This document discusses genomic instability and its relationship to cancer development. It defines genomic instability as an increased rate of DNA alterations and describes some of the causes, including exposure to radiation, chemicals, and viruses. Genomic instability can lead to diseases like cancer through mechanisms like microsatellite instability (MSI). MSI occurs due to variations in short repetitive microsatellite DNA sequences and is commonly observed in certain cancer types. It can result from errors in DNA replication or defects in DNA damage repair pathways. Defects in these pathways are also associated with hereditary cancers like Lynch syndrome. The document outlines several methods for detecting MSI and discusses how telomerase dysfunction relates to cancer development through shortening of telomeres and genomic instability.
Microsatellite instability testing is an important part in diagnostics in Metastatic cancer settings after the FDA has given approval for tissue agnostic indications in almost all solid cancers. MSI by PCR and MMR status by IHC is also helpful for evaluation of genetic risk in Colon and Endometrial cancers
Microsatellite instability testing is an important part in diagnostics in Metastatic cancer settings after the FDA has given approval for tissue agnostic indications in almost all solid cancers. MSI by PCR and MMR status by IHC is also helpful for evaluation of genetic risk in Colon and Endometrial cancers
Introduction
Etiology of cancer
Genetic and molecular basis of cancer
The cell cycle
Pathology of cancer
Tumor origin
Tumor characteristics
Invasion and metastasis
Diagnosis and staging
Screening
Diagnosis
Staging and workup
Its about cancer biology where it includes characteristics features of cancer, hallmarks of cancer, protooncogenes oncogenes, tumor suppressor genes, chromosomal translocation, oncogenic viruses, cellular transformation to induce cancer, molecular basis of diagnosis of cancer, development of cancer, carcinogenes, types of cancer, mutation in developing cancer, prevelance of cancer, conversion of proto-oncogenes to oncogenes, oncogene in human cancer, oncogene fusion protein, oncogene activation by chromosomal translocation, BRCA1 and BRCA2, p53, oncogene targeted drugs, CAR-T-cell therapy, Immunotherapy, Monoclonal antibodies.
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Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
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2. Genomic Instability
• Genomic instability refers to an increased rate of
alterations in the DNA sequence of an organism's
genome.
• It can be caused by a variety of factors, including
exposure to radiation, chemicals, and viruses.
• Genomic instability can lead to various diseases,
including cancer and genetic disorders.
• There are different types of genomic instability,
including chromosomal instability, microsatellite
instability, and.
• Understanding genomic instability is crucial
3. Cont…
• Microsatellites and Minisatellites are
repeating DNA sequences found throughout
the human genome.
• They are important for various cellular
processes, including DNA replication,
recombination, and repair.
• However, instability in these sequences can
lead to the development of cancer.
4. Microsatellites
• Microsatellites are short, repetitive DNA
sequences that consist of 1-6 base pairs.
• They are located in both coding and non-
coding regions of the genome.
• Microsatellite instability (MSI) occurs when
there are variations in the number of repeats
in these sequences.
5. Minisatellites
• Minisatellites are longer, repetitive DNA
sequences that consist of 10-60 base pairs.
• They are primarily located in non-coding
regions of the genome.
• Like microsatellites, instability in minisatellites
can lead to cancer development.
6. Difference
MICROSATELLITES DNA MINISATELLITES DNA
The repeat size of microsatellites in a
hypervariable family in 1-4 base pairs
The repeat size of minisatellites in a
hypervariable family is 10-60 base pairs
The most commonly repeated base is
adenine (A) and cytosine (C)
They share a common core sequence
GGGCAGGANG, where 'N' is any base
The sequence is dispensed throughout
the genome.
Dispersed the sequence mainly in the
core
7. MSI and Cancer
• MSI is commonly observed in certain types of
cancer, including colorectal, gastric, and
endometrial cancers.
• MSI can be either sporadic or hereditary, with
the latter being associated with Lynch
syndrome.
• MSI can lead to cancer development by
altering the expression of genes involved in
cell growth and proliferation.
8. Mechanisms of MSI
• Several mechanisms can cause MSI, including
errors in DNA replication, defects in DNA
mismatch repair, and defects in DNA damage
response pathways.
• These mechanisms can lead to alterations in
the number of repeats in micro- and
minisatellites, resulting in MSI.
9. Errors in DNA Replication
• Errors during DNA replication can result in
slippage, which is the addition or deletion of
nucleotides in micro- or minisatellites.
• Slippage can occur due to misalignment of the
DNA strands during replication, resulting in a
new repeat unit being added or deleted.
• This can lead to MSI if the number of repeats
in the sequence is altered.
10. Defects in DNA Mismatch Repair
(Muts + MutL = Exonuclease)
• DNA mismatch repair (MMR) is a process that
corrects errors that occur during DNA
replication.
• MMR is responsible for detecting and
repairing base-pair mismatches, insertion-
deletion loops, and other DNA lesions.
• Defects in MMR can lead to MSI, as errors in
the number of repeats in micro- and
minisatellites are not corrected.
11. Defects in DNA Damage Response
Pathways
• DNA damage response pathways are responsible
for detecting and repairing damaged DNA.
• Defects in these pathways can result in the
accumulation of DNA damage, including errors in
micro- and minisatellites.
• This can lead to MSI if the errors are not
corrected or if cells with MSI are not eliminated
by the immune system.
12.
13. Lynch Syndrome
• Lynch Syndrome is a genetic condition that
increases the risk of developing certain types
of cancer, especially colon and rectal cancer.
• It is an inherited condition caused by
mutations in DNA mismatch repair genes,
which can result in errors in DNA replication
and lead to the development of tumors.
• Lynch Syndrome is also known as Hereditary
Nonpolyposis Colorectal Cancer (HNPCC).
14. • Lynch Syndrome is usually diagnosed based on
family history, genetic testing, and a colonoscopy
to detect any abnormal growths in the colon.
• Symptoms of Lynch Syndrome include abdominal
pain, diarrhea, constipation, and blood in the
stool.
• Lynch Syndrome can also increase the risk of
developing other types of cancer, including
endometrial, ovarian, pancreatic, and gastric
cancer.
15. Detection of MSI
• MSI can be detected using various methods,
including polymerase chain reaction (PCR),
DNA sequencing, and immunohistochemistry.
• MSI testing is routinely performed in certain
types of cancer to determine prognosis and
guide treatment decisions.
17. Functions of telomere
• Telomeres prevent erosion of
coding DNA
• Telomeres prevent genomic
instability
• Telomeres regulate the lifespan
of cells
• Telomeres maintain the structure
and stability of chromosomes
• Telomeres regulate gene
expression
18. Dysfunction of Telomerase
• Telomerase is an enzyme that maintains the
length of telomeres, the protective caps at the
ends of chromosomes
• Telomerase dysfunction is a common feature
of cancer cells
• In this presentation, we will explore the link
between telomerase dysfunction and cancer
19. • Telomerase dysfunction can lead to shortening of
telomeres, which can result in genomic instability
• Genomic instability can cause DNA damage,
mutations, and chromosomal abnormalities,
which can contribute to the development of
cancer
• Telomerase dysfunction can also activate cell
signaling pathways that promote cell growth and
survival, which can also contribute to cancer
development
20. • Telomerase dysfunction is commonly found in
cancer cells
• Telomerase activation allows cancer cells to
maintain telomere length and continue to divide
indefinitely, which is a hallmark of cancer
• Inhibition of telomerase can induce telomere
shortening and trigger cell death, making
telomerase an attractive target for cancer therapy
21. Telomerase Dysfunction and Cancer
Types
•Breast cancer
•Prostate cancer
•Lung cancer
•Colorectal cancer
•Pancreatic cancer
•Telomerase dysfunction is also found in
some rare cancers, such as certain types of
sarcomas and gliomas
22. Methods can be used to identify telomerase dysfunction
in cells and tissues:
• Telomere length analysis: Telomerase dysfunction can
result in telomere shortening, which can be measured
using techniques such as Southern blotting, qPCR, or flow
cytometry.
• Telomerase activity assays: Telomerase activity can be
measured using a variety of assays, such as the TRAP assay
or the qPCR-based telomeric repeat amplification protocol
(qPCR-TRAP).
• Telomerase gene expression analysis: Telomerase
dysfunction can result from changes in the expression of
telomerase genes, such as TERT or TERC. Gene expression
analysis techniques, such as RT-PCR or microarray analysis,
can be used to detect such changes.
23. Conclusion
• Telomerase dysfunction is a common feature of
cancer cells that contributes to genomic
instability, cell growth and survival
• Telomerase is a potential target for cancer
therapy, and telomerase inhibitors are currently
being developed as anticancer agents
• Further research on telomerase and its role in
cancer development is needed to fully
understand its potential as a therapeutic target.