means that three PSA determinations equally spaced
over two years is the minimum testing schedule.
A nonzero PSA velocity is expected in men with
prostate cancer but also in men with BPH, as BPH is
also a progressive process. Because the rate of
release of PSA from hyperplastic prostate tissue is
usually small and that from cancerous prostate tissue
is generally large, the PSA velocity would be
expected to be lower in men with BPH than in men
with tumors. However, in men with PSA concentra-
tions less than 4 µg/L, the PSA velocity in men with
prostate cancer is similar to that in men with BPH
(Carter
et al.
1992). A dramatic increase in PSA
velocity is found in most men with prostate cancer
only after their PSA concentration exceeds 4 µg/L
(Carter
et al.
1992). It appears, therefore, that PSA
velocity does not improve the lead time for detection
of prostate cancer when compared to simple screen-
ing based on a critical PSA concentration of 4 µg/L.
Alternative markers.
The approaches to im-
proving screening performance considered in the
preceding paragraphs do not address the issue that is
often at the heart of the failure of a plasma substance
to serve as a satisfactory screening marker which is
that the would-be marker does not have a high
degree of cancer specificity. Markers that are not
specific for cancer cannot perform well in a setting
in which there is a high prevalence of benign
disease. In such circumstances it is necessary to
identify a screening marker that is more cancer
specific. Usually this entails finding another marker
substance altogether but, in some cases, a certain
form of the original marker can be identified that is
more highly cancer specific. The cancer specificity
of the form may arise from its preferential synthesis
in cancer cells or from some cancer-specific post-
translational modification of the marker. No plasma
substance has yet been found to be more specific for
prostate cancer than PSA.
There is, however, a form of PSA that appears
to be somewhat more cancer specific, protein-bound
PSA (Polascik
et al.
1999). PSA exists in the circu-
lation in four forms: (1) proPSA (Mikolajczyk
et al.
1997), which is the enzymatically inactive precursor
form of PSA, (2) active PSA, (3) nicked PSA,
which is the product of the action of nicking enzyme
on either proPSA or active PSA, and (4) other
degradation products of PSA (Hilz
et al.
1999,
Charrier
et al.
1999). In tissue (Jung
et al.
2000)
and at the time of release into the circulation, all of
these forms of PSA exist as free species. In the
circulation, active PSA is rapidly inactivated by
binding to the plasma protease inhibitors,
α
2
-macro-
globulin and
α
1
-antichymotrypsin. Essentially all of
the circulating active PSA is inhibitor-bound. Both
forms are cleared from the circulation by the liver.
The
α
2
-macroglobulin-bound form is removed very
rapidly (half-life of minutes) while the
α
1
-anti-
chymotrypsin-bound form is removed slowly (half-
life of days). Consequently, even though active PSA
is more avidly bound by
α
2
-macroglobulin than by
α
1
-antichymotrypsin, the
α
1
-antichymotrypsin-bound
form is the predominant plasma form. Nicked PSA
binds very slowly to
α
2
-macroglobulin and not at all
to
α
1
-antichymotrypsin. As a result, it is present in
plasma predominantly in the free form. The other
degradation products, as well as proPSA, are present
entirely in the free state.
It has been found that the percentage of PSA
present in the free state in plasma is lower in
prostate cancer than in BPH. This finding means
that, in prostate cancer, a greater fraction of the
circulating PSA is present in the
α
1
-antichymo-
trypsin-bound form. One way that this could come
about is if the PSA entering the circulation from
cancerous tissue were enriched in the active form.
Then, of that not rapidly eliminated by binding to
α
2
-macroglobulin, most would bind to
α
1
-anti-
chymotrypsin. Alternatively, the release of human
kallikrein 2, the prostatic enzyme that activates
proPSA (Rittenhouse
et al.
1998), could be greater
from cancerous tissue than from BPH, resulting in a
greater fraction of the PSA being activated and
ending up bound to
α
1
-antichymotrypsin. It is
currently not known if these or other mechanisms
explain the clinical findings (Stenman
et al.
1999).
Screening for a genetic predisposition to
cancer.
The development and evolution of cancer
appear to result from an accumulation of genetic
lesions within the cell of origin (Kinzler and Vogel-
stein 1996). These lesions include gain-of-function
mutations of oncogenes, loss-of-function mutations
of tumor-suppressor genes, and loss-of-function
mutations of DNA repair genes (Lynch
et al.
1997).
When a lesion with oncogenic potential is present as
a germline mutation, the total number of somatic
genetic lesions that need to occur for the develop-
ment of cancer is fewer. Consequently, there is an
increased probability that the individual bearing the
mutation will develop cancer. This predisposition
may be predominantly to cancer of a particular organ
or it may be to cancers of several different organs.
Cancer
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