DESCRIPTION: (Applicant's Description)
Radiation and chemotherapy are mutagenic towards germ cells of experimental
animals and cause genetic disease in their offspring. However, in humans
the assessment of the mutagenic effects of these therapies has been limited
by the low frequency of mutations, small numbers of offspring, and limited
follow-up of offspring. To overcome such difficulties, genetic changes at
the highly mutable DNA repeat loci (mini- and microsatellites) directly in
the DNA of individual sperm cells from men exposed to radiation or
chemotherapeutic drugs will be measured. Efficient detection of DNA
sequence mutations in individual cells is now possible with a novel method
called the small-pool polymerase chain reaction (SP-PCR). DNA from up to
100 sperm is amplified at a repeat locus by PCR, separated in one lane by
electrophoresis, and analyzed for bands representing individual mutant
sperm. Thousands of sperm can be screened in one experiment and mutation
frequencies as low as 0.2 percent can be accurately determined.
The objective of this pilot study is to test the hypothesis that DNA repeat
loci in humans are very sensitive to the induction of repeat number
mutations by genotoxic agents. The mutation frequencies in sperm will be
measured by SP-PCR. A longitudinal study design will be employed. Semen
samples will be obtained from patients after radio or chemotherapy, and the
mutation frequencies will be compared with those obtained before treatment.
If elevations are observed after therapy, additional samples will be
obtained to determine whether there are changes in the mutation frequency
The study population includes men with Hodgkin's disease, seminoma, and
chronic myelogenous leukemia who receive alkylating or non-alkylating agent
chemotherapy or radiotherapy. Mutation analysis will be performed at the
mini-satellite M5205, M532, and CEB1 loci and at the microsatellite
trinucleotide repeats associated with the myotonic dystrophy and Huntington
disease loci and the androgen receptor gene.
The results will be used to compare the mutagenic potentials of different
cancer treatment regimens and determine whether the mutagenic effects are
persistent or decline with time; eventually these data may be used for
estimation of mutagenic risks. This information would be extremely valuable
in the reproductive counseling of long-term survivors of cancer therapy.
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