Chromosome 8p Deletions and 8q Gains are Associated with Tumor Progression and Poor Prognosis in Prostate Cancer

Abstract

Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown.Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization.Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT 2 cancers, 38.5%/9.8% of 379 pT 3a cancers, 43.5%/8.9% of 237 pT 3b cancers, 40.7%/14.8% of 27 pT 4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P < 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P < 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P < 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence.Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56-64. ©2010 AACR.Prostate cancer is the most frequently diagnosed malignancy and the second most frequent cause of cancerrelated death among western males (1).Currently, clinical prediction tools rely solely on clinical (clinical stage), serologic (prostate-specific antigen), and histologic variables (Gleason grading; ref. 2).Because the development and progression of cancer is driven by molecular alterations, the analysis of molecular features may eventually allow better prediction of the behavior of individual cancers.Alterations on the DNA level would be especially suitable as prognostic markers. DNA alterations have the advantage of being less vulnerable to perioperative and postoperative ischemia or fixation procedures than RNA or proteins (3, 4). Deletions of 8p and gains of 8q are among the most frequent genomic alterations in prostate cancer. Several studies have proposed a relationship between 8p−/8q+ with adverse histopathologic findings (5-11). Studies suggesting associations with prostatespecific antigen progression, however, were limited to <100 cancers (12)(13)(14). Whereas considerable evidence points toward a role of chromosome 8 changes in prostate cancer biology, it is also evident that much larger patient cohorts are now needed to further cl...

A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

“…The reduced copy number status of each of these four validated 8p genes was significantly associated with survival (Fig. S6A), which is consistent with previous reports examining the collective impact of 8p loss on survival (4,25) and the fact each gene is invariably codeleted (Fig. S5A).…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…In the past decades several drivers for prostate cancer and progression were identified at the genomic, transcriptional and protein-level [119,[173][174][175][176][177][178][179][180][181][182]. The acquisition of these driver mutations and subsequent tumor progression could either follow a linear pathway or a molecular diversity model as suggested by Rubin et al, 2011 [178].…”

Clinical significance of different types ofp53gene alteration in surgically treated prostate cancer

“…Presence or absence of cancer tissue was validated by immunohistochemical AMACR and 34BE12 analysis. 16 The molecular database attached to this TMA contained results on ERG expression in 9,628, ERG break apart FISH analysis in 6 21 and 3p13 deletions and breakage (FOXP1) in 1,814 tumors. 22 …”

“…We and others have previously described a strong link of PTEN and 3p13 deletion to ERG positivity and of 5q21 and 6q15 deletions to ERG negativity [18][19][20]22 and a high fraction of 8p21 deletion. 21 To estimate whether p53 alterations might be particularly linked to one of these genomic alterations, p53 data were compared with pre-existing deletion data on 3p13 (FOXP1), 5q21 (CHD1), 6q15 (MAP3K7), 8p21 (LPL) and PTEN (10q23) deletions. This analysis revealed a strong association between presence of PTEN deletions and high p53 immunostaining as well as with TP53 deletions if all cancers were analyzed together (p < 0.0001 each), as well as in the subsets of ERGnegative (p < 0.0001 each) and ERG-positive cancers (p < 0.0001 for p53 immunostaining and p 5 0.0007 for TP53 deletion, data not shown).…”