Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma

Abstract

Background: Over 90% of cancer-related deaths in clear cell renal cell carcinoma (RCC) are caused by tumor relapse and metastasis. Thus, there is an urgent need for new molecular markers that can potentiate the efficacy of the current clinical-based models of prognosis assessment. The objective of this study is to evaluate the potential significance of lactate dehydrogenase A (LDHA), assessed by immunohistochemical staining, as a prognostic marker in clear cell renal cell carcinoma in relation to clinicopathological features and clinical outcome.

Methods: We assessed the expression of LDHA at the protein level, by immunohistochemistry, and correlated its expression with multiple clinicopathological features including tumor size, clinical stage, histological grade, disease-free and overall survival in 385 patients with primary clear cell renal cell carcinoma. We also correlated the LDHA expression with overall survival, at mRNA level, in an independent data set of 170 clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases. Cox proportional hazards models adjusted for the potential clinicopathological factors were used to test for associations between the LDHA expression and both disease-free survival and overall survival.

Results: There is statistically significant positive correlation between LDHA level of expression and tumor size, clinical stage and histological grade. Moreover, LDHA expression shows significantly inverse correlation with both disease-free survival and overall survival in patients with clear cell renal cell carcinoma. Our results are validated by examining LDHA expression, at the mRNA level, in the independent data set of clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases which also shows that higher lactate dehydrogenase A expression is associated with significantly shorter overall survival.

Conclusion: Our results indicate that LDHA up-regulation can be a predictor of poor prognosis in clear cell renal cell carcinoma. Thus, it represents a potential prognostic biomarker that can boost the accuracy of other prognostic models in patients with clear cell renal cell carcinoma.

Figure 1

Representative photomicrographs showing the expression of LDHA protein by immunohistochemistry. (A) Normal kidney proximal tubular epithelium, (B) weak, (C) moderate, and (D) strong staining Clear Cell Renal Cell Carcinoma (all figures are original magnification X400).

Figure 2

Box plot representing LDHA expression levels in relation to tumor size. There is a statistically significant association between the LDHA level of expression and tumor size; with larger tumors showing significantly higher proportion of LDHA expression (p < 0.001). Bold lines represent the median value (50th percentile) for each patient cohort. P value is calculated by “Jonckheere-Terpstra Test”.

Figure 3

Kaplan-Meier curve for DFS of patients with low, moderate and high expression of LDHA protein. Patients in the high LDHA expression arm have a statistically significant decrease in disease-free survival (p = 0.001) compared to those in the low LDHA expression arm.

Figure 4

Kaplan-Meier curve for OS of patients with low, moderate and high expression of LDHA protein. Patients in the high LDHA arm have a statistically significant decrease in overall survival (p < 0.001) compared to those in the low and moderate LDHA expression arm.

Figure 5

Kaplan-Meier survival curve for overall survival of patients with low and high expression of LDHA. mRNA data was obtained from the Cancer Genome Atlas (TCGA) dataset. On the basis of LDHA expression, patients are classified as LDHA high expression and LDHA low expression. Similar to the results of imunohistochemical analysis, the curve indicates a statistically significant reduction in overall survival with higher LDHA mRNA expression (p = 0.04).