Gene expression and regulation in endocrine cancers

背景内分泌恶性肿瘤（包括甲状腺、肾上腺、甲状旁腺和胰腺神经内分泌肿瘤）是美国增长最快的癌症诊断之一，但很难通过常规临床、实验室和影像学研究区分良性和恶性肿瘤。因此，即使是那些看似良性的内分泌肿瘤患者也经常选择接受手术以获得明确的诊断，希望排除癌症。大多数内分泌癌患者的预后相对较好。然而，从10%到40%（取决于肿瘤类型）的任何地方都有侵袭性疾病，这些疾病在初始治疗时通常无法可靠地确定。能够可靠地对具有高复发和死亡风险的患者进行风险分层的预后标志物将有助于确定哪些患者应该接受积极的初始治疗和密切随访。此外，预后标志物也可以帮助确定哪些患者可能对标准治疗有反应，如果确定了不同的分子表型，哪些患者对标准治疗没有反应。总结我们在内分泌肿瘤的泛基因组（mRNA和microRNA表达，拷贝数变化和DNA甲基化）分析方面取得了进展，以确定内分泌恶性肿瘤（甲状腺，肾上腺，神经内分泌胰腺）的候选诊断和预后标志物，并了解内分泌癌中失调的基因/途径。我们的分析显示了mRNA/蛋白质表达和microRNA表达水平的关键变化，以及DNA甲基化状态，这些变化可作为极好的诊断标志物。这些研究已经扩展到包括血清和尿液样本的分析，以检测肿瘤样本中发现的microRNA，蛋白质和DNA甲基化变化的水平变化。在该分析中，我们发现一些microRNA（在癌症中下调）基于体外和首次在人静脉取样研究在外来体中主动分泌。我们的基因组数据的综合分析，特别是在甲状腺癌和肾上腺癌中，也发现了可能在甲状腺和肾上腺癌的发生和发展中发挥作用的新途径，我们正在使用功能基因组学研究在体外和体内证实。

Background Endocrine malignancies (including thyroid, adrenal, parathyroid, and pancreatic neuroendocrine tumors) are among the fastest growing cancer diagnoses in the United States, but it is difficult to distinguish benign from malignant tumors by routine clinical, laboratory, and imaging studies. So, even patients who have seemingly benign endocrine tumors often choose to undergo surgery to get a definitive diagnosis in the hopes of ruling out cancer. Most patients with endocrine cancers have a relatively good prognosis. However, anywhere from 10% to 40% (depending on tumor type) have aggressive disease which often cannot be reliably determined at the time of initial treatment. Prognostic markers which can reliably risk stratify patients with high risk of recurrence and death would help determine which patients should receive aggressive initial treatment and close follow up. Furthermore, prognostic markers may also help identify which patients are likely to respond to standard therapy and which patients do not respond to standard therapy if a distinct molecular phenotype is identified. Summary We have made progress with our pan-genomic (mRNA and microRNA expression, copy number changes, and DNA-methylation) analysis of endocrine neoplasms to identify candidate diagnostic and prognostic markers for endocrine malignancies (thyroid, adrenal, neuroendocrine pancreas), and to understand the dysregulated genes/pathways in endocrine cancers. Our analysis shows key changes in mRNA/protein expression and microRNA expression levels, and DNA-methylation status that serve as excellent diagnostic markers. These studies have been expanded to include the analysis of serum and urine samples to detect altered levels of microRNAs, proteins and DNA-methylation changes found in the tumor samples. In this analysis we found some microRNAs (downregulated in cancer) to be actively secreted in exosomes based on both in vitro and first in human venous sampling studies. The integrated analysis of our genomic data, especially in thyroid cancer and adrenal cancers, have also uncovered possible novel pathways which may have a role in thyroid and adrenal cancer initiation and progression which we are confirming using functional genomics studies in vitro and in vivo.