PTEN loss in Gleason grade 7 prostate tumors exhibits intratumoral heterogeneity and is associated with unfavorable pathological features

C G Picanço-Albuquerque,C S Pereira,J A Squire,T Vidotto,M Koti,F P Saggioro,D M Berman,R B Reis,T Jamaspishvili

doi:10.1186/s41241-018-0071-y

C G Picanço-Albuquerque, C S Pereira + Show 7 more

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https://doi.org/10.1186/s41241-018-0071-y

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Abstract

BackgroundPTEN loss is observed in 20–30% of prostate cancers and is associated with a poor outcome, but clinical details of the impact of this biomarker are unclear for intermediate grade tumors.MethodsWe investigated 43 radical prostatectomy-derived grade 7 prostate tumors from the Clinics Hospital of Ribeirão Preto. Tissue microarray (TMA) blocks were constructed and PTEN copy number status was determined for all patients through fluorescence in situ hybridization (FISH). To determine the presence of PTEN protein loss in our study cohort, we performed immunohistochemistry (IHC) in TMA sections. We then developed an automated algorithm in HALO™ to identify regions of PTEN protein loss in whole prostate scanned sections from ten patients with known PTEN deletion status by FISH. Clinical analyses were conducted to determine the associations between PTEN loss and patient outcome. All statistical analyses were conducted in R v3.4.3 with P-values below 0.05 being considered statistically significant.ResultsIn this study of 43 grade 7 tumors, we found PTEN deletions by FISH in 18.9% of tumors, and PTEN protein loss by IHC in 16.3% of tumors. Both techniques were highly concordant and complementary. Clinical analysis demonstrated that PTEN deletion by FISH was significantly associated with positive margin invasion (P = 0.04) and Gleason score upgrade (P = 0.001). Digital image analysis of ten representative tumors demonstrated distinct intratumoral heterogeneity for PTEN protein loss in four tumors.ConclusionsThis study shows that PTEN loss in Gleason grade 7 tumors can be heterogeneous and that a systematic analysis of this biomarker using a combination of FISH, IHC, and digital imaging may identify patients with a greater risk of poor outcome.

Highlights

Prostate Cancer (PCa) is the most common solid tumor in men and is the third more common cancer type in the world [1]
Comparison between fluorescence in situ hybridization (FISH) and IHC for Phosphatase and tensin homolog (PTEN) loss The analysis of PTEN copy number using FISH was conclusive for 95% (41/43) of the patients
FISH analysis of the Tissue microarray (TMA) showed that PTEN deletion was present in 18.9% (8/41), with PTEN hemizygous deletions in 11.6% (5/41) and PTEN homozygous deletions in 7.3% (3/41) of tumors

Summary

Introduction

Prostate Cancer (PCa) is the most common solid tumor in men and is the third more common cancer type in the world [1]. Phosphatase and tensin homolog (PTEN) is located in 10q23.31 and is the most frequent somatically mutated tumor suppressor gene in a variety of human malignancies (reviewed in [2]). Immunohistochemistry and fluorescence in situ hybridization (FISH) assays of PTEN loss in PCa [3–5] have shown high specificity to identify tumors that carry the poor prognostic biomarker. PTEN inactivation in prostate tumors is found in 20–30% of patients and is associated with adverse outcome [6]. PTEN was found to be an independent prognostic indicator of PCa-specific death in both conservatively treated and surgically treated patients and may be employed in the clinical setting as a biomarker for disease stratification (reviewed in [7]). PTEN loss is observed in 20–30% of prostate cancers and is associated with a poor outcome, but clinical details of the impact of this biomarker are unclear for intermediate grade tumors

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