LOSS OF HETEROZYGOSITY. Tumorigenesis , Alfred G. Knudson in the early 1970s. Hereditary retinoblastoma and sporadic tumors had similar molecular mutations involving the retinoblastoma gene. Knudson’s hypothesis Tumor suppressor gene (TSG).
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Tumorigenesis , Alfred G. Knudson in the early 1970s.
Hereditary retinoblastoma and sporadic tumors had similar molecular mutations involving the retinoblastoma gene.
Tumor suppressor gene (TSG).
In the sporadic, nonhereditary situation, normal cells have two functional copies of a wild-type (nonmutated) TSG, one inherited from each parent.
The second genetic hit alters the second copy of the TSG; this hit commonly occurs from larger deletion mutations. It is uncommon for cells to have two large deletion mutations (biallelic deletion).
The cells that harbor two mutated copies of the TSG have a loss of function of the TSG activity, and this contributes to carcinogenesis.
Knudson’s hypothesis AND Familial colon cancer progression.
Many studies have used the deletion of a TSG as a surrogate marker for inactivation of the TSG. Deletions of TSGs can be assessed in several assays. One of the most common is
the loss of heterozygosity (LOH).
INFORMATIVE vs NON INFORMATIVE GENOTYPE
When an individual has inherited two copies of a polymorphism that are different from each other (have different numbers of repeats on each copy), they are said to have an “informative genotype” at that locus.
If an individual is homozygous for the polymorphism, the locus is noninformative and the PCR products will be identical whether both are present or one allele is deleted.
A SINGLE NUCLEOTIDE POLYMORPHISM WITH TWO DIFFERENT ALLELE POSSIBILITIES.
TYPICAL APPEARANCE OF A SINGLE PCR PRODUCT (P) ANALYZED ON CAPILLARY ELECTROPHORESIS
Electropherograms from a normal sample from a patient with an oligodendroglioma. Two different areas of tumor were microdissected, and polymerase chain reaction was performed for a marker on 1p. The two tumor samples show loss of the larger allele (*). The ratio of the peak heights is measured in relative fl uorescent units and given in the box next to each peak. The ratio of the allele heights in the tumor is compared to that in the normal sample to assess for loss of heterozygosity.
(a. NOMENCLATURE FOR DESCRIBING SEQUENCE CHANGES
See www.dmd.nl/mutnomen.html and Den Dunnen and Antonarakis (2001) for full details.
(b. VARIOUS WAYS TO REDUCE OR ABOLISH THE PRODUCTION OF A FUNCTIONING GENE PRODUCT