Ocular adnexal sebaceous carcinoma (OASeC) is an aggressive eyelid carcinoma. Analysis of molecular-genetic drivers of this disease could reveal new prognostic markers and actionable targets for treatment. To identify somatically acquired genomic mutations in OASeC and explore their associations with metastasis, whole-exome sequencing on DNA extracted from retrospectively collected tumor samples was performed. Thirty-one patients in two orbital oncology centers with OASeC were included. Sequencing results were analyzed to detect mutations and explore their possible association with metastasis. The median patient age was 64 years. A total of 1780 candidate somatic mutations were identified with median mutation rate of 1.0/Mb (range, 0.2-13.6). The five most commonly mutated genes (as determined by MutSig; q value < 0.25) were TP53 (mutated in 22 cases), ZNF750 (13 cases), RB1 (12 cases), NOTCH1 (8 cases), and PCDH15 (5 cases). Mutations in ZNF750 or NOTCH1 pathway genes were present in 24 (77%) of the 31 cases; there was a trend toward mutual exclusivity of ZNF750 and NOTCH1 mutations. All eight tumors with NOTCH1 mutations also had TP53 and/or RB1 mutations. Four of the five PCDH15 mutations and all four PCDH15 missense mutations were identified in patients with metastatic disease, including one patient with distant metastasis and three with nodal metastasis. PCDH15 was significantly associated with metastasis (P = 0.01). We identified the most commonly mutated genes in a series of OASeCs and found a previously unreported mutation in OASeC, PCDH15 mutation, that was significantly associated with metastasis. NOTCH1 mutation is an actionable mutation; clinical trials targeting this mutation are available throughout the US and could be considered for patients with metastatic NOTCH1-mutant OASeC. TP53, ZNF750, RB1, and PCDH15 mutations are most likely loss-of-function mutations and may have diagnostic and prognostic importance.

中文翻译：

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眼附件皮脂腺癌的全外显子组测序表明 PCDH15 是一种与转移相关的新突变。

眼附件皮脂腺癌 (OASeC) 是一种侵袭性眼睑癌。分析这种疾病的分子遗传驱动因素可以揭示新的预后标志物和可行的治疗目标。为了识别 OASeC 中体细胞获得的基因组突变并探索它们与转移的关联，对从回顾性收集的肿瘤样本中提取的 DNA 进行了全外显子组测序。两个 OASeC 眼眶肿瘤中心的 31 名患者被纳入。分析测序结果以检测突变并探索它们与转移的可能关联。患者的中位年龄为 64 岁。共鉴定出 1780 个候选体细胞突变，中位突变率为 1.0/Mb（范围，0.2-13.6）。五个最常见的突变基因（由 MutSig 确定；q 值 < 0。25）分别为TP53（22例）、ZNF750（13例）、RB1（12例）、NOTCH1（8例）、PCDH15（5例）。31 例病例中有 24 例 (77%) 存在 ZNF750 或 NOTCH1 通路基因突变；ZNF750 和 NOTCH1 突变有相互排斥的趋势。具有 NOTCH1 突变的所有八个肿瘤也具有 TP53 和/或 RB1 突变。五种 PCDH15 突变中的四种和所有四种 PCDH15 错义突变在转移性疾病患者中被发现，包括一名远处转移患者和三名淋巴结转移患者。PCDH15 与转移显着相关 (P = 0.01)。我们确定了一系列 OASeC 中最常见的突变基因，并在 OASeC 中发现了一个以前未报道的突变，即 PCDH15 突变，它与转移显着相关。NOTCH1突变是一个可操作的突变；针对这种突变的临床试验在美国各地都可以进行，并且可以考虑用于转移性 NOTCH1 突变 OASeC 患者。TP53、ZNF750、RB1 和 PCDH15 突变很可能是功能丧失突变，可能具有诊断和预后意义。