Stratification of Wilms tumor patients using physicochemical properties of the adaptive immune receptor polypeptides, IGL and TRG.

Abstract

Introduction: Wilms tumor (WT) is the most common pediatric renal malignancy. Current guidelines that stratify WT risk and determine treatment courses are inadequate, as over 60 % of WT survivors develop treatment-related complications. Recently, numerous advances in establishing patient sub-groups with different clinical features have been realized by evaluating the adaptive immune receptor (IR) complementarity determining region-3 (CDR3) amino acid (AA) sequences, a reasonable series of successes, given the prominent role of the CDR3 in antigen binding, including tumor antigen binding. However, the possibility that adaptive IR chemical variability correlates with distinct survival outcomes for WT has not yet been explored.

Objective: The goal of this study was to isolate the T-cell receptor and B-cell receptor recombination, sequencing reads from WT RNAseq files, representing the actual tumor tissue, translate the sequences to AAs, identify the adaptive IR CDR3 domains, and determine whether the physicochemical properties of those CDR3 AA sequences correlated with survival probability distinctions.

Study design: WT RNA-seq files were mined to obtain the CDR3 AAs for various adaptive IRs. The physicochemical properties of these CDR3s were examined for trends in how those properties correlated with survival probabilities for WT patients, using a Kaplan-Meier analyses, verified via several approaches.

Results: The above processes indicated the association of the (a) IGL CDR3s' instability index and the (b) TRG CDR3s' fraction disorder promoting features with better outcomes. Additionally, the IGL CDR3 data were assessed using the Predictor of Natural Disordered Regions web tool, which strengthened the evidence for the association with the IGL CDR3 instability index with a better outcome.

Discussion: The approaches described here indicate that greater adaptive IR CDR3 instability and flexibility may serve as prognostic indicators; and may indicate the flexibility of CDR3 domains provides for greater opportunity to bind tumor antigens.

Conclusion: Further exploration and development of these approaches and findings may lead to new guidelines for more precise treatment regimens, or even watchful waiting periods, that could thereby decrease the lifetime occurrence of adverse events.