Overexpression of High Mobility Group A1 Protein in Human Uveal Melanomas: Implication for Prognosis

Yi Qu,Yue Zhang,Wenbin Wei,Yan Wang,Hao Li,Jinlan Ma,Nana Meng,Yupeng Wang,Varda Rotter

doi:10.1371/journal.pone.0068724

Abstract

There is increasing evidence that the high mobility group A1 (HMGA1) protein, which functions as a transcriptional master regulator, plays critical roles in tumor progression. We evaluated HMGA1 expression in 89 primary uveal melanomas (UM) by immunohistochemistry to determine the clinicopathological and prognostic value of HMGA1 in UM after adjusting for other prognostic variables. Nuclear expression of HMGA1 was detected in 44% UMs. High expression levels of HMGA1 were more frequent in UMs with high levels of epithelioid cell pattern, mitoses count, and Ki67 labeling index (P = 0.025, P<0.0001, P = 0.0018; respectively), and HMGA1 expression levels were directly correlated with Ki67 labeling indexes and mitoses counts (R = 0.31, P <0.0001; R = 0.27, P<0.0068; respectively). High expression of HMGA1 was also independently associated with an increased risk of distant metastases as determined using the Cox proportional hazards regression model (multivariate hazard ratio: 3.44; 95% confidence interval: 1.56–7.60; log rank P = 0.0022). Moreover, high HMGA1 expression was associated with shorter UM-specific survival (multivariate hazard ratio: 2.41; 95% confidence interval: 1.10–5.53; log rank P = 0.041). These findings suggest that high levels of HMGA1 are associated with adverse clinical outcomes in UM patients and that further evaluation of HMGA1 as a potential therapeutic target in UM is warranted.

Highlights

Uveal melanomas (UMs), which arise from neural crest-derived melanocytes within the choroidal plexus of the eye including iris, ciliary body, and choroid are the most common primary intraocular malignant tumors in adults and the most common noncutaneous melanomas
Nuclear expression of high mobility group A1 (HMGA1) was frequent in UM, and high expression levels of HMGA1 were more prevalent in UM with high levels of epithelioid cell pattern, mitoses counts, and Ki67 labeling index (LI)
As originally speculated high expression levels of HMGA1 protein were associated with highly malignant phenotypes of UM and can be considered as a marker for poor prognosis

Summary

Introduction

Uveal melanomas (UMs), which arise from neural crest-derived melanocytes within the choroidal plexus of the eye including iris, ciliary body, and choroid are the most common primary intraocular malignant tumors in adults and the most common noncutaneous melanomas. They comprise approximately 5% of all diagnosed melanoma cases, their incidence is only 6 per 1 million per year among white and even less among non-white races [1,2,3]. As no effective therapies are currently available to decrease the risk of metastases, efforts have been made to identify high-risk patients in order to target systemic adjuvant therapy aimed at preventing or delaying metastatic disease

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Conclusion