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Lecture 6

Bio of Cancer Lecture 6


Department
Biology
Course Code
BIOL 4010
Professor
Samuel Benchimol
Lecture
6

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Biol 4010 Lecture 6 10/25/2010
Review
Rb first hit is inheriting a mutation from one parent
2nd hit we want to have a bi-allelic mutation
Rb behaves as a recessive gene
inactivating mutation that is inherited
2nd Hit:
1. point mutation on remaining wild type allele
independent mutation
2. independent deletion
small internal deletion (3 codon to a bunch of exons)
point mutation (frameshift) leading to truncations
chromosomal deletions
3. mutations that disrupts expression
compound heterozygote 2 different mutations targeting the same
gene
4. Chromosome loss
5. epigenetic silencing
allelic conversion results in the same mutation

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non-disjunction the chromosomes do not move to the poles
equally, so the mutation chromosome goes to one cell and gets
duplicated (this is what is most commonly seen in Rb)
LOH showed that it was the complex mechanism and not the simple
mechanism (deletion, chromosome loss, etc) that occurs in the
body
gene conversion can give rise to loss of heterozygosity although
more rare
hemizygous one allele that has a mutation, affecting its function
Loss of heterozygosity (LOH)
to do a LOH, you need a probe and you need to know where the
probe maps on the chromosome
probe is pYNZ22 is polymorphic, mapped to chromo 17 short arm
has no functional significance, its just a useful marker used to
distinguish variant DNA
DNA was digested with BamHI and probe hybridized to DNA using
Southern blot
need normal and tumor DNA from the same patient

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probe must detect polymorphism (at least 2 distinct bands) in
normal cell
in patient 1, the C and N gels look the same no LOH
the number of probes gives you more information, to identify
whether a deletion is taking place, etc
in patient 2, one of the alleles is lost
normal tissue or lymphocytes are in the lanes that have residual
bands due to impurity
adenoma does not show loss of DNA, reveals loss of DNA is a late
step of tumor generation
renal cell carcinoma [cancer of kidney]
they used diff probes that have been mapped, can identify
microsatellites which are more informative and more common
in the genome (highly polymorphic in the human population)
need DNA from normal and tumor tissue from same patient
probe 4 and down --> no loss of heterozygosity
we suspect there's a tumor suppressor gene, and it maybe
lies between probe 1-3
look for smallest region of overlap between patients helps
define where the tumor suppressor gene may lie
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