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CHROMOSOMAL ABERRATIONS
à Types of Genetics Aberrations associated with Cancer:
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Chromosomal translocations
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Chromosomal duplications
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Chromosomes:
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3
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5
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Cytogenetic Analysis of Chromosomes:
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3
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Cytogenetic analysis of chromosomes in cancer:
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e
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2
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Subgroups have distinct prognoses (favourable/poor) that
influences treatment type
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3
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This gives an idea of whether the
cancer is still present or has gone into remission
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Analysis allows us to improve the understanding of mechanisms leading to
cancer and also the development of novel treatments
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It is a phenomenon where up to thousands of clustered chromosomal
rearrangements occur in a single event in localised and confined genomic regions in
or a few chromosomes, and is known to be involved in 25% of all bone cancers and
2-3% of cancers overall
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e
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Chromosomal Aberrations:
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§ Therapy with cytotoxic drugs, i
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increased incidence of monosomy 5
(5q-) or monosomy 7 (7q-) AML after treatment with alkylating agents
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e
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e
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e
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The details of
the DNA repair defects are often not known
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2
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A high incidence of chromosome translocations is found in haematological
cancers, i
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liquid tumours (leukaemia’s and lymphoma’s)
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§
Dysregulation of genes leading to aberrant expression of normal
proteins
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CML is an example of a cancer associated with a fusion protein
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It affects pluripotent haemapoietic stem cells (i
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undifferentiated stem
cells) and accounts for 15% of leukaemia’s that can occur at any age
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This cancer is associated with a massive increase in the white blood cell
count, i
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200 x 109 /L vs
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Philadelphia (Ph) Chromosome Formation:
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§ ABL is a 145 Kda non-receptor tyrosine kinase mainly present in the
nucleus
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e
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§ BCR is a 160 Kda cytpoplasmic ser/thre kinase, whose function is
unclear
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These result is a BCR-ABL fusion cytoplasmic protein that is much larger (210)
and has enhanced tyrosine kinase activity, due to the dimerization through a
coiled-coil domain of BCR
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The consequence is increased phosphorylation of tyrosine residues on
cytoplasmic signalling proteins thus promoting cell proliferation and leading
to the malignant cancer phenotype
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Treatment for this translocation is tyrosine kinase inhibition by blocking the
adenosine triphosphate (ATP) binding site of the tyrosine kinase enzyme thus
preventing the phosphorylation of the substrate
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Imatinib is a first generation TKI and is the cheapest TKI in the current
market
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§ Ponatinib – this is an effective TKI against CML but only those with a
T315l mutation in the BCR-ABL region
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Within days, the white blood cell count rapidly returns normal, the frequency
of the Ph chromosome decrease and the BCR-ABL1 transcripts in the blood
decline
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Most patients become transcript negative, and if the transcripts rise, patients
usually respond well to renewed TKI treatment
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This is a translocation caused by the fusion of two genes that are normally on
different chromosomes leading to the formation of a fusion protein
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t(15;17) reciprocal translocation, in which the PML gene on chromosome 15 is
fused to retinoic acid receptor a (RARa) gene on chromosome 17
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PML gene at 15q22 may break at one of the three breakpoints (BCR-1, 2 or 3)
and joins exons 3-9 of RARa gene at 17q22
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Treatment involves trans retinoic acid (ATRA)
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Under normal physiological conditions, RARa is a transcription activator that
normally forms heterodimers with retinoid X receptor protein (RXR)
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The fusion protein fails to respond to normal levels of RA
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This transcription repression results in a cellular phenotype of arrested
differentiation – accumulation of this leads to the development of cancer cells
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However, pharmacological levels of RA overcome the defect and drive
differentiation of the target genes
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Translocation almost always involves an immunoglobulin or TCR, and
most frequently involves Ig heavy chain (IgH) loci on chromosome 14
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Majority of lymphomas possess translocations, i
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Non-Hodgkin
lymphoma’s: 85% involve B cell translocations and 15% involve T or NK
cell translocations
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Rearrangements in the variable region of genes immunoglobins and T cell
receptors leads to the specificity of these proteins for their substrates
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Recombinases join up the adjacent pieces of DNA after excision of
intervening sequences
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Burkitt’s Lymphoma:
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It
causes a massive lymphadenoopathy (swollen lymph nodes), often seen in the
jaw due to an accumulation of unproliferated B cells, and is treated by
chemotherapy
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It is endemic in Africa, where there are prevalent areas with chronic malaria
exposure and Epstein-Barr virus (EBV) infection
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It is also increased with incidence of HIV infection
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Almost all cases of Burkitt’s lymphoma involve over-expression of MYC and is
caused by a reciprocal translocation in the MYC gene on the long arm (q) on
chromosome 8
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Translocation can involve one of three Ig genes, with the most frequent
translocation being t(8;14) of the Ig heavy chain gene on chromosome 14, which
moves the MYC gene to chromosome 14
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Other translocation variants: t(8;2) and t(8;22) leave MYC on chromosome 8 but
place parts of the kappa or lambda Ig light chains next to the 3’ end of the gene
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The consequence of the typical translocation is that the myc protein is expressed
in parts of the cell cycle when it should be switched off
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The translocation event separates MYC from its normal transcriptional promoter
and places it under the control of a highly active transcriptional regulators of an
Ig gene
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This leads to the loss of the normal modulation of MYC expression by
physiological signals – thus, it is constitutively expressed at high levels as
opposed to the tight control
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Initially, following translocation, MYC is structurally normal but subsequently
acquires point mutations
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Myc is a growth promoting transcription factor that: promotes proliferation and
represses differentiation
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It belongs to a family of basic helix-loop-helix transcription factors that act as
heterodimers to modulate the transcription of a large cohort of target genes
possessing E-box sequences
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Myc-Max complexes act to promote transcription, while Mad-Max complexes act
to repress transcription of most target genes
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As cells differentiate, Mad levels increase progressively and Myc is displaced by
Mad, resulting in the disappearance of Myc-Mad complexes, which otherwise
would block differentiation
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Within the cell cycle, Myc activates the activators of the cell cycle in partnership
with Max, i
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into the early G1 phase, and represses the inhibitors in partnership
with Miz-1, i
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once again its effects are felt both in early/mid and late G1
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Translocation therefore continuously pushes the cells through the cell cycle,
leading to constant proliferation and no differentiation – malignant phenotype
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Chronic infection with the Plasmodium parasites induces widespread genomic
instability and promotes AID expression in mature B cells thus increasing the risk
of chromosome translocation
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EBV is a herpes group virus that infects B cells and epithelial cells and has
oncogenic potential
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It is speculated that the virus immortalises B cells driving them to proliferate
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Thus increasing the chances
of translocation events occurring
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Mantel cell lymphoma causes an altered cell cycle like Burkitt’s lymphoma
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2
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Majority of these cancers have
a translocation event: t(14;18) that leads to constitutive expression of the BCL-2
gene, which prevents apoptosis (programmed cell death), thus causing
malignancy
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An example is acute lymphoblastic leukaemia (T-ALL), which involves TCRb locus
on chromosome 7 and the Notch receptor locus on chromosome 9, leading to
the expression of a truncated Notch protein
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This protein is also likely to have activating notch point mutations as the disease
progresses
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Ø But in the last 10 years, with the advent of next generation sequencing, these
translocations are also being identified in solid tumours
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e
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