Clinical Cancer Research Vol. 6, 4647-4652, December 2000
© 2000 American Association for Cancer Research
8pter–p23 Deletion Is Associated with Racial Differences in Prostate Cancer Outcome1
Joseph G. Washburn2,
Kirk J. Wojno3,
Jyotirmoy Dey,
Isaac J. Powell and
Jill A. Macoska4
Departments of Surgery, Section of Urology [J. G. W., K. J. W., J. A. M.] and Pathology [K. J. W.], and the Comprehensive Cancer Center [K. J. W., J. A. M.], The University of Michigan, Ann Arbor, Michigan 48109-0946, and Departments of Pathology and Urology [J.D.], Wayne State University, Detroit, Michigan 48202
 |
ABSTRACT
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Deletions of chromosome sequences mapping to the short arm of chromosome
8 have been observed frequently in a variety of human cancers. A small
number of studies have suggested that the terminal portion of the short
arm of chromosome 8, 8pter–p23, may be deleted independently of other
portions of 8p in human tumors, and that deletion of the 8pter–p23
region may be correlated with poor prognosis. The aim of the present
study was to physically define the minimal region of 8pter–p23
deletion and to define the frequency and prognostic significance of
8pter–p23 loss in human prostate tumors. DNA was purified from normal
and tumor tissues of 45 radical prostatectomy specimens and amplified
for 15 highly polymorphic microsatellite sequences, 13 spanning
8pter–p23 and 2 proximal 8p markers. Allelic loss of 8p sequences was
observed in 28 of 45 (62%) tumors examined. Of these, approximately
half (12 of 28; 43%) demonstrated independent loss of the 8pter–p23
region, with several tumors defining a 5-cM minimal region of
deletion spanning D8S264-D8S1824-D8S1781-D8S262-D8S1798.
When serum prostate-specific antigen was used as a surrogate end point
marker for survival, 8pter–p23 loss was significantly associated with
reduced disease-free progression (log-rank P =
0.0426). Moreover, loss of the 8pter–p23 region was significantly
associated with poor survival for American Caucasian (log-rank
P = 0.0024) but not African-American (log-rank
P = 0.5832) prostate cancer patients. These studies
suggest that independent deletion of 8pter–p23 is differentially
associated with disease recurrence and poor outcome in American
Caucasian but not African-American prostate cancer patients.
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Introduction
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Deletions of chromosome sequences mapping to the short arm of
chromosome 8 have been observed frequently in a variety of human
cancers. Most of these studies reported deletion of the 8p22–12 region
(1, 2, 3, 4, 5, 6, 7)
. However, deletion of the 8pter–p23 region
separate from deletion of other portions of the short arm of chromosome
8 has been reported for laryngeal cancers (8, 9, 10)
, renal
clear cell carcinomas (11)
, ovarian tumors
(12)
, and prostate tumors (5
, 13)
. Moreover,
some of these studies have positively correlated deletion of the
8pter–p23 region with poor prognosis (5
, 10)
. On the
basis of these observations, we hypothesized that a minimal common
region of deletion within the 8pter–p23 region could be defined for
prostate tumors, and that deletion of this region might correlate with
disease recurrence using postoperative serum
PSA5
values as surrogate end point markers for survival. We now report the
results of an extensive allelotyping of the 8pter–p23 region in 45
human prostate tumors and the association between loss of 8pter–p23
sequences with tumor pathology, patient demographics, and disease
outcome.
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Materials and Methods
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Determination of Pathological Parameters and PSA Status.
Prostate tissue was obtained after radical prostatectomy from 45
patients diagnosed with prostate cancer. After an initial pathological
evaluation, presumed malignant and normal tissues were snap frozen in
liquid nitrogen and stored at -70°C. The tumor pathological stage
and grade were defined using standard criteria (14
, 15)
.
Tumor specimens comprising areas of at least 70% malignant cells and
nontumor specimens comprising normal benign or hyperplastic epithelium
were serially sectioned. One section was stained with H&E to define
areas of discrete histology. These areas were then microdissected from
adjacent nonstained sections, and DNA was extracted as described
previously (7)
. Postoperative serum PSA values were used
as surrogate end point markers for disease outcome (16
, 17)
. Patients whose postoperative serum PSA values were
undetectable after surgery and remained undetectable thereafter were
classified as disease free. In contrast, patients whose postoperative
serum PSA values were detectable and escalated either immediately after
surgery or at some point thereafter were considered to be in
biochemical progression with persistent or recurrent disease. For the
purposes of statistical analysis, survival was defined as the number of
postoperative disease-free days, i.e., the time until rising
PSA values first became detectable (e.g., biochemical
progression). PSA follow-up data were available for 44 of the 45
patients in this study, with a median follow-up time of 60 months (5
years). Clinical and pathological information for the specimens and
patients included in this study are summarized in Table 1
.
Analysis of DNA for Allelic Loss.
PCR amplification assays targeted 14 sequences containing highly
polymorphic microsatellite repeats at loci of interest on chromosome 8p23. The linkage order of these markers has been reported as:
pter-D8S504-D8S264-D8S1824-D8S1781-D8S262-D8S1798-D8S518-D8S561-D8S277-D8S503-D8S550-D8S265-D8S552D8S261-centromere.
Primer sequences and linkage information were obtained from data bases
maintained by the Human Genome
Database,6
Center for Genome Research at the Whitehead Institute for Biomedical
Research,7
and the National Center for Biotechnology
Information8
as accessed through the Internet. PCR reactions were accomplished as
described previously using 1 µM oligonucleotide
primers and 100 ng of oligonucleotide primer end-labeled with
[
-32P]dATP (7)
. Aliquots of
each reaction were electrophoresed on 6% acrylamide/7
M urea-sequencing gels, and the gels were
autoradiographed (5
, 7)
. Allelic loss was scored by visual
inspection of two independent observers (J. G. W. and J. A. M.)
when the ratio of allelic signal intensities in tumor tissue was 
50%
of that for the same alleles in normal tissue from the same
heterozygous patient.
Statistical Analysis.
For the purposes of statistical analysis, survival was defined as the
number of postoperative disease-free days, i.e., time
until rising PSA values first became detectable (e.g.,
biochemical progression). Kaplan-Meier estimates for the distributions
of outcome, measured as the time to progression, after surgery, were
computed for strata defined by 8p loss status. Log-rank tests for
homogeneity of disease-free survival time distribution across 8p loss
categories were performed both on the entire sample and by race.
P 0.05 was considered to indicate significant
differences in survival distribution across 8p loss categories.
A multivariable Cox proportional hazards regression model was fitted to
the entire data to estimate the effects of pathological tumor stage,
age, race, preoperative serum PSA value, and 8p loss pattern on
survival time, and the significance of each was tested, controlling for
all other variables in the model. A step-down variable selection
procedure, as described by Mantel (18)
, was adopted
to arrive at a final model. Because our primary goal was to assess the
effect of 8p loss patterns on outcome, terms related to such effects
were not considered for deletion from the model at any step. Thus, the
final model consisted of predictors that had a significant effect on
disease-free survival time in the presence of 8p loss terms in the
model.
Two separate approaches were followed to assess the effect of 8p
loss patterns on outcome in a multivariable analysis. In the first
approach, the effect of each 8p loss category, i.e., loss in
the 8pter–p23 region, loss in other parts of 8p, and loss of all
informative 8p loci, compared with no 8p loss was assessed. In the
second approach, the outcome of those with losses in the 8p terminal
arm was compared with the outcome of all other patients in the sample.
Associations among predictors were tested prior to fitting the
multivariable models using suitable t tests and
2 tests. Multivariable analyses following both
approaches, and with 8p loss terms and all other predictors, except
race, that were significant or approached significance in the fit to
the entire set of patients was performed for each race (19)
.
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Results
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Frequency and Distribution of Allelic Losses within 8pter–p23.
Forty-five paired normal and tumor samples from radical prostatectomy
specimens were examined for allelic dosage at 13 loci spanning 0–29 cM
within 8pter–p23 and two loci mapping more proximally,
D8S549 at 31 cM and D8S261 at 39 cM. Twenty-eight
of the 45 tumors examined (62%) demonstrated loss of at least one
locus mapping to 8p. Although the deletion patterns demonstrated by
these 28 tumors were complex, three allelic loss groups, as well as a
minimal common region of deletion, could be discerned. Twelve of the 28
tumors (43%) demonstrated loss of all or part of 8pter–p23 spatially
separate from more proximal loci (designated as 8pter–p23 in Table 2
). Five of these 12 tumors also demonstrated more distal
deletions, but these were not contiguous with the more extensive
proximal region of deletion. Six of the 28 tumors (21%) demonstrated
loss of all 8p loci examined in this study (all 8p; Table 2
), and 10
(36%) demonstrated loss of isolated loci (cases 80, 111, 500, and 210)
or two or more loci spanning both proximal and distal sequences (other
8p; Table 2
). Within the 12 tumors demonstrating loss of all or part of
8pter–p23 spatially separate from more proximal loci, three–504, 520,
and 410–defined the distal boundary of loss at D8S264, and
two–9 and 125–defined the proximal boundary of loss at
D8S1798. Thus, the minimal common region of deletion within
8pter–p23 may be defined by a 5-cM interval spanning loci
D8S264-D8S1824-D8S1781-D8S262-D8S1798. An autoradiographic
example of deletions at the D8S1824 locus is shown in Fig. 1
.
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Fig. 1. Autoradiograph of deletion at the
D8S1824 locus in human prostate tumors. Allelotyping of
paired normal (N) and tumor (T) specimens
from the cases is shown at the D8S1824 locus. The upper
allele is deleted in tumor specimens from cases 408, 410, and 29
(arrow); both alleles are retained in tumor 80.
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Effect of 8pter–p23 Loss and Clinical/Pathological Parameters
on Patient Survival.
For the purposes of statistical analysis, survival was defined as the
number of postoperative disease-free days and ended when rising
postoperative serum PSA values first became detectable
(e.g., biochemical progression). Survival was assessed for
the four patterns of 8p loss observed in the prostate tumors examined:
8pter–p23 loss, loss of other 8p sequences, loss of the entire 8p arm,
and no loss. Log-rank tests indicated a significant difference in
survival among the four groups, with the 8pter–p23 loss group
demonstrating the most rapid rate of biochemical failure over time
(log-rank P = 0.0426; Fig. 2
). This significant difference was maintained when survival of the 8pter
loss group was compared against the other three allelic loss groups
combined (log-rank P = 0.0068; Fig. 2
). Moreover, 50%
of patients whose tumors demonstrated 8pter–p23 loss were in
biochemical failure by 340 days after surgery compared with 1340 days
for all other patients (Fig. 2)
. These findings show that loss of the
8pter–p23 chromosomal region is specifically and significantly
associated with poor disease outcome in prostate cancer patients.
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Fig. 2. Kaplan-Meier survival analysis of 8pter–p23
deletions in human prostate tumors. A, disease-free
survival versus survival time is shown for patients with
tumors deleted for 8pter–p23 (•), all 8p ( ), other 8p
(diamonds) or without 8p deletions ( ). Tumors
with 8pter–p23 deletions are significantly associated with decreased
survival (log-rank P = 0.0426). B,
disease-free survival versus survival time is shown for
the 12 patients with tumors deleted for 8pter–p23 () compared with
all others (•). Tumors with 8pter–p23 deletions are significantly
associated with decreased survival (log-rank P =
0.0068). C, disease-free survival versus
survival time is shown for ACM prostate cancer patients with tumors
deleted for 8pter–p23 (•), all 8p (), other 8p
(diamonds) or without 8p deletions (). Tumors with
8pter–p23 deletions are significantly associated with decreased
survival (log-rank P = 0.0024). D,
disease-free survival versus survival time is shown for
AAM prostate cancer patients with tumors deleted for 8pter–p23 (•),
all 8p (), other 8p (diamonds) or without 8p
deletions (). Tumors with 8pter–p23 deletions are not associated
with decreased survival (log-rank P = 0.5832).
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A multivariable Cox proportional hazards model was fitted to the data
to estimate the effects of pathological tumor stage, patient’s age at
surgery, patient’s race, preoperative serum PSA values, and 8p loss
patterns on survival, and the significance of each was tested,
controlling for all other variables in the model. Because pathological
tumor stage is strongly correlated with combined Gleason score
(Mantel-Haenszel P = 0.002) in our sample, it was
decided not to include both predictors simultaneously in the analysis.
Separate analyses for each indicated that tumor stage was a better
predictor of outcome and hence was preferred over combined Gleason
score.
Following our first approach, a step-down variable selection algorithm
eliminated three predictors in successive steps (model 1; Table 3A
). Of all of the variables in the initial model, patient race was the
least significant predictor of outcome and was not considered further.
Patient age at surgery and preoperative serum PSA, in that order, were
dropped in subsequent fits. As described earlier, the 8p loss pattern
terms were never considered for deletion from the model at any step.
Our final model consisted of pathological tumor stage
(P = 0.014) and 8p loss terms as important predictors
of outcome. Although pathological stage was significant at every step
of the model selection process, the effect of 8pter–p23 loss on
outcome compared with patients with no 8p loss was seen to be
significant only in the absence of preoperative PSA in the model
(P = 0.022). This analysis also estimated that loss of
the 8pter–p23 region, apart from loss of other 8p sequences or loss of
the entire 8p arm, was associated with an estimated 3.36-fold increase
in risk (95% confidence interval, 1.19–9.49) for poor disease outcome
compared with patients with no 8p loss. Similar results were observed
following our second approach (model 2; Table 3B
).
These results are consistent with results obtained from
univariate log-rank tests and Kaplan-Meier survival function estimates
and indicate that loss of the 8pter–p23 chromosomal region may be
specifically associated with poor disease outcome in prostate cancer
patients (Fig. 2)
. Suitable t tests indicated no significant
difference in mean preoperative serum PSA levels between the 8pter–p23
loss group and other patients. Therefore, we attribute the lack of
significance of the effect of 8pter–p23 loss on survival in the
presence of preoperative serum PSA to the differential effect these
variables individually have on outcome for each race.
Although equivalent numbers of ACM (14 of 24; 42%) and AAM (12
of 20; 40%) patients experienced biochemical failure, log-rank tests
indicate that time to failure was significantly associated with
8pter–p23 loss only for ACM patients. Separate multivariable analyses
for ACM and AAM prostate cancer patients were performed to estimate the
effects of pathological stage, preoperative PSA, and 8p loss categories
on survival. Of all variables in the initial Cox model fitted to the
entire data, only these predictors were either significant or
approached significance (Table 3C)
. Loss of the 8pter–p23 region was
seen to be significantly associated with poor survival, compared with
patients with no 8p loss, for ACM (P = 0.006) but not
AAM (P = 0.707) patients (Table 3C)
. On the other hand,
preoperative serum PSA was an important predictor for AAM
(P = 0.042) but not ACM (P = 0.897)
patients (Table 3D)
. This analysis estimated that, for ACM patients,
loss of the 8pter–p23 region conferred a 10.85-fold higher risk (95%
confidence interval, 2.57–45.83) of poor outcome, compared with
patients with no 8p loss. These data suggest that loss of the
8pter–p23 chromosomal region may be specifically and significantly
associated with poor disease-free survival in ACM but not AAM prostate
cancer patients.
The predictive accuracy of our multivariable model selection
procedure suffers because of our small sample size and the not-so-small
set of known and important prognostic factors to be controlled for in a
meaningful assessment of the effect of 8p loss patterns on outcome. The
results of our statistical analyses will require external validation on
other similar patient populations. Further study with a larger sample
of patients, and hence, greater statistical power and more precise
estimates of risk ratios with narrower confidence limits are sought to
confirm our findings.
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Discussion
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In this study, 62% of 45 tumors examined demonstrated loss
of at least one locus mapping on 8p, and almost half of those tumors
(12 of 28) demonstrated independent loss of the 8pter–p23 region. The
highest contiguous frequencies of loss were observed within an
extremely p-terminal 5-cM interval including loci
D8S264-D8S1824-D8S1781-D8S262-D8S1798 which, together,
defined a minimal common region of loss that was deleted independently
of other 8p sequences. This region is almost identical to that reported
by Sunwoo et al. (8)
as the minimal common
region of deletion on 8pter in squamous cell carcinomas of the
larynx and oral cavity spanning loci
D8S264-D8S1806-D8S1824-D8S1781-D8S1788. Using physical
mapping information provided by the Center for Genome Research at the
Whitehead Institute for Biomedical
Research7
and reported by Sun et al.
(9)
, this interval may be described contiguously as
D8S264-D8S1806-D8S1824-D8S1781-D8S1788-D8S262-D8S1798,
with the markers used by both the current study and that of Sunwoo
et al. in bold italic (8)
. This interval
includes an 8pter region described as frequently deleted in
oropharyngeal squamous cell carcinomas by Wu et al.
(20)
and also overlaps with that reported deleted in
squamous cell carcinomas of the head and neck by Ishwad et
al. (21)
. Moreover, homozygous deletions within this
interval have been reported by Ishwad et al.
(21)
spanning D8S1781-D8S262 in three oral
squamous carcinoma cell lines, and by Sun et al. (9)
spanning D8S1824-D8S1788 in four head and neck squamous
carcinoma cell lines. Taken together, these studies suggest that the
interval between D8S264 and D8S1798 likely
contains at least one tumor suppressor gene whose inactivation is
critical for tumorigenesis in the prostate, larynx, and oral cavity.
Previous studies have shown that biochemical progression,or the
development of detectable serum PSA values, within 2 years after
radical prostatectomy predicts distant metastases in 90–93% of cases
(16)
. Moreover, the median actuarial time to death after
the development of metastatic disease is 5 years (17)
.
Therefore, the detection of rising postoperative serum PSA values
serves as a suitable surrogate end point marker for prostate cancer
recurrence and death from metastatic disease. Our laboratory
had reported previously a positive correlation between the deletion of
8pter sequences and biochemical progression (5)
. That
observation was confirmed by the current study, which found that
separate deletion of 8pter–p23 was significantly associated with
decreased survival measured as biochemical progression (log-rank
P = 0.0068). Moreover, 50% of patients whose tumors
demonstrated 8pter–p23 loss were in biochemical progression by
340 days after surgery compared with 1340 days for all other patients.
This conclusion was supported by a Cox proportional hazards analysis of
the data showing that tumor pathological stage (P =
0.013) and 8pter–p23 loss (P = 0.0984) were clearly
associated with poor survival, and that loss of the 8pter–p23
region, apart from loss of other 8p sequences or loss of the entire 8p
arm, was associated with a 2.7-fold increase in risk for poor disease
outcome. Scholnick et al. (10)
have shown that
loss of the 8pter–p23 region, especially of the D8S264
locus, in squamous cell carcinomas of the head and neck is
significantly associated with both a shorter disease-free interval and
reduced disease-specific survival. Our data now show that loss of the
8pter–p23 region, inclusive of the D8S264 locus, in
human prostate tumors is also associated with a shorter disease-free
interval for prostate cancer patients. These studies suggest that loss
of the 8pter–p23 region serves as a marker for poor prognosis and may
inactivate tumor suppressor genes critical for tumorigenesis in at
least two types of human tumors.
A unique feature of the current study is the finding that,
although equivalent numbers of ACM and AAM patients experienced
biochemical progression, loss of the 8pter–p23 region was
significantly associated with poor survival for ACM, but not AAM,
patients by both Kaplan-Meier (log-rank P = 0.0024) and
Cox proportional hazards model (P = 0.006) analysis.
Moreover, this analysis showed that loss of the 8pter–p23 region
conferred a 8.67-fold higher risk for poor survival for ACM patients.
These data suggest that loss of the 8pter–p23 chromosomal region is
specifically and significantly associated with poor disease outcome in
ACM, but not AAM, prostate cancer patients. Recent studies have
suggested that racial differences in the morbidity and mortality
associated with prostate cancer, especially for non-organ-confined
disease, may be based upon genetic and epigenetic differences
(22)
. Our study shows that specific loss of the 8pter–p23
region increases the risk for poor survival for ACM patients, but that
other genetic events likely contribute to poor survival for AAM
prostate cancer patients. Further studies should confirm the prognostic
value of 8pter–p23 loss as a marker for prostate cancer recurrence and
progression and should facilitate the isolation of putative tumor
suppressor genes mapping to this region.
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FOOTNOTES
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by awards from the
Department of Veterans Affairs (to J. A. M.) and NIH Grant
1R29CA60948 (to J. A. M.). 
2 Present address: Department of Genomics,
Esperion Therapeutics, 3621 South State Street, 695 KMS Place, Ann
Arbor, MI 48108.
3 Present address: Department of Pathology, St.
John’s Hospital, 2201 Moross Road, Detroit, MI 48236-2172.
4 To whom requests for reprints should be
addressed, at Department of Surgery, Section of Urology, The University
of Michigan, 7306 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI
48109-0946. Phone: (734) 647-8121; Fax: (734) 647-9480; E-mail: jcoska{at}umich.edu
5 The abbreviations used are: PSA,
prostate-specific antigen; ACM, American Caucasian men; AAM,
African-American men.
6 Internet address: http://www.gdb.org/.
7 Internet address:
http://www-genome.wi.mit.edu/.
8 Internet address:
http://www.ncbi.nlm.nih.gov/.
Received 6/12/00;
revised 10/ 2/00;
accepted 10/ 4/00.
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ABSTRACT
Introduction
