Nguyen Thi Hai Yen, Nguyen Tin, Nguyen Quang-Huy, Le Duc-Hau
Department of Computational Biomedicine, Vingroup Big Data Institute, Hanoi, Vietnam.
Department of Computer Science and Engineering, University of Nevada, Reno, Reno, NV, United States.
Front Oncol. 2021 Oct 20;11:731548. doi: 10.3389/fonc.2021.731548. eCollection 2021.
Uveal melanoma (UM) is a comparatively rare cancer but requires serious consideration since patients with developing metastatic UM survive only for about 6-12 months. Fortunately, increasingly large multi-omics databases allow us to further understand cancer initiation and development. Moreover, previous studies have observed that associations between copy number aberrations (CNA) or methylation (MET) versus messenger RNA (mRNA) expression have affected these processes. From that, we decide to explore the effect of these associations on a case study of UM. Also, the current subtypes of UM display its weak association with biological phenotypes and its lack of therapy suggestions. Therefore, the re-identification of molecular subtypes is a pressing need. In this study, we recruit three omics profiles, including CNA, MET, and mRNA, in a UM cohort from The Cancer Genome Atlas (TCGA). Firstly, we identify two sets of genes, CNAexp and METexp, whose CNA and MET significantly correlated with their corresponding mRNA, respectively. Then, single and integrative analyses of the three data types are performed using the PINSPlus tool. As a result, we discover two novel integrative subgroups, IntSub1 and IntSub2, which could be a useful alternative classification for UM patients in the future. To further explore molecular events behind each subgroup, we identify their subgroup-specific genes computationally. Accordingly, the highest expressed genes among IntSub1-specific genes are mostly enriched with immune-related processes. On the other hand, IntSub2-specific genes are highly associated with cellular cation homeostasis, which responds effectively to chemotherapy using ion channel inhibitor drugs. In addition, we detect that the two integrative subgroups show different age-related risks and survival rates. These discoveries can influence the frequency of metastatic surveillance and support medical practitioners to choose an appropriate treatment regime.
葡萄膜黑色素瘤（UM）是一种相对罕见的癌症，但由于发生转移性UM的患者仅能存活约6至12个月，因此需要认真对待。幸运的是，越来越多的大型多组学数据库使我们能够进一步了解癌症的发生和发展。此外，先前的研究已经观察到，拷贝数变异（CNA）或甲基化（MET）与信使核糖核酸（mRNA）表达之间的关联影响了这些过程。据此，我们决定在一个UM病例研究中探索这些关联的影响。此外，UM目前的亚型与生物学表型的关联较弱，且缺乏治疗建议。因此，重新识别分子亚型迫在眉睫。在本研究中，我们从癌症基因组图谱（TCGA）的一个UM队列中收集了三种组学数据，包括CNA、MET和mRNA。首先，我们识别出两组基因，即CNAexp和METexp，它们的CNA和MET分别与其相应的mRNA显著相关。然后，使用PINSPlus工具对这三种数据类型进行单变量和综合分析。结果，我们发现了两个新的综合亚组，即IntSub1和IntSub2，它们可能在未来成为UM患者有用的替代分类。为了进一步探索每个亚组背后的分子事件，我们通过计算识别出它们的亚组特异性基因。相应地，IntSub1特异性基因中表达最高的基因大多富集于免疫相关过程。另一方面，IntSub2特异性基因与细胞阳离子稳态高度相关，使用离子通道抑制剂药物对化疗有有效反应。此外，我们检测到这两个综合亚组显示出不同的年龄相关风险和生存率。这些发现可以影响转移监测的频率，并支持医生选择合适的治疗方案。
