Absence of nuclear Programmed cell death 4 as an indicator of poor prognosis in uveal melanoma patients

Abstract

PurposeUveal melanoma (UM) is the most frequently occurring intraocular malignancy in adults. Arising from the uncontrolled proliferation of melanocytes in the choroid, ciliary body and iris, UMs have a strong propensity to metastasise to the liver, where they are fatal. In a previous study, proteomic examination of UMs at either a high or low risk of developing metastasis identified the down regulation of Programmed Cell Death 4 (PDCD4) levels with increasing metastatic risk.MethodsThis study examined PDCD4 protein expression and subcellular localisation in UM patient samples by immunohistochemistry (IHC). 165 primary (PUM) and 18 metastatic UM (MUM) samples with full clinical, histological and genetic data were included in the study. Slides were assessed and scored according to (A) percentage of tumour cells with cytoplasmic PDCD4 expression; (B) intensity of cytoplasmic staining and (C) percentage of PDCD4 positive tumour nuclei.ResultsIn PUM and MUM samples, PDCD4 was localised primarily to the cytoplasm. An equal percentage of primary and metastatic samples expressed nuclear PDCD4 (28%). Loss of nuclear PDCD4 was strongly associated with factors associated with a poor prognosis, in particular, monosomy 3 (p = 0.014) and loss of nuclear BAP1 (p = 0.012). PUMs with nuclear PDCD4 in ≥10% of tumour cells had an improved survival time compared with PUMs with <10% nuclear expression of PDCD4 (p = 0.105).ConclusionsThe tumour suppressor PDCD4 shuttles between the nucleus and cytoplasm to exert its effects in normal cells. In PUM samples, an absence of nuclear PDCD4 localisation was associated with a poor outcome. Further functional studies are necessary to determine how PDCD4 localisation influences UM cell behaviour.