Hierarchal gene master regulators of one case of papillary thyroid cancer

The incidence of thyroid cancer (TC) has doubled in recent years but the molecular mechanisms responsible for various TC forms are largely unknown. We hypothesize that, in a thyroid tumor, cancer nodules and surrounding benign tissue are governed by different gene master regulators (GMRs). GMRs are defined as coding/non-coding RNAs whose strongly protected (by the homeostatic mechanisms) abundance modulates most functional pathways by coordinating the expression of their composing genes. GMRs are the most legitimate targets for TC gene therapy. However, because of strong expression control, GMRs are not selectable among TC biomarkers whose frequent regulation in large cancer patient populations indicates low protection as for minor players. We tested the hypothesis by profiling the transcriptomes of the papillary cancer and benign tissue from a surgically removed TC. The hierarchy of the known biomarkers was established for both cancer and benign regions of the tumor based on their gene commanding height (GCH), an original measure combining the expression control and coordination with expression of other genes. We found that 1/3 of the 544 known biomarkers had higher GCH in the malignant region, 1/3 in the benign region, while the rest did not discriminate between the two, raising the question of the biomarkers’ utility. Two-conditions (N=normal/benign region of the tumor, T=papllary thyroid cancer region of the tumor), 4 replicas of each condition

近年来甲状腺癌 (thyroid cancer, TC) 的发病率已翻倍，但不同类型甲状腺癌的致病分子机制仍未完全明确。我们提出假说：甲状腺肿瘤中的癌结节与周边良性组织，受不同的基因主调控因子 (gene master regulators, GMRs) 调控。基因主调控因子被定义为编码RNA或非编码RNA，其丰度受稳态机制严格保护，并通过协调其调控基因的表达，调控绝大多数功能通路。GMRs是甲状腺癌基因治疗最合理的靶点。然而，由于GMRs自身表达受到严格调控，它们无法从甲状腺癌生物标志物中筛选得到——这类生物标志物在大型癌症患者群体中频繁出现表达异常，表明其作为次要调控因子所受的保护程度较低。我们通过对手术切除的甲状腺癌组织中的乳头状癌病灶与良性组织进行转录组分析，验证了上述假说。我们基于基因主导度 (gene commanding height, GCH) ——这一结合了表达调控程度与基因间表达协调能力的原创指标——为肿瘤的癌区与良性区分别构建了已知生物标志物的层级排序。我们发现，在544个已知生物标志物中，1/3在恶性区域的GCH值更高，1/3在良性区域更高，其余则无法区分癌区与良性区域，这一结果引发了关于此类生物标志物实用性的质疑。本数据集包含两组实验条件：N组为肿瘤的正常/良性组织区域，T组为甲状腺乳头状癌病灶区域；每组均设置4个生物学重复。