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09 - Cancer Genetics

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Medical Genetics
Lecture #09
Cancer Genetics
Ephraim Imhotep Zulu, BSc BMS, MSc Path
University of Zambia
College of Medicine & Health Sciences,
School of Health Sciences,
Dept. of Biomedical Sciences,
Pathology Unit
Synopsis
• Cancer is usually a genetic disease at the cellular level, but not at the wholebody level and
• It results from a series of molecular events that fundamentally alter the
normal properties of cells.
• Loss of control of the cell cycle is one of the critical steps in the development
of cancer.
• In cancer cells the normal control systems that prevent cell overgrowth and
the invasion of other tissues are disabled.
• These altered cells divide and grow in the presence of signals that normally
inhibit cell growth; therefore, they no longer require special signals to
induce cell growth and division.
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Cell Cycle - Overview
In cancer cells genes that control
cell cycle are mutated so cells
divide excessively producing
cancers
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Telomeres
• Telomeres, or chromosome tips, protect chromosomes from breaking. Telomeres
shortens for every cell division.
• Gametes keep their telomeres long thanks to an enzyme, telomerase. Telomerase
moves down the DNA like a zipper, adding six “teeth” (bases) at a time.
• In normal, specialized cells, telomerase is turned off, and telomeres shrink, signaling a
halt to cell division when they reach a certain size. In cancer cells, telomerase is turned
back on. Telomeres extend, and this releases the normal brake on rapid cell division.
• However, turning on telomerase production in a cell is not sufficient in itself to cause
cancer. Many other things must go wrong for cancer to begin.
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Characteristics of Cancer Cells
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The Molecular Basis of Cancer
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Molecular Basis Of Cancer cont.,
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Genetic Basis of Cancer
• Many Genes Contribute to Cancer
• Genes that guide a cell toward the cancerous state when mutant are considered in two
broad categories, based on their effects.
• “Gatekeeper” genes control mitosis and apoptosis, which must be in balance to
maintain the number of cells forming the affected tissue. Their effect is direct.
“Caretaker” genes, in contrast, control the mutation rates of gatekeepers, and may
have the overall effect, when mutant, of destabilizing the genome.
• Most, if not all, cancers are the culmination of a series of changes in several genes,
including gatekeepers and caretakers.
• Most mutations that cause cancer are in oncogenes or tumour suppressor genes or
mismatch mutations in DNA repair genes that allow other mutations to persist.
When such mutations activate oncogenes or inactivate tumour suppressor genes,
cancer results.
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Oncogenes
• Genes that normally trigger cell division when it is
appropriate are called proto-oncogenes.
• They are active where and when high rates of cell
division are necessary
• When proto-oncogenes are turned on at the wrong time
or place, they function as oncogenes (“onco” means
cancer).
• Oncogenes may also block apoptosis.
• As a result, damaged cells do not die, but divide.
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Abnormal activation of a proto-oncogene
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Tumour Suppressor Genes
• Some cancers result from loss or silencing of a gene that normally
suppresses tumour formation by blocking the activities of other genes.
• Such a tumour suppressor gene normally inhibits expression of genes
involved in all of the activities that turn a cell cancerous
• Cancer can result when a tumor suppressor’s control is lifted. This can
happen if the gene has a deletion, or if the promoter region binds too many
methyl (CH3) groups, which blocks transcription.
• Binding of CH3 groups to “CpG islands”—regions in the starts of genes where
the sequence “CG” repeats many times—turns off transcription.
• Such hypermethylation is an epigenetic change, because the mRNA sequence
is unaffected.
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Tumour Suppressor Genes..,
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Some Examples of Tumour Suppressor Genes
GENE
CANCER
CHROMOSOME
ISOLATED
Four of these genes have been widely studied and absence of
their products leads to the development of various cancers
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Tumour Suppressor Genes..,
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Tumour Suppressor Genes..,
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Tumour Suppressor Genes..,
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RB Protein
• The Retinoblastoma (RB), is the first, and prototypic, tumor
suppressor gene discovered.
• RB protein, the product of the RB gene, is a nuclear phosphoprotein
that plays a key role in regulating the cell cycle. RB exists in an active
state in quiescent cells and an inactive state in the G1/S cell cycle
transition.
• The importance of RB lies in its enforcement of G1. Once cells cross
the G1 checkpoint they can pause the cell cycle for a time, but they
are obligated to complete mitosis.
• In G1, however, cells can exit the cell cycle, either temporarily, called
quiescence, or permanently, called senescence.
• In G 1, therefore, diverse signals are integrated to determine whether
the cell should enter the cell cycle, exit the cell cycle and
differentiate, or die. RB is a key node in this decision process.
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p53: Guardian of the Genome
• The p53 gene is the most common target for genetic alteration in
human tumors.
• A little over 50% of human tumors contain mutations in this gene.
• Homozygous loss of p53 occurs in virtually every type of cancer.
• p53 acts as a “molecular policeman” that prevents the propagation of
genetically damaged cells. p53 is a transcription factor that is at the
center of a large network of signals that sense cellular stress, such as
DNA damage, shortened telomeres, and hypoxia.
• If DNA damage can be repaired during cell cycle arrest, the cell
reverts to a normal state; if the repair fails, p53 induces apoptosis or
senescence.
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http://voer.edu.vn/file/54018
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DNA Repair Genes
• A third type of gene associated with cancer is the
group involved in DNA repair and maintenance of
chromosome structure.
• When a DNA repair gene is mutated its product is no
longer made, preventing DNA repair and allowing
further mutations to accumulate in the cell.
• These mutations can increase the frequency of
cancerous changes in a cell.
• A defect in a DNA repair gene called XP (Xeroderma
pigmentosum) results in individuals who are very
sensitive to UV light and have a thousand-fold
increase in the incidence of all types of skin cancer.
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Micro-RNAs
• MicroRNAs are small RNA molecules that act as
“dimmer switches,” blocking translation of certain
genes into proteins by binding to their mRNA
transcripts.
• Because microRNAs normally control the expression
of certain proto-oncogenes and tumour suppressor
genes, when microRNAs themselves have mutations
or their expression is too high or too low, cancer can
result.
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Environmental Causes of Cancer
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References & Credits
• Robert A Weinberg, The Biology of Cancer, 1st Edition
• Alberts, Johnson, Lewis, Raff et al. Molecular Biology of the Cell 4th
Edition
• Robbins SL and Kumar V (2007). Basic Pathology (8th Edition).WB
Saunders Co. London.
• Ricki Lewis (2009) Cell and Molecular Biology Human Genetics:
Concepts and Applications, 9 th
Edition McGraw−Hill Primis,
ISBN−13: 978−0−39−023244−1
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Ephraim Imhotep Zulu
End of Lecture
Medical Genetics
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