title: Interphase cytogenetics of prostatic tumor progression: specific chromosomal abnormalities are involved in metastasis to the bone.
abstract: 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 the 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.
authors.affiliation: Department of Pathology, Erasmus University Rotterdam, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Alers
authors.forename: P J
authors.initials: PJ
authors.lastname: Krijtenburg
authors.forename: C
authors.initials: C
authors.lastname: Rosenberg
authors.forename: W C
authors.initials: WC
authors.lastname: Hop
authors.forename: A M
authors.initials: AM
authors.lastname: Verkerk
authors.forename: F H
authors.initials: FH
authors.lastname: Schröder
authors.forename: T H
authors.initials: TH
authors.lastname: van der Kwast
authors.forename: F T
authors.initials: FT
authors.lastname: Bosman
authors.forename: H
authors.initials: H
authors.lastname: van Dekken
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary*; D002869:Chromosome Aberrations / Q000235:genetics* / Q000473:pathology*; D025063:Chromosome Disorders; D002898:Chromosomes, Human, Pair 8; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D006801:Humans; D017403:In Situ Hybridization; D007399:Interphase / Q000235:genetics*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D004273:DNA, Neoplasm