Genomic deletion of chromosome 12p is an independent prognostic marker in prostate cancer

Abstract

Deletion of 12p is a recurrent alteration in prostate cancer, but the prevalence and clinical consequences of this alteration have not been studied in detail. Dual labeling fluorescence in situ hybridization using probes for 12p13 (CDKN1B; p27) and centromere 12 as a reference was used to successfully analyze more than 3700 prostate cancers with clinical follow-up data assembled in a tissue microarray format. CDKN1B was selected as a probe because it is located in the center of the deletion, which spans > 10 Mb and includes > 50 genes in 80% of cancers with 12p deletion. Deletion of 12p was found in 13.7% of cancers and included 13.5% heterozygous and 0.2% homozygous deletions. 12p deletion were linked to advanced tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), rapid tumor cell proliferation (p < 0.0001), lymph node metastasis (p = 0.0004), and biochemical recurrence (p = 0.0027). Multivariate analysis including pT stage (p < 0.0001), Gleason grade (p < 0.0001), pN status (p = 0.0001), preoperative PSA levels (p = 0.0001), and resection margin status (p = 0.0001) revealed an independent prognostic value of 12p deletion (p = 0.0014). Deletion of 12p was unrelated to the ERG fusion status. Deletion of 12p was only marginally linked to reduced p27 expression, which by itself was unrelated to clinical outcome. This argues against p27 as the key target gene of 12p deletions. In summary, the results of our study demonstrate that 12p deletion is frequent in prostate cancer and provides independent prognostic information. 12p deletion analysis alone, or in combination with other prognostic parameters may thus have clinical utility.

13q deletion is linked to an adverse phenotype and poor prognosis in prostate cancer

“…Our findings identify 13q deletion as a genomic alteration that is largely unrelated to ERG‐status. Using the same set of cancers we have previously identified a few other deletions, including loss of 12p and 8p that are unrelated to the ERG status.…”

“…Our scoring criteria for deletion analysis in TMA sections had earlier been validated by comparison of PTEN FISH and aCGH copy number data from a previous study in our lab . Furthermore, these scoring criteria had been successfully used to analyze other deletions in our prognosis TMA . In comparison with these studies 13q deletion is the third most frequent genomic alteration after TMPRSS2:ERG fusion (52%) and deletion of 8p (36%) being equally frequent as deletions of 16q23 (21%) …”

“…This result is typical for deletions in prostate cancer. Using our large TMA resource we have studied deletions of PTEN , 3p, 5q, 6q, 16q, 8p, 18q, and 12p and found that all of these deletions are linked to an adverse tumor phenotype. Although the role of PTEN and CHD1 for 10q and 5q deletions is well established in prostate cancer, we strongly believe that most of these deletions might harbor more than 1 tumor relevant gene.…”

“…Depending on the chromosomal area deletions occur in up to 40% of prostate cancers . All chromosomal deletions that were analyzed in large cohorts of prostate cancers were found to be associated with advanced disease and early recurrence . Interestingly, most chromosomal deletions are strongly linked to either ERG‐negative or ERG‐positive cancers .…”

5q21 deletion is often heterogeneous in prostate cancer

“…Homozygous deletions are rare in prostate cancer. FISH studies of thousands of tumors have failed to reveal any homozygous deletions in 8p, 6q, 12p, 18q, and 17p13 15,[32][33][34][35]. It is likely that essential genes in these chromosomal areas are required for the survival of neoplastic prostatic epithelial cells.…”