Abstract
Uveal melanoma (UM) is an ocular tumor with a dismal prognosis. Despite the availability of precise molecular and cytogenetic techniques, clinicopathologic features with limited accuracy are widely used to predict metastatic potential. In 51 UM tissues, we assessed a correlation between the expression of nine proteins evaluated by immunohistochemistry (IHC) (Melan-A, S100, HMB45, Cyclin D1, Ki-67, p53, KIT, BCL2, and AIFM1) and the presence of UM-specific chromosomal rearrangements measured by multiplex ligation-dependent probe amplification (MLPA), to find IHC markers with increased prognostic information. Furthermore, mRNA expression and DNA methylation values were extracted from the whole-genome data, achieved by analyzing 22 fresh frozen UM tissues. KIT positivity was associated with monosomy 3, increasing the risk of poor prognosis more than 17-fold (95% CI 1.53–198.69, p = 0.021). A strong negative correlation was identified between mRNA expression and DNA methylation values for 12 of 20 analyzed positions, five located in regulatory regions of the KIT gene (r = −0.658, p = 0.001; r = −0.662, p = 0.001; r = −0.816; p < 0.001; r = −0.689, p = 0.001; r = −0.809, p < 0.001, respectively). DNA methylation β values were also inversely associated with KIT protein expression (p = 0.001; p = 0.001; p = 0.015; p = 0.025; p = 0.002). Our findings, showing epigenetic deregulation of KIT expression, may contribute to understanding the past failure to therapeutically target KIT in UM.
Highlights
Uveal melanoma (UM), a rare form of melanoma, is the most common intraocular cancer in adults [1]
51 UM patients were enrolled between August 2018 and September 2020; nine (17.6%) had detectable metastases at the time of primary tumor diagnosis, one developed metastases eight months after surgery (Table 1)
The majority of UMs (78.4%) arose from the choroid (C69.3), followed by the ciliary body (21.6%; C69.4). 51.0% of tumors were defined as spindle-cell, while 47.0% as epithelioid or mixed
Summary
Uveal melanoma (UM), a rare form of melanoma, is the most common intraocular cancer in adults [1]. The presence of 6p amplification represents a protective factor due to its association with a good prognosis and lowered metastatic risk [13] Another way to predict the risk of metastasis is via gene expression analysis. Four molecular subsets were proposed recently, based on more complex classification [15,16] Besides chromosomal rearrangements, this includes generally mutually exclusive secondary driver mutations with prognostic potential, occurring in the BAP1 (BRCA1-associated protein 1), EIF1AX (eukaryotic translation initiation factor 1A X-linked), or SF3B1 (splicing factor 3b subunit 1) genes [17]. We assessed the association between the expression of nine proteins, Melan-A, S100, HMB45, Cyclin D1, Ki-67, p53, KIT, BCL2, AIFM1 and UM-specific chromosomal rearrangements in UM tissues, to increase prognostic accuracy of routinely investigated IHC markers. A better understanding of epigenetic regulation might contribute to the development of effective therapy for poor prognosis UMs
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