LOSS OF HETEROZYGOSITY
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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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LOSS OF HETEROZYGOSITY

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Loss of heterozygosity

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).


Loss of heterozygosity

  • In the sporadic, nonhereditary situation, normal cells have two functional copies of a wild-type (nonmutated) TSG, one inherited from each parent.

  • Two Hit Model

  • One copy of the TSG develops an inactivating mutation and is termed the first genetic hit.

  • can also be inherited in cancer syndromes that make patients susceptible to tumors.

  • REMEMBER

  • 1st hit alone not enough for tumorigenesis

  • WHY????

  • What you think TSGs

  • Recessive or

  • Dominant

  • (Think before you speak)


Loss of heterozygosity

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.


Loss of heterozygosity

  • Knudson’s hypothesis AND Familial colon cancer progression.

  • In this classic model, germline mutations in the familial adenomatouspolyposis gene (APC, on chromosome 5q21) are inherited as the first hit, and somatic mutations (usually deletions) in the second copy of the APC gene represent the second hit.

  • The colonic adenoma–to–carcinoma pathway is probably one of the best-studied examples of tumorigenesis using a tumor suppressor pathway.

  • Dysplasia

  • Neoplasia

  • In fact, TSGs have been implicated as being a part of tumorigenesis in nearly every type of sporadic tumor.


Loss of heterozygosity

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.


Loss of heterozygosity

A SINGLE NUCLEOTIDE POLYMORPHISM WITH TWO DIFFERENT ALLELE POSSIBILITIES.


Loss of heterozygosity

A TETRANUCLEOTIDE UNIT THAT IS HETEROZYGOUS OR INFORMATIVE


Loss of heterozygosity

APPEARANCE OF MONO, DI AND TETRANUCLEOTIDE STRs


Loss of heterozygosity

TYPICAL APPEARANCE OF A SINGLE PCR PRODUCT (P) ANALYZED ON CAPILLARY ELECTROPHORESIS


Loss of heterozygosity

LOH ANALYSIS OF NORMAL CELLS (A) AND TUMOR CELLS (B)


Loss of heterozygosity

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.


Loss of heterozygosity

ASSIGNMENT

(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


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