Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia.
School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia.
Hum Genet. 2024 Oct;143(9-10):1145-1162. doi: 10.1007/s00439-024-02673-2. Epub 2024 Apr 20.
Copper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. Utilising RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, we generated gene regulatory networks to identify the critical cuproplasia-related genes across 23 different cancer types. From this, we identified a novel 8-gene cuproplasia-related gene signature associated with pan-cancer survival, and a 6-gene prognostic risk score model in low grade glioma. These findings highlight the use of gene regulatory networks to identify cuproplasia-related gene signatures that could be used to generate risk score models. This can potentially identify patients who could benefit from copper-chelation therapy and identifies novel targeted therapeutic strategies.
铜是一种重要的必需微量营养素，参与许多生物过程，是肿瘤细胞生长和迁移的必需组成部分。铜通过一种称为铜生（cuproplasia）的过程影响肿瘤生长，定义为异常依赖铜的细胞生长和增殖。针对该过程的铜螯合疗法已在几项针对癌症的临床试验中证明了疗效。虽然与铜生相关的分子途径部分已知，但不同癌症类型的遗传异质性限制了对铜生如何影响患者生存的理解。利用来自癌症基因组图谱（TCGA）和基因型组织表达（GTEx）数据集的 RNA 测序数据，我们生成了基因调控网络，以确定 23 种不同癌症类型中与铜生相关的关键基因。由此，我们确定了一个与泛癌生存相关的新型 8 基因铜生相关基因特征，以及低级别胶质瘤中的 6 基因预后风险评分模型。这些发现强调了使用基因调控网络来识别与铜生相关的基因特征，这些特征可用于生成风险评分模型。这可能有助于确定可能从铜螯合疗法中受益的患者，并确定新的靶向治疗策略。
