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Janneke C.
Alers, Pieter-Jaap Krijtenburg, Carla Rosenberg, Wim C. J. Hop, Annet M.
Verkerk, Fritz H. SchrAdoder, Theodorus H. van der Kwast, Fre T. Bosman,
and Herman van Dekken |
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Departments
of Pathology (JCA, PJK, THvdK, HvD), Epidemiology and Biostatistics (WCJH),
and Urology (AMV, FHS), Erasmus University Rotterdam, and Department of
Pathology (CR), Dr. Daniel den Hoed Cancer Center, Rotterdam, and Department
of Cytochemistry and Cytometry (CR), Leiden University, Leiden, The Netherlands;
and Department of Pathology (FTB), University of Lausanne, Lausanne, Switzerland |
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Only limited data are available
on chromosomes specifically involved in the multistep tumorigenesis of prostate
cancer. To investigate the cytogenetic status at different stages of prostatic
tumor development, we have applied interphase in situ hybridization (ISH)
with a set of (peri) centromeric DNA probes--specific for chromosomes 1,
7, 8, and Y--to routinely processed tissue sections of prostatic specimens
from 75 different individuals. Our panel consisted of: 16 normal/benign
prostatic hyperplasia specimens; 23 primary, localized, prostatic tumors
(N0M0 stage); 20 regional lymph node metastases (M0 stage); and 16 distant
metastases. Numerical aberrations of at least one chromosome were not observed
in normal/benign prostatic hyperplasia cases, but were present in localized
tumors (39%), regional lymph node metastases (40%), and distant metastases
(69%). Within the different pTNM groups, we observed the following aberrations
(listed, within each series, in decreasing order of frequency): -Y, +8,
-8, +7 in primary tumors; +8, +7, -Y, +Y, -8 in regional lymph node metastases;
and +8, +7, +1, -Y, -8 in distant metastases. In primary tumors, the number
of aberrant cases increased significantly with local tumor stage (p <
0.05). A significant increase in gain of chromosome 8 was also observed
(p < 0.02). Gain of chromosome 7 and/or 8 showed a significant increase
with progression of local tumor stage (p < 0.02). Specific involvement
of chromosome 8 was seen in bone metastases, but not in hematogenous metastases
to other sites (p = 0.02). Comparative genomic hybridization analysis of
these bone metastases disclosed centromere 8 gains as amplifications of
the (whole) 8q arm, whereas centromeric loss appeared to be due to loss
of 8p sequences. With progression toward metastatic disease, an accumulation
of genetic changes was seen as exemplified by gain of chromosome 1, which
was solely observed in distant metastases. With tumor progression, gain
of chromosomes 7 and/or 8 significantly increased (p = 0.03), whereas he
number of cases with aberrations of the Y chromosome did not change. Furthermore,
ploidy status determined by ISH revealed a significant increase in the number
of aneuploid cases along with advancement of pTNM stage (p = 0.04). Collectively,
the data strongly suggest that: (a) gain of chromosome 7 and/or 8 sequences
is implicated in prostatic tumor progression; (b) gain of chromosome 8 sequences
is related to local tumor growth; (c) overrepresentation of 8q sequences,
most likely by isochromosome 8q formation, is involved in metastatic spread
to the bone; and (d) changes in the centromeric copy number, as detected
by interphase ISH, might in some cases represent structural alterations,
such as an isochromosome. |
