Clinical Utility of Serum Autoantibodies Detected by Protein Microarray in Melanoma

Michael S Sabel,Yashu Liu,David M Lubman,Jintang He,Xaiolei Xie,Kent A Griffith

doi:10.1155/2011/413742

Michael S Sabel, Yashu Liu + Show 4 more

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https://doi.org/10.1155/2011/413742

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Abstract

Better prognostic and predictive markers in melanoma are needed to select patients for therapy. We utilized a dual-lectin affinity chromatography and a natural protein microarray-based analysis to select a subproteome of target glycoproteins to profile serum antibodies against melanoma associated antigens that may predict nodal positivity. We identified 5 melanoma-associated antigens using this microarray coupled to mass spectrometry; GRP75, GRP94, ASAH1, CTSD and LDHB. We evaluated their predictive value for nodal status adjusting for age, gender, Breslow thickness, mitotic rate and ulceration using standard logistic regression. After adjustment, ASAH1, CTSD and LDHB were significantly negatively associated with nodal status (P = 0.0008) and GRP94 was significantly positively associated (P = 0.014). Our best multivariate model for nodal positivity included Breslow thickness, presence of serum anti-ASAH1, anti-LDHB or anti-CTSD, and presence of serum anti-GRP94, with an area under the ROC curve of 0.869. If validated, these results show promise for selecting clinically node negative patients for SLN biopsy. In addition, there is strong potential for glycoprotein microarray to screen serum autoantibodies that may identify patients at high risk of distant metastases or those likely or unlikely to respond to treatment, and these proteins may serve as targets for intervention.

Highlights

The present staging system for melanoma, using Breslow thickness, ulceration, mitotic rate, and the presence of regional and distant metastases, stratifies patients into heterogenous groups, with wide variability in outcome or response to therapy
We chose to examine serum protein markers, hypothesizing that antibody discovery was ideal for the patient with malignant melanoma, as primary tumor tissue is not required and the presence of an immune response to melanoma-associated antigens has been well documented [1,2,3,4]
As most of the tumor-associated antigens are cell surface proteins or released to the extracellular matrix, where glycosylation is the major type of posttranslational modifications [5, 6]

Summary

Introduction

The present staging system for melanoma, using Breslow thickness, ulceration, mitotic rate, and the presence of regional and distant metastases, stratifies patients into heterogenous groups, with wide variability in outcome or response to therapy. The large-scale analysis of gene expression at the RNA level can provide patterns of gene expression that may stratify patients better than TNM staging and help guide therapy. This approach requires fresh tissue from a large number of primary tumors, a unique challenge in melanoma where the primary is often only a few millimeters in size, with no residual tissue after the diagnosis has been made. Glycoproteins are considered to be the linkage between T cells and antigenpresenting cells to help the orientation of binding, and play important roles in the generation and loading of antigenic peptides into MHC class I and MHC class II [5,6,7]

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