Genetic and epigenetic insights into uveal melanoma

Abstract

Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to exam the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifications and signaling pathways as well as possible biomarkers in UM. In addition, different research models for UM are discussed. New insights and major challenges are outlined in order to evaluate the current status for this potentially devastating disease.

Genome organization in proximity to the BAP1 locus appears to play a pivotal role in a variety of cancers

“…Hence, the differentially identified signature of repetitive sequences suggests a shared and unique molecular feature associated with repetitive elements and the cancer genome. The prevalence of repetitive sequences in the functional parts of genomes and their association with human diseases remains undisputed . Whether the absence of these repeats in monosomy of chromosome 3 in UM tumors or the 3p deletion syndrome is compensated by additional factors or alternative genomic regions needs further elucidation.…”

“…Given the frequent involvement of (the short arm of) chromosome 3 in multiple human cancers, it has been proposed that some regions could harbor multiple tumor suppressor genes . The contribution of monosomy 3 in uveal melanoma (UM), the most frequent primary intraocular tumor in Caucasian adults, was recognized nearly three decades ago and represents, along with other factors, a predictive factor for the development of systemic metastasis (reviewed in Sharma et al) . Interestingly, BAP1 (BRCA1‐associated protein 1) is frequently mutated in metastatic UM, but also plays a significant role in pleural mesothelioma, lung adenocarcinoma, and renal cell carcinoma .…”

“…The contribution of monosomy 3 in uveal melanoma (UM), the most frequent primary intraocular tumor in Caucasian adults, was recognized nearly three decades ago and represents, along with other factors, a predictive factor for the development of systemic metastasis (reviewed in Sharma et al) . Interestingly, BAP1 (BRCA1‐associated protein 1) is frequently mutated in metastatic UM, but also plays a significant role in pleural mesothelioma, lung adenocarcinoma, and renal cell carcinoma . Apart from BAP1 , other genes at chromosome 3, such as PBRM1 , SETD2 (renal cell carcinoma), ADAMTS9 (esophageal squamous cell carcinoma), SOX2 , ECT2 , PRKCI , PIK3CA (lung squamous cell carcinoma), and ROBO1 (breast cancer and colorectal cancer) show genetic alterations in cancer.…”

Basal cell carcinomas developing independently from BAP1‐tumor predisposition syndrome in a patient with bilateral uveal melanoma

“…Bringing clinical and histopathological information together is important in the field of oncology. In recent years, efforts from the field of ocular oncology and pathology have broadened our insights into genetics of different eye tumors, in particular in uveal melanoma (UM) . For instance, somatic and germline BRCA‐1 associated protein‐1 ( BAP1) pathogenic variants have been shown to be associated with UM pathogenesis and prognosis …”

“…In recent years, efforts from the field of ocular oncology and pathology have broadened our insights into genetics of different eye tumors, in particular in uveal melanoma (UM). 1 For instance, somatic and germline BRCA-1 associated protein-1 (BAP1) pathogenic variants have been shown to be associated with UM pathogenesis and prognosis. [2][3][4][5] BAP1 is a tumor suppressor gene located on the short arm of chromosome 3 (p21.1).…”