Glycolytic Biomarkers Predictive of Transformation in Patients with Follicular Lymphoma

Introduction

Follicular lymphoma (FL) is an indolent lymphoma derived from germinal center B cells, covering approximately 20% of all lymphomas. The malignancy is generally considered an incurable condition, hence with a median survival time exceeding 10 years. A portion of patients experience early progression or histological transformation (HT) to a more aggressive lymphoma, typically diffuse large B cell lymphoma which occurs in up to 45% of FL patients, reducing the median survival after transformation to 1-2 years. Early detection of reliable predictors of HT would allow pre-emptive therapeutic intervention strategies and aim at improved survival for patients with transformed FL. In this study, we focus on the two glycolytic enzymes, Aldolase A and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Both proteins have previously been found to be upregulated at diagnosis in various solid cancers and associated with poor survival. In addition to its glycolytic effects, GAPDH has been recognized for its non-glycolytic effects including regulation of DNA replication and repair, RNA nuclear export and apoptosis.

Aim

The aim of this study was to identify biomarkers predictive of HT in patients with FL, by investigating the correlation between intratumoral aldolase A and GAPDH expression levels with the risk of transformation in pre-therapeutic tumor samples from FL patients.

Materials and Methods

Immunohistochemical aldolase A and GAPDH expression levels were quantified using digital image analysis in pre-therapeutic tumor tissue from FL patients at time of diagnosis for patients without (n=51) or with (n=41) subsequent HT, as well as in sequential samples at time of transformation (n=41). Staining intensities were assessed as area fractions (AFs) of the stained area normalized to the region of interest on whole biopsy sections.

Results

At time of initial FL diagnosis, FL patients with subsequent transformation had significantly higher levels of aldolase A and GAPDH expression compared to patients with no subsequent transformation, (p<0.001 and p=0.005). High levels of aldolase A expression (75^th percentile cut-off), were found to be associated with a significantly shorter transformation free survival (TFS) (p=0.015) and progression free survival (PFS) (p=0.001). Furthermore, high levels of GAPDH expression were found to be associated with a significantly shorter TFS (p<0.001), PFS (p=0.034) as well as overall survival (OS) (p=0.018).

Conclusion

These results suggest that at time of initial FL diagnosis, aldolase A expression and GAPDH expression, maybe as indicators of high metabolic turnover, may be predictive of the patient's risk of subsequent histological transformation.