PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade

Abstract

Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous ¼ 42 and homozygous ¼ 14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (Po0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P ¼ 0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2-ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

Identification of Combinatorial Genomic Abnormalities Associated with Prostate Cancer Early Recurrence

“…7,8 The prognostic significance of PTEN deletion by FISH was also observed when we applied the same PTEN FISH technique on two population-based case-control studies of primary prostate cancer. 13 PTEN loss by immunohistochemistry (IHC) was also associated with decreased time to metastasis in high-risk patients surgically treated for prostate cancer and earlier death in lowrisk patients.…”

Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer

“…6,35 Haploinsufficiency of PTEN has been extensively associated with aggressive prostate cancer phenotype. [9][10]17,[36][37][38][39][40] Cells with haploinsufficiency of PTEN have been reported to be more unstable, defining a role for PTEN in maintaining chromosomal stability, as well increasing PI3K/AKT upregulation. [36][37][38][39][40][41] Although PTEN loss in prostate cancer has been reported as a progressive later event in prostate cancer, contradictory literature exists on the occurrence in high-grade prostatic intraepithelial neoplasia.…”

“…[9][10]17,[36][37][38][39][40] Cells with haploinsufficiency of PTEN have been reported to be more unstable, defining a role for PTEN in maintaining chromosomal stability, as well increasing PI3K/AKT upregulation. [36][37][38][39][40][41] Although PTEN loss in prostate cancer has been reported as a progressive later event in prostate cancer, contradictory literature exists on the occurrence in high-grade prostatic intraepithelial neoplasia. 10,17,23 In this study PTEN loss was assessed in 30 patients with high-grade prostatic intraepithelial neoplasia adjacent to the prostate cancer by whole-genome mate pair sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry.…”

A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

“…Tumor fusion status is not associated with lethal progression in most studies (22), but our group recently presented the first evidence that tumor fusion status may modify the association of prostate cancer risk factors with lethal prostate cancer progression (23). PTEN loss is more common in fusion-positive compared with fusion-negative disease (10,(24)(25)(26)(27), and PTEN loss almost certainly occurs subsequent to ERG rearrangement (19,28,29). Thus, presence of the TMPRSS2:ERG gene fusion may modify the effects of PTEN loss on disease progression.…”