Molecular cytogenetic analysis of prostatic adenocarcinomas from screening studies : early cancers may contain aggressive genetic features

Abstract

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Figure 1.

Chromosomal ideograms showing the summary of DNA copy number changes, detected by CGH, in tumors of 52 patients with different tumor volumes. Losses are displayed on the left of the ideogram, gains are shown on the right. A: Small cancers (T_v < 0.5 ml; n = 13), showing loss of 6q, 13q, and Y, as well as gain of 20q. B: Intermediate cancers (T_v between 0.5–1.0 ml; n = 23), displaying loss of 5q, 6q, 8p, 16q, 18q, and Y. C: Large cancers (T_v > 2.0 ml; n = 16), revealing recurrent loss of 5q, 6q, 8p, 13q, and Y and frequent gain of 3q, 7pq, 8q, 9q, and Xq sequences.

Figure 2.

Comparison of the chromosomal aberrations between small, intermediate, and large prostate cancers, showing the average number (± SEM) of altered chromosomes per patient. The average number of aberrant chromosomes per patient significantly increased with increasing exact tumor volume (R_s = 0.36, P = 0.009). The same was true for the number of chromosomes showing loss or, especially, gain per case (R_s = 0.27, P = 0.05; R_s = 0.48, respectively; P < 0.001).