Molecular Cancer | 2021
Liquid biopsy proteomics of uveal melanoma reveals biomarkers associated with metastatic risk
Abstract
Main text Uveal melanoma (UM) is the most common primary intraocular tumor in adults [1]. Approximately 50% of patients with UM develop metastatic disease and up to 85% of these patients succumb to their visceral metastases. Currently, patients are screened with serial body imaging, which typically presents 2–4 years after primary diagnosis. However, it is suspected that micro-metastatic disease may develop 1–5 years prior to detection. Determining which patients are likely to metastasize has been the focus of recent molecular testing. To determine patients at higher risk for developing metastatic disease, clinical or histopathologic risk factors are considered [2]. More recently, gene expression analysis (i.e., gene expression profiling [GEP] and preferentially expressed antigen in melanoma [PRAME] status) after direct surgical tumor sampling has enhanced prognostic accuracy [3–5]. While tumor biopsies are beneficial for assessing mortality risk, they are still subject to certain risks (e.g., risk of retinal detachment and tumor dissemination) and not amenable to repeat testing [3–5]. Furthermore, they do not identify protein targets to direct new adjuvant treatments. In contrast, liquid biopsies offer a minimally invasive method for real-time molecular assessment of the primary tumor. Diagnostic vitrectomies are reproducible, repeatable, and carry a lower risk of adverse outcomes since they do not require invasion of the primary tumor. Serial fluid biopsies from the eye might allow prospective metastatic surveillance. Global protein changes may provide an independent biomarker that reflects the total sum of the tumor effects or a supplemental biomarker that could enhance diagnostic sensitivity and specificity. Our research has demonstrated that retinal proteins leak into the vitreous, and that proteomic analysis of vitreous biopsies can detect molecular changes in the adjacent retina, uncover biomarkers, and identify protein targets for adjuvant therapy [6]. These biomarkers are concentrated in fluid compartments adjacent to the primary tumor (Fig. 1a). There have been proteomic studies on UM tumor cells which have suggested differentially expressed proteins (DEPs), but liquid protein markers have yet to be validated (Table S1). Few studies utilized quantitative platforms and none, to date, measure protein biomarkers in the vitreous. In this study, we use proteomics to detect candidate biomarkers for UM and identified targets for drug repositioning.