PTEN Abnormalities in Clinically Insignificant and Significant Prostate Cancer: An Analysis by Mate-Pair Next Generation and Sanger Sequencing
Edgardo R Parrilla Castellar, John C Cheville, Benjamin R Kipp, Stephen J Murphy, Simone B Terra, Geaorge Vasmatzis, R Jeffrey Karnes, William R Sukov. Mayo Clinic, Rochester, MN
Background: Deletion of PTEN is associated with worse prognosis in prostate cancer. However, little is known about the impact of PTEN mutations, and there is limited data regarding the frequency and clinical impact of deletion and mutation in clinically insignificant tumors compared to significant tumors.
Design: Massively parallel mate-pair next generation sequencing (NGS) of whole genome-amplified DNA extracted from laser capture microdissected tissue was performed on 40 prostatic adenocarcinomas consisting of 8 clinically insignificant tumors (GS6 and tumor volume 0.5 cm3), 8 cases of large volume (>1.0 cm3) GS6, 23 cases of GS7, and 1 case of GS8. Sequence analysis of exonic regions performed using standard Sanger methodology. Follow-up information was available for 31 patients. Tumor-free survival from prostatectomy was tested using KM log-rank test.
Results: PTEN deletion detected by mate-pair NGS occurred in 10 cases, and 3 of these cases showed additional deleterious mutations (2 nonsense and 1 frameshift) in the remaining PTEN allele by Sanger sequencing. Although not mutually exclusive, alterations in PTEN occurred more frequently in the setting of ERG rearrangements (70%). PTEN abnormalities were absent in clinically insignificant GS6 and large volume GS6, but were prevalent in GS7 or higher tumors (10/23 cases; 43%)(p=0.003). Radiographic or biochemical recurrence occurred in 5 patients with PTEN abnormalities (HR=4.65, p=0.036), including metastatic recurrences in 2 of the 3 patients with confirmed bi-allelic loss of PTEN. The overall 5-year tumor-free survival rate among patients with Gleason 7-8 tumors was 57% with PTEN abnormalities and 79% in the remaining cases (p=0.039).
Conclusions: PTEN abnormalities were absent in clinically insignificant and large volume GS6 tumors, but occurred in a significant number of GS7 cases. Although our series is small, patients that had PTEN deletion and mutation had a significantly worse outcome. These results suggest that PTEN abnormalities identify a subset of prostatic adenocarciomas at higher risk for progression, for which molecular and cytogenetic testing for PTEN abnormalities may provide significant prognostic information.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 67, Tuesday Morning