Genomic Gain of 16p13.3 in Prostate Cancer Predicts Poor Clinical Outcome after Surgical Intervention

Abstract

Identifying tumors with high metastatic potential is key to improving the clinical management of prostate cancer. Recently, we characterized a chromosome 16p13.3 gain frequently observed in prostate cancer metastases and now demonstrate the prognostic value of this genomic alteration in surgically treated prostate cancer. Dual-color FISH was used to detect 16p13.3 gain on a human tissue microarray representing 304 primary radical prostatectomy (RP) cases with clinical followup data. The results were validated in an external dataset. The 16p13.3 gain was detected in 42% (113/267) of the specimens scorable by FISH and was significantly associated with clinicopathologic features of aggressive prostate cancer, including high preoperative PSA (P ¼ 0.03) levels, high Gleason score (GS, P < 0.0001), advanced pathologic tumor stage (P < 0.0001), and positive surgical margins (P ¼ 0.009). The 16p13.3 gain predicted biochemical recurrence (BCR) in the overall cohort (log-rank P ¼ 0.0005), and in subsets of patients with PSA 10 or GS 7 (log-rank P ¼ 0.02 and P ¼ 0.006, respectively). Moreover, combining the 16p13.3 gain status with standard prognostic markers improved BCR risk stratification and identified a subgroup of patients with high probability of recurrence. The 16p13.3 gain status was also associated with an increased risk of developing distant metastases (log-rank P ¼ 0.03) further substantiating its role in prostate cancer progression.Implications: This study demonstrates the prognostic significance of the 16p13.3 genomic gain in primary prostate tumors, suggesting potential utility in the clinical management of the disease by identifying patients at high risk of recurrence who may benefit from adjuvant therapies.

The combination of PTEN deletion and 16p13.3 gain in prostate cancer provides additional prognostic information in patients treated with radical prostatectomy

“…The advantage of this combinatorial approach was further evidenced by an increase of the C-index, which reached its maximum when coupled with the CAPRA-S score risk groups. Interestingly, the PTEN deletion status identified patients of CAPRA-S low-risk group who have an increased risk of biochemical recurrence, while the 16p13.3 gain status alone did not further stratify the low-risk group as we reported [18]. These results are in agreement with previous studies showing that combinations of genomic features such as gene expression changes and copy number alterations, including PTEN deletion status, can add prognostic information to the CAPRA-S score [30,31].…”

“…We recently reported that the 16p13.3 gain was associated with aggressive clinicopathologic features of prostate cancer as well as an increased risk of biochemical recurrence and distant metastases in the same radical prostatectomy specimens surveyed here for PTEN deletion [18]. Moreover, the 16p13.3 gain status improved the stratification of patients with intermediate and high risk of disease progression based on their CAPRA-S score.…”

“…PTEN deletion has been shown to be associated with poor outcome in prostate cancer after radical prostatectomy [13][14][15][16][17]. Recently, we reported that the 16p13.3 gain was also associated with adverse outcome after radical prostatectomy [18]. In the current study, we demonstrated that the PTEN genomic deletion measured by FISH is a strong independent predictor of poor clinical outcome after radical prostatectomy, including in low-intermediate risk patients and showed that the combination of PTEN deletion and 16p13.3 gain status improved patient risk stratification.…”

“…The final Gleason grade was assigned according to the latest International Society of Urological Pathology/World Health Organization recommendations [20]. The clinicopathologic characteristics of 303 of the 332 cases were reported previously [18] and those of the entire expanded cohort are summarized in Table 1. The mean preoperative serum prostate-specific antigen level was 8.66 (±8.27) and the distribution of Gleason grade group 1 (Gleason score 6), 2 (Gleason score 3 + 4), 3 (Gleason score 4 + 3), 4 (Gleason score 8), and 5 (Gleason score ≥ 9) was 21%, 46%, 24%, 3%, and 6%, respectively.…”

“…Of note, patients who did not undergo a lymph node dissection were considered to have negative lymph node for CAPRA-S score calculation as previously described [22]. The chromosome 16p13.3 gain data recently reported by our lab for this cohort [18] was used for the combinatorial approach.…”