National Ophthalmic Laboratory, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, Ireland.
Department of Medical Oncology, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
J Cancer Res Clin Oncol. 2018 Oct;144(10):1861-1868. doi: 10.1007/s00432-018-2705-6. Epub 2018 Jul 14.
BACKGROUND/AIMS: Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance.
DNA was extracted from 36 intraocular melanoma patient samples and 4 metastatic melanoma samples among the patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel.
Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM.
Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.
背景/目的：葡萄膜黑色素瘤（UM）是一种高度侵袭性的恶性肿瘤，在癌症治疗方面存在着显著的临床未满足需求。本研究旨在鉴定出爱尔兰患者队列中以前未报道的 UM 突变，这些突变可能具有潜在的临床意义。
通过对福尔马林固定石蜡包埋组织块的显微切割，从 36 例眼内黑色素瘤患者样本和 4 例转移性黑色素瘤患者样本中提取 DNA，并进行基因分型，以检测 42 个癌症相关基因中的已知单核苷酸多态性。这些突变使用定制设计的 sequenom 面板进行分析。
通过高通量基因分型，在 34 例 UM 患者中的 31 例中检测到 GNAQ 和 GNA11 突变，这些突变是相互排斥的，同时还检测到了一些在已确立的癌症驱动基因 PHLPP2、MET、PIK3R1 和 IDH-1 中的非同义变化，这些变异以前与 UM 无关。
鉴于本 UM 队列中鉴定出的变异缺乏关于其临床意义的知识，以及它们在其他癌症中的可能致病性质，有必要进一步研究这些变异突变的功能影响，以确定其在 UM 发病机制中以前未描述的可能作用，这可能为未来的治疗提供额外的靶点。
