Transcript 5th Module, 2nd Lecture

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TRANSLOCATIONS AND CANCERS
Dr Gihan Gawish
Cytogenetic
Translocations Generate Novel Chromosomes
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Translocations are more often associated with
negative consequences such as aneuploidy,
infertility, or cancer.
Translocations are indeed common in cancer cells,
and some translocations produce oncogenes that
are responsible for malignant transformation.
Dr Gihan Gawish
Classify
Translocations by
Karyotypes
Chromosome translocations.
a) An idiogram of a
reciprocal translocation
between chromosomes
12 and 17.
b) b) An ideogram of a
Robertsonian
translocation between
chromosomes 14 and
21.
Copyright 2002 Nature Publishing
Group, Braude, P.,
et.
al.,
Preimplantation
genetic diagnosis,
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Nature Reviews Genetics 3, 941-953
Dr Gihan Gawish
Metaphase cells from an untreated acute myelogenous leukemia (AML) patient
were analyzed using Multi-Color FISH to Scan for Translocations analysis
Rearrangements are caused
by
•translocations (t),
•deletions (del),
•dicentric chromosomes (dic).
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Dr Gihan Gawish
Translocation Carriers Face
Reproductive Issues
Conclusion: Gametes resulting from
adjucent-1 and adjusent-2 segregation are
nonviable because some genes are present
in two copies whereas others are missing
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Dr Gihan Gawish
Translocations and Cancers
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Depending on the chromosome breakpoints, a translocation can
result in the disruption or misregulation of normal gene function.
These molecular rearrangements, in many cases, are considered
to be the primary cause of various cancers.
clinical cytogeneticists have been able to link specific
chromosome breakpoints to clinically defined cancers, including
subtypes of leukemias, lymphomas, and sarcomas.
Virtually all of the translocations observed in tumors have
arisen through somatic mutations, so these are not inherited in
families.
Dr Gihan Gawish
Translocations Can Produce Oncogenes
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Copyright 2001 Nature Publishing Group, Rowley, J. D. Chromosome translocations: Dangerous liaisons revisited, Nature Reviews Cancer 1, 245-250
Figure 4 : The consequences of recurring chromosome translocations.
a) In some lymphomas and leukemias, chromosome translocations lead to the juxtaposition of
promoter/enhancer elements from one gene (gene A, purple) with the intact coding region of
another gene (gene B, red). b) By contrast, translocations seen in CML and many of the acute
leukemias result in recombination of the coding regions of two different genes. This results in a
fusion protein that might have a new function. This is the case for theDr BCR-ABL
fusion protein that is
Gihan Gawish
encoded by the Philadelphia chromosome.
Translocations Can Produce Oncogenes
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Figure 4a, the translocation places the coding sequence of
one gene (Gene B) in proximity to the regulatory sequence
for a different gene (Gene A). The first translocation of
this kind to be described was a translocation involving
chromosomes 8 and 14 in patients with Burkitt's lymphoma.
This particular translocation places the MYC protooncogene from chromosome 8 under the control of the
powerful immunoglobin heavy chain gene (IGH) promoter
on chromosome 14. The MYC protein normally signals for
cell proliferation, and the translocation causes high levels
of MYC overexpression in lymphoid cells, where the IGH
promoter is normally active.
Dr Gihan Gawish
Translocations Can Produce Oncogenes
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In other cancers, translocations fuse the coding sequences of two genes together
to generate potent oncogenes (Figure 4b). An example of historic interest is the
Philadelphia chromosome, which was initially identified as a minute, or
unusually small, chromosome in patients with chronic myelogenous leukemia
(CML). With the advent of chromosome banding techniques, Janet Rowley was
able to show that the Philadelphia chromosome was actually a product of a
reciprocal translocation involving small segments at the ends of the q arms of
chromosomes 9 and 22 (Rowley, 1973). Subsequent molecular analyses
involving multiple laboratories revealed that the translocation fused the coding
sequence of the BCR (breakpoint cluster region) gene on chromosome 22 with
the coding sequence of the ABL gene on chromosome 9. The BCR-ABL fusion
protein encoded by the chimeric gene is a protein tyrosine kinase that
constitutively activates signaling pathways involved in cell growth and
proliferation. Knowledge of this particular breakpoint has led to a successful
treatment for CML, because investigators were able to use the sequence
information to overexpress and crystallize the BCR-ABL protein, which in turn
led to the development of drugs that inhibit this protein's activity.
Dr Gihan Gawish
Detect Translocations Help in good
Prognosis for Cancer
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Hundreds of translocations have now been linked to
cancer, and this information has been catalogued and is
freely available online to cytogeneticists. The database
continues to grow as investigators uncover new links
between genes, chromosomes, and cancer. It is interesting
to consider that approximately one century has elapsed
since Theodor Boveri predicted that growth-stimulatory
chromosomes were present in cancer cells. Scientists
continue to identify new molecular rearrangements that
occur in cancer, with the hope that this information will
translate into new treatments for a devastating disease.
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Dr Gihan Gawish