In search of better methods
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October 2000 William Check, PhD
Even as physicians seek the place of HPV testing in the detection of cervical
neoplasia, newer potential adjuncts to Pap cytology are emerging.
"I think there is going to be a better answer than HPV testing along the lines
of a novel cellular marker," predicts Dr. Elizabeth Unger, acting chief of the
Human Papillomavirus Section, Centers for Disease Control and Prevention. Only
a small fraction of HPV infections transform into oncogenic processes. A downstream
cellular marker might specifically identify infections that are most likely
to proceed to neoplasia. Using gene expression arrays, Dr. Unger is searching
for cellular changes in a population with well-characterized HPV types and variants.
A group in Germany, she says, has found that a tumor suppressor gene, p16INK4a,
is upregulated in some cervical lesions. The German group further discovered
that p16INK4a disinhibition is actually a surrogate for activity of E7, an HPV
protein known to be crucial to transformation. "The advantage of measuring a
cellular gene such as p16INK4a," Dr. Unger says, "is that the same effect will
be seen for all HPV types." Protein E7 differs among HPV types. There is evidence
that immunostaining for p16INK4a helps identify CIN3 lesions on Pap cytology
slides.
Another innovation is HPV testing by polymerase chain reaction. Roger A. Hubbard,
PhD, director of molecular pathology and president and CEO of Molecular Pathology
Laboratory, Maryville, Tenn., notes that HPV testing was started more than 10
years ago, but early kits were incomplete. "HPV testing only came back into
widespread use with the advent of Digene’s Hybrid Capture II kit," Dr. Hubbard
says.
"Now we are trying to be more specific in phenotyping HPV," he adds. Hybrid
Capture II segregates HPV types into high-risk and low-risk groups. "The cocktail
approach is better than nothing, but I don’t think it’s going to be adequate
in the long run," Dr. Hubbard says. "Different HPV types vary dramatically in
their oncogenic potential. Using PCR, we are categorizing which HPV types are
present in cells obtained during cervical sampling."
HPV viral load, measured by PCR, may also be an independent predictor of progress
to cervical lesions and cervical cancer. "What I foresee," Dr. Hubbard says,
"is a risk matrix in which HPV type and viral load are considered along with
cervical cytology."
Viral load and viral type probably will not be clinically useful in the short
term. "But viral load and HPV type will eventually be important in terms of
individual frequency of followup and therapy," Dr. Hubbard predicts. Only a
small proportion of women who have persistent infections with oncogenic HPV
types develop cervical cancer. Determining the HPV type may help identify which
patients will progress.
William Check, PhD
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