Genomic instability plays an important role in cancer development by accelerating the accumulation of genetic changes in cancer cells. Several mechanisms can cause genomic instability, including defects in DNA repair pathways like base excision repair, mismatch repair, and double-strand break repair. Loss of function in DNA repair genes like MLH1 and MSH2 can lead to hypermutation and microsatellite instability in colorectal cancer. Other causes include problems with DNA replication, chromosome segregation, and telomere dysfunction. Genetic disorders involving genomic instability include ataxia-telangiectasia, neurofibromatosis type 1, Bloom syndrome, and ring chromosomes.

2. Genomic instability
Genomic instability is a prominent characteristic of most cancer
types that has an essential role in tumorigenesis by accelerating
the accumulation of genetic changes that are responsible for
cancer cell evolution

3. Chromosome Organization

4.  LINEs (Long Interspersed Nuclear Elements)
LINE-1
 SINEs (Short Interspersed Nuclear Elements)
Alu
 Segmental duplications are large blocks of the genome (1000 200,000 nucleotide pairs) that are present at 2 or more locations in
the genome
 Simple sequence repeats : short Tandem Repeats (STR) that are
repeating sequences of 2-6 bp of DNA . microsatellite DNA for
long stretches (arises by unequal crossovers during recombination )
Microsatellite
 Transposons are all mobile genetic elements that have
multiplied in our genome by replicating themselves and inserting
new copies in different positions

5. Main pathways implicated in genomic instability
 Base and nucleotide excision repair
Excise & Repair abnormal bases or
nucleotides, such as UV radiation
induced pyrimidine dimers
* mutations in components of these pathways :
predispose people to skin cancers

7.  Mismatch repair (MMR)
during DNA replication
* Loss of function of MSH2 and MLH1, which are required for mismatch
repair, results in hypermutation and microsatellite instability

8. Colorectal cancer (CRC)
 Microsatellite instability (MSI)
system
 MSI in colorectal cancers (CRC)
deficient mismatch repair
silencing of MLH1
Additional mutations accumulate
Colorectal Cancer: Tumor cells with almost normal karyotype

10.  DNA replication
Deregulated DNA replication
* Deregulation can occur through oncogene activation , loss of certain tumour
suppressors, DNA polymerase inhibition , replication stress

12.  Chromosome segregation
Defects in chromosome segregation :
defects in the mitotic checkpoint , sister chromatid cohesion , spindle geometry
and spindle dynamics
Aberrant chromosome-spindle attachments
missegregation of chromatids
Aneuploid

15.  Double-strand break repair (DSBR)
Homologous recombination repair of
double-strand breaks (DSBs) uses the
sister DNA molecule as a template to
repair the break
important for repair of stalled or
collapsed replication forks

16. HR

17. Ataxia-telangiectasia (A-T)
 autosomal mutations in the ATM gene at gene map locus 11q23
 ATM is activated in response to double-strand DNA breaks
It has a central role in a network of proteins that regulate cellular
responses to DNA damage and recombination

18. NF1
 Autosomal dominant 17q11.2
 Frequency 1:3500
 skeletal deformities
 Predisposition to tumors of nervous
system
 The mutations are deletions, insertions(
Alu ) , base substitutions
 translocation involving the
long arm of chromosome 17 with
breakpoints at 17q11.2 and CpG islands

20. Bloom Syndrome (BLM)
 BLM gene 15q26.1 is a
ReqQ helicase involved in
DNA replication and repair
Helicase
deficiency
 SCE frequency increased
(shows increased chromosome
breaks) – genomic instability
 The hallmark is a tenfold increase in the
spontaneous rate of sister chromatid exchanges
 Breaks in one or both
chromatids and exchanges
between homologous
chromosomes occur in about
1–2% of metaphase cells
 Mainly protein-truncating
nonsense mutations are distributed fairly
evenly along the gene but some missense
mutations exist.

22. Telomers
 Protect chromosome from degradation
 Regulate telomerase activity at chromosome ends
 Essential for chromosome stability

23.  Formed by tandem repeats of TTAGGG sequence
 Bounded by a specialized six-proteins complex known as shelterin
 Elongated by telomerase

25. Telomere dysfunction and genomic instability
 One of the important source of genomic instability is telomere
shortening
deficient of telomerase
deficient of shelterin proteins
loss of the telomere protective structure

26. The molecular mechanisms that related to telomere defects

28. TPE & FSHD
 telomere position effects (TPE) could change gene expression at
intermediate telomere lengths in cultured human cells.
facioscapulohumeral muscular
dystrophy (FSHD)
 FSHD is a late-onset disease genetically residing only 25–60 kilobases from the
end of chromosome 4q
 DUX4, the primary candidate for FSHD pathogenesis, is upregulated over tenfold in FSHD

30. Ring chromosome
1. Two DNA breaks, one in each arm of the same chromosome followed by
fusion of the proximal broken ends
2. By fusion of dysfunctional telomeres (end-terminal part) from the same
chromosome

31.  In R20 a little piece of genetic
material is missing from each
end of one of the number 20
chromosomes and the ends
fuse together to form a ring
 The first symptom of R20 is
usually epilepsy and can start at
any time from day one of life
until 17 years
Normal chromosome 20 and ring
chromosome 20 in an heterozygote
patient

32. Thanks For Your Attention
E-mail : reza_sahebi2001@yahoo.com