chromosomal segments.

6. Chromosomal Instability
Chromosomal breakage Numerical instability Structural chromosomal
instability instability
• Side effect?

8. DNA repair defects
 Mismatch Repair and Microsatellite Instability
Nucleotide Excision Repair
Base Excision Repair

9. Mismatch repair system: A system that increases the accuracy of
DNA synthesis by an additional two to three orders of magnitude.
This system faces 2 challenges:
(1) Rapidly find the mismatches/mispairs and repair before second
round of replication
(2) Accurately correct the mismatch
• Defective MMR results in
mirosatellite instability (MSI),
characterized by the expansion
or contraction of the number
of tandem repeats, due to
polymerase slippage at the
many microsatellite loci that
occur throughout the genome.

10. Nucleotide Excision Repair
• Damaged regions of DNA unwind and are removed and by
specialized proteins; new DNA is synthesized by DNA
polymerase.

11. Base Excision Repair
• Responsible for repairing damage induced by endogenous
metabolic processes such as methylation, deamination,
reactive oxygen species (ROS) and hydrolysis.
• Multiple proteins contribute to BER pathway and enable it to
correct non-bulky damaged nucleotides, abasic sites as well as
single-strand breaks.

12. Role of Epigenetic Modifications in
Genetic Instability
Methylation in Tumourigenesis
• DNA methylation or the covalent modification of the C-5
position of cytosine residues occurs primarily at the short
stretches of CG dinucleotides known as CpG islands.
Histone modification

13. The role of the environment in genetic
instability
• Role of tumour microenvironment in genetic
instability- tumour microenvironment may
represent in mammalian cells a conserved
evolutionary mechanism that increases the rate of
mutation in response to cellular stresses, which
preferentially gives cancer cells a survival
advantage

14. Involvement of BRCA1 and BRCA2 in
maintaining genomic stability
• BRCA1 and BRCA2 gene products are involved in
repair of DNA damage and control of genomic
integrity .
• Both proteins co-localize with the recombination and
repair protein RAD51, with BRCA2 binding RAD51
directly, and both proteins have been implicated in
repair of DNA double strand breaks.

15. ATM and ATR
• The products of the ATM gene (mutated in ataxia
telangiecasia) and ATR (ataxia telangiecasia and RAD3
related) play a key role in a damage response network
activating a number of different pathways.

16. Role of telomeres and telomerase in genomic
instability
• IMPORTANCE OF TELOMERE END PROTECTION
o Telomeres serve at least three essential functions:
(1) protecting natural chromosomal DNA ends from being
inappropriately recognized as double-stranded breaks
(DSBs) and therefore initiating an inappropriate DNA
damage response (DDR)
(2) protecting chromosomal ends from inappropriate
enzymatic degradation and
(3) Preventing chromosomal end-to-end fusions.

17. • TELOMERE DYSFUNCTION-INDUCED CELLULAR
SENESCENCE AS A TUMOR SUPPRESSOR
MECHANISM
• ROLE OF TELOMERES AND TELOMERASE IN TUMOR
INITIATION AND PROGRESSION

19. Genomic instability — an evolving
hallmark of cancer

20. How cancer arises
• Disease in which a group of abnormal cells grow
uncontrollably by disregarding the normal rules of cell
division.
• Normal cells are constantly subject to signals that dictate
whether the cell should divide, differentiate into another cell
or die. Cancer cells develop a degree of autonomy from these
signals, resulting in uncontrolled growth and proliferation.
• If this proliferation is allowed to continue and spread, it can
be fatal.
• In fact, almost 90% of cancer-related deaths are due to
tumour spreading – a process called metastasis.

21.  Cancer is clonal in origin
• cancer is a multi-gene, multi-step disease originating from a
single abnormal cell (clonal origin) with an altered DNA
sequence (mutation).

22. Clonal expansion. Normal cells are subject to signals that regulate their proliferation
and behaviour. All cancers disrupt normal controls of cell proliferation & for each cell there is a
finite number of ways this disruption can occur. Cancer cells develop a degree of autonomy
from external regulatory signals that are responsible for normal cellular homeostasis. Multiple
mutations lead to a tumour mass. Subsequent mutations lead to malignant tumour which
break through the basal membrane and spread to distant locations