Purpose

To determine genetic mutational profiles in patients with Ocular Surface Squamous Neoplasia (OSSN) using whole exome sequencing.

Methods

Prospective, case-series study. Patient recruitment was conducted in a single tertiary referral center from April to September 2017. Specimens were obtained by incisional biopsies of tumors from ten eyes with histopathologic confirmation of OSSN. DNA whole exome sequencing and mutation analysis were performed.

Results

Ten patients with clinically-diagnosed OSSN underwent DNA whole exome sequencing analysis. Deleterious mutations in 305 genes known to drive tumor development and progression were found. These mutations centered around two main pathways: DNA repair/cell cycle and development/growth. All ten samples had at least one mutation in a DNA repair/cell cycle gene and all but one sample had one in a development/growth gene. The most common mutation was found in TP53 and HGF (both present in 50% of cases) and mutually exclusive mutations were found in BRCA1 and BRCA2 (50% of cases). Mutations in APC, MSH6, PDGFRA, and PTCH1 were found in 40% of cases. Global mutation analysis identified ultraviolet induced radiation as the only mutational signature present in the dataset.

Conclusions

Mutations found in samples from patients with OSSN are mainly induced by ultraviolet radiation and occur within two main pathways related to DNA repair/cell cycle and development/growth. There are many clinically available drugs and several others being evaluated in clinical trials that target the genes found mutated in this study, offering new therapeutic options for OSSN.

中文翻译：

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眼表鳞状瘤的全外显子组分析和突变分析。

目的

使用全外显子组测序确定眼表鳞状细胞瘤 (OSSN) 患者的基因突变谱。

方法

前瞻性病例系列研究。患者招募于 2017 年 4 月至 9 月在一个单一的三级转诊中心进行。样本是通过对 10 只眼睛的肿瘤进行切开活检并获得 OSSN 的组织病理学确认来获得的。进行了 DNA 全外显子组测序和突变分析。

结果

10 名临床诊断为 OSSN 的患者接受了 DNA 全外显子组测序分析。在 305 个已知驱动肿瘤发展和进展的基因中发现了有害突变。这些突变围绕两个主要途径：DNA 修复/细胞周期和发育/生长。所有十个样本在 DNA 修复/细胞周期基因中至少有一个突变，除了一个样本外，所有样本在发育/生长基因中都有一个。在TP53和HGF 中发现了最常见的突变（在 50% 的病例中都存在），在BRCA1 和 BRCA2（50% 的病例中）发现了相互排斥的突变。APC、MSH6、PDGFRA和PTCH1 中的突变在 40% 的病例中被发现。全局突变分析将紫外线诱导的辐射确定为数据集中存在的唯一突变特征。

结论

在 OSSN 患者样本中发现的突变主要由紫外线辐射诱导，发生在与 DNA 修复/细胞周期和发育/生长相关的两个主要途径中。有许多临床可用的药物和其他几种正在临床试验中评估的药物，这些药物针对本研究中发现的突变基因，为 OSSN 提供了新的治疗选择。