Biological copper levels in oral squamous cell carcinoma: A meta-analysis with insights into disease progression and prognosis

Abstract

Background: Oral squamous cell carcinoma (OSCC) is a common, aggressive cancer characterized by frequent local invasion, metastasis, and recurrence. Previous research has reported altered copper levels in OSCC; however, studies employed different methods to assess these levels, leading to inconsistent or inaccurate measurements. This variability impacts the evaluation of copper's potential as a biomarker in OSCC.

Aim: This systematic review and meta-analysis aimed to evaluate copper concentrations in serum, saliva, and tissue of OSCC patients compared to healthy controls and explore its potential association with disease progression and prognosis.

Method: ologyA comprehensive search across electronic databases identified 147 studies, with 18 meeting the inclusion criteria following full-text screening. Data from 751 OSCC patients and 628 healthy controls were analysed. A random-effects meta-analysis was employed to compute standardized mean differences (SMD). Subgroup analyses based on sample type and analytical technique were performed. Risk of bias was assessed using established quality checklists.

Results: Serum copper levels were significantly higher in OSCC patients (SMD: 2.22 μg/ml; I² = 98 %), with improved effect size (SMD: 2.71 μg/ml) after excluding high-risk studies. Salivary copper levels were also elevated (SMD: 0.49 μg/ml), increasing further upon sensitivity analysis (SMD: 0.75 μg/ml; p = 0.02). One study showed markedly higher copper in tumor tissue. Studies using ICP-OES showed lower heterogeneity. No conclusive evidence linked copper levels to clinical outcomes.

Conclusion: Copper concentrations are significantly elevated in OSCC across serum and saliva. However, current evidence does not support its role as a prognostic biomarker. Standardized, prospective studies are warranted.

Keywords: Biomarker; Copper; Meta-analysis; Oral squamous cell carcinoma (OSCC); Prognosis; Saliva; Serum; Systematic review; Tissue; Trace elements.

Fig. 1

PRISMA Flowchart of Study Selection: the systematic selection process of studies included in this review. The diagram details the number of records identified through database searches, screened for eligibility, and excluded at various stages. It also highlights the final studies included in the qualitative and quantitative synthesis.

Fig. 2

Assessment of the risk of bias across all the included studies based on JBI criteria.

Fig. 3

Forest plot comparing serum copper levels in OSCC vs. healthy individuals. The meta-analysis shows significantly higher serum copper levels in OSCC patients (I² = 98 %, Z = 3.09, P = 0.002). Subgroup analysis by technique: AAS (I² = 99 %, Z = 2.16, P = 0.03) and ICP-OES (I² = 36 %, Z = 7.03, P < 0.00001) confirm elevated copper levels, with lower heterogeneity in ICP-OES.

Fig. 4

Forest plot comparing salivary copper levels between OSCC patients and healthy individuals (CI = 95 %). The overall meta-analysis showed no significant difference in salivary copper levels between OSCC and healthy individuals (I² = 91 %, Z = 1.14, P = 0.25). Subgroup analysis revealed a significant difference between estimation methods (I² = 77.3 %, P = 0.01), contributing to heterogeneity.

Fig. 5

Assessment of publication bias across studies.(a) Funnel plot for studies on serum copper levels in OSCC vs. controls, showing symmetric distribution and minimal visual evidence of publication bias.(b) Egger's regression plot for (a); no significant intercept (p = 0.459) indicates absence of small-study effects.(c) Funnel plot for studies on salivary copper levels in OSCC vs. controls, with approximate symmetry but an indistinct funnel shape, likely due to few studies.(d) Egger's regression plot for (c); no significant intercept (p = 0.160), suggesting no publication bias, though limited by small sample size (n = 5).