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Genes Chromosomes Cancer. 2018 Aug;57(8):387-400. doi: 10.1002/gcc.22541.

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma.

Author information

1
Department of Internal Medicine (DIMI), University of Genoa, Genova, Italy.
2
Department of Earth Sciences, Environment, and Life (DISTAV), University of Genoa, Genova, Italy.
3
Department of Biotherapy, Ospedale Policlinico San Martino, Genova, Italy.
4
Department of Pathology Unit, E.O. Ospedali Galliera, Genova, Italy.
5
Department of Ocular Oncology Unit, E.O. Ospedali Galliera, Genova, Italy.
6
Department of Clinical Trial Unit/Scientific Direction, E.O. Ospedali Galliera, Genova, Italy.
7
Department of Tumor Epigenetics Unit, Ospedale Policlinico San Martino, Genova, Italy.
8
Department of Health Sciences, University of Genoa, Genova, Italy.
9
Department of Molecular Pathology Unit, Ospedale Policlinico San Martino, Genova, Italy.
10
Department of Medical Oncology Unit, E.O. Ospedali Galliera, Genova, Italy.
11
Department of Human Genetics Laboratory, E.O. Ospedali Galliera, Genova, Italy.

Abstract

Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.

KEYWORDS:

BAP1 expression; UM genetic profile; Uveal melanoma

PMID:
29689622
DOI:
10.1002/gcc.22541
[Indexed for MEDLINE]

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