The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p < 0.0001 each) and positive surgical margin (p 5 0.0004). 16q Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p < 0.0001), and was linked to other ERG-associated deletions including phosphatase and tensin homolog (PTEN) (p < 0.0001) and 3p13 (p 5 0.0303). In univariate analysis, the deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p < 0.0001). Tumors with codeletions of 16q and PTEN had a worse prognosis (p 5 0.0199) than those with PTEN or the deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low-and intermediated grade prostate cancers.Prostate cancer is the most frequent malignancy in men. The clinical behavior ranges from slowly growing indolent tumors to highly aggressive and metastatic cancers. Based on the results of large autopsy studies-demonstrating a high prevalence of prostate cancers also in men who never experienced symptoms of the disease during their life time-it is estimated that a significant fraction of prostate cancer patients may be manageable without surgery and its associated severe side effects.1 It is hoped that a better understanding of the molecular features underlying prostate cancer development and progression will substantially improve the prediction of the clinical course of prostate cancer patients.Chromosomal rearrangements are a major mechanism for activating and inactivating oncogenes and tumor suppressor genes in cancer. In contrast to most other cancers, chromosomal rearrangements mostly involve translocations and deletions but only rarely copy number gains or amplifications in prostate cancer. With the exception of the TMPRSS2:ERG fusion occurring in subpopulations of most prostate cancers, individual translocations generally occur at very low frequency (<5%).2 Many chromosomal deletions, however, are highly recurrent and occur at frequencies >10% of cancers, including 8p (40-50%), 13q14, 16q22-q24, 6q12-q22, 10q23 (20-30% each), 12p12-p13, 3p13 (15-20% each) and 5q21 (10%).3-9 The exact biological mechanism of how the...
Prostate cancer is characterized by recurrent deletions that can considerably vary in size. We hypothesized that large deletions develop from small deletions and that this “deletion lengthening” might have a “per se” carcinogenic role through a combinatorial effect of multiple down regulated genes. In vitro knockdown of 37 genes located inside the 6q12-q22 deletion region identified 4 genes with additive tumor suppressive effects, further supporting a role of the deletion size for cancer aggressiveness. Employing fluorescence in-situ hybridization analysis on prostate cancer tissue microarrays, we determined the deletion size at 6q and 16q in more than 3,000 tumors. 16q and 6q deletion length was strongly linked to poor clinical outcome and this effect was even stronger if the length of both deletions was combined. To study deletion lengthening in cancer progression we eventually analyzed the entire cancers from 317 patients for 6q and 16q deletion length heterogeneity and found that the deletion expanded within 50-60% of 6q and 16q deleted cancers. Taken together, these data suggest continuous “deletion lengthening” as a key mechanism for prostate cancer progression leading to parallel down regulation of genes with tumor suppressive properties, some of which act cooperatively.
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