Prognostic Significance of PTEN Loss in Prostate Cancer: A Meta-Analysis of Gleason Grade and Clinical Outcomes

Abstract

Aims: Prostate cancer (PCa) presents ongoing challenges in differentiating aggressive from indolent disease using traditional biomarkers such as prostate-specific antigen (PSA). The Phosphatase and Tensin Homolog (PTEN), a key tumour suppressor involved in cellular growth regulation, is emerging as a promising biomarker for risk stratification. This meta-analysis aims to evaluate the prognostic significance of PTEN loss in PCa, particularly its relationship with Gleason grade groups (GG), as defined by the ISUP system, and clinical outcomes.

Methods: A systematic review and meta-analysis of 16 studies encompassing 11,375 patients was conducted in accordance with PRISMA guidance. Studies included evaluated PTEN loss, stratified by hemizygous and homozygous deletions, and its association with GG and clinical endpoints such as biochemical recurrence and lethal progression. Pooled odds ratios (ORs) and hazard ratios (HRs) were calculated using a random-effects model.

Results: PTEN loss was significantly associated with tumour aggressiveness. Compared to GG1 tumours, the odds of PTEN loss were markedly increased in Gleason GG 2 and 3(OR: 2.78, 95% CI: 1.95-3.61) and GG ≥ 4 (OR: 6.35, 95% CI: 5.37-7.33). Homozygous PTEN deletions were more strongly associated with high-grade tumours than hemizygous deletions. Clinically, PTEN loss was predictive of adverse outcomes, including increased risk of biochemical recurrence (HR: 1.78, 95% CI: 1.31-2.25) and lethal progression (HR: 2.57, 95% CI: 1.12-3.95).

Conclusion: PTEN loss correlates with higher GG and poorer clinical outcomes in PCa. Incorporating PTEN assessment into clinical decision making could improve risk stratification, guiding early intervention strategies and identifying patients suitable for active surveillance.

Keywords: Gleason Grade; PTEN loss; prostate cancer; risk stratification.

Figure 1

Growth factors and chemokines activate receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs), engaging class I PI3K (p85/p110) to convert PIP₂ to PIP₃ at the membrane. PIP₃ recruits AKT, which is phosphorylated (Thr308 by PDK1, Ser473 by mTORC2) to drive mTORC1 dependent protein synthesis and survival. The lipid phosphatase PTEN reverses this step (PIP₃ to PIP₂) and hence restrains AKT-mTOR signalling. Reduced PTEN activity elevates PIP₃ and amplifies the pathway. In the nucleus, PTEN also supports genomic stability and DNA repair. Conventions: green arrows, activation; dashed lines, inhibition. Abbreviations: RTK, receptor tyrosine kinase; GPCR, G-protein-coupled receptor; PI3K, phosphoinositide 3-kinase; p85/p110, PI3K regulatory/catalytic subunits; PIP₂, phosphatidylinositol-4,5-bisphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homologue; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Ser/Thr, serine/threonine; P, phosphate.

Figure 2

PRISMA Flow Diagram of Study Selection Process.

Figure 3

Traffic-light risk-of-bias assessment across included studies (QUIPS) [5,19,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Each row represents a study; columns D1–D6 are QUIPS domains: D1 participation, D2 attrition, D3 prognostic-factor measurement, D4 outcome measurement, D5 confounding, D6 statistical analysis & reporting. Colours indicate judgment (green low risk, yellow moderate, red high). The Overall column summarises domain-level judgments for each study [37].

Figure 4

Forest Plot of PTEN Loss in Relation to Gleason Grades GG 1, GG2 and GG 3, and ≥4. Individual study odds (OR, black dots) and 95% confidence intervals (horizontal lines) for PTEN loss are shown for tumours with GG ≤ 1 (top panel), GG = 2 and 3 (middle panel), and GG ≥ 4 (bottom panel) [5,19,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. GG1 is the reference category (OR fixed at 1.0 for orientation only; not meta-analysed). Red diamonds indicate the pooled OR for each subgroup. Gleason 2 and 3: OR 2.78 (95% CI 1.95–3.61), GG ≥ 4: OR 6.35 (95% CI 5.37–7.33).

Figure 5

Forest Plot Comparing PTEN Loss in GG 2 vs. GG 3 in PCa. Individual study odds ratios (OR, black dots) and 95% confidence intervals (horizontal lines) for PTEN loss are shown separately for GG 2 (top panel) and GG 3 (bottom panel) [23,24,26,28,29,33,34,35,36]. Red diamonds indicate the pooled OR for each subgroup. GG 2: OR 2.18 (95% CI 1.38–2.97), GG 3: OR 3.72 (95% CI 1.91–5.52). The bottom-most red diamond shows the overall pooled OR across both subgroups: 2.79 (95% CI 1.20–4.38).

Figure 6

Forest Plot of Hemi- and Homozygous PTEN Loss in Relation to GG 2, 3, and ≥4 in PCa. Individual study odds ratios (black dots) and 95% confidence intervals (horizontal lines) are shown separately for homozygous (top row in each panel) and hemizygous (bottom row in each panel) PTEN loss across three GG: 2 (left panel), 3 (middle panel), and ≥4 (right panel) [23,26,28,34]. Red diamonds denote the pooled effect for each loss type and grade. GG 2 Homozygous PTEN loss OR: 3.19 (95% CI 1.53–4.85), Hemizygous PTEN loss OR: 1.67 (95% CI 0.39–2.95), GG 3 Homozygous PTEN loss OR: 4.39 (95% CI 2.31–6.47), Hemizygous PTEN loss OR: 1.96 (95% CI 0.27–3.65), GG ≥ 4 Homozygous PTEN loss OR: 5.29 (95% CI 3.23–7.36), Hemizygous PTEN loss OR 3.38 (95% CI 1.88–4.89). The bottom-most red diamond shows the overall pooled OR for any PTEN loss across all grades: 3.26 (95% CI 2.09–4.42).

Figure 7

Forest Plot of Clinical Outcomes Stratified by PTEN Loss. Individual study hazard ratios (HR, black dots) and 95% confidence intervals (horizontal lines) are shown separately for lethal progression (top panel, pooled HR: 2.57 (95% CI 1.12–3.95) shown as a red diamond) and recurrence-free survival (bottom panel, pooled HR: 1.78 (95% CI 1.31–2.25) shown as a red diamond) [23,24,26,27,29,34,35,36].