Background/Objectives: Uveal melanomas (UMs) are rare but often deadly malignancies that urgently require viable treatment options. UMs often exhibit tumour heterogeneity, with macroscopic and microscopic differences in morphology between different regions of the same tumour. However, to date, the clinical significance of this and how it may help guide personalised therapy have not been realised.Methods: Using targeted DNA and RNA sequencing of a small case series of large, high-risk primary UMs, we explored whether morphologically distinct regions of the same tumour were associated with distinct molecular profiles.Results: In four of the seven tumours analysed, we detected different sets of genetic variants following the separate analysis of microdissected melanotic and amelanotic regions of the same tumour. These included aMETexon 14 skipping RNA transcript that predicts sensitivity to crizotinib and variants in other genes that are important in active clinical trials for patients with UM and advanced solid tumours. The integration of TCGA data also identified recurrent mutational events in genes that were not previously implicated in UM development (FANCA,SLX4,BRCA2, andATRX).Conclusions: Our findings show that the molecular analysis of spatially separated and morphologically distinct regions of the same tumour may yield additional, therapeutically relevant genetic variants in uveal melanomas and have implications for the future molecular testing of UMs to identify targeted therapies.
背景/目的：葡萄膜黑色素瘤（UMs）是一种罕见但通常致命的恶性肿瘤，亟需有效的治疗方案。UMs常表现出肿瘤异质性，同一肿瘤的不同区域在宏观和微观形态上存在差异。然而，迄今为止，这种异质性的临床意义及其如何帮助指导个体化治疗尚未明确。方法：通过对一组高风险大型原发性UMs进行靶向DNA和RNA测序，我们探讨了同一肿瘤中形态学不同的区域是否与不同的分子特征相关。结果：在分析的七例肿瘤中，有四例在分别分析同一肿瘤的色素沉着区与无色素沉着区后，检测到了不同的遗传变异组合。这些变异包括预测对克唑替尼敏感性的MET外显子14跳跃RNA转录本，以及其他在UM和晚期实体瘤患者临床试验中具有重要意义的基因变异。整合TCGA数据还发现了先前未涉及UM发展的基因（FANCA、SLX4、BRCA2和ATRX）中的复发性突变事件。结论：我们的研究结果表明，对同一肿瘤中空间分离且形态学不同的区域进行分子分析，可能会在葡萄膜黑色素瘤中发现更多具有治疗相关性的遗传变异，并对未来通过分子检测识别靶向治疗具有重要启示。
肿瘤(癌症)患者之家