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，但很难通过常规的临床、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，如果鉴定出不同的分子表型，则预后标志物还可以帮助鉴定哪些患者可能对标准疗法有反应，哪些患者对标准疗法没有反应。（mRNA和microRNA表达，拷贝数变化，和DNA甲基化）研究，以鉴定内分泌恶性肿瘤的候选诊断和预后标志物（甲状腺、肾上腺、神经内分泌胰腺）。我们已经完成了对肾上腺肿瘤的分析，并确定了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。基于这些发现，我们有一个临床试验开放，这是积累的主题，以测试这些候选标记物在肾上腺肿瘤患者的诊断效用。我们的初步数据表明，在肾上腺活检标本中进行分子标志物评价是可行的。我们还使用泛基因组数据来确定人类甲状腺癌和肾上腺癌细胞系中失调基因的功能。我们已经发现这些基因中的许多调节恶性细胞表型的标志（细胞增殖、侵袭、迁移等）。此外，这些基因中的几个已被证明是极好的体内治疗靶基因。最后，在对泛基因组数据的综合分析中，我们发现甲基化和microRNA表达的改变与人类甲状腺癌和肾上腺癌中改变的途径和基因表达显著相关。

BackgroundEndocrine 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.SummaryWe have made progress with our pan-genomic (mRNA and microRNA expression, copy number changes, and DNA-methylation) studies in human tumor tissue samples to identify candidate diagnostic and prognostic markers for endocrine malignancies (thyroid, adrenal, neuroendocrine pancreas). We have completed our analysis of adrenal neoplasm and have identified key changes in mRNA/protein expression and microRNA expression levels, and DNA-methylation status that serve as excellent diagnostic markers. Based on these findings, we have a clinical trial open, which is accruing subjects to test the diagnostic utility of these candidate markers in patients with adrenal neoplasm. Our preliminary data shows that molecular marker evaluation in adrenal biopsy samples is feasible. We have also used the pan-genomic data to determine the function of deregulated genes in human thyroid and adrenal cancer cell lines. We have found many of these genes regulate the hallmarks of malignant cell phenotype (cell proliferation, invasion, migration, etc.). Furthermore, several of these genes have proven to be excellent therapeutic target genes in vivo. Lastly, in integrated analysis of the pan-genomic data, we have found alterations in methylation and microRNA expression are significantly associated with altered pathways and genes expression in human thyroid and adrenal cancers.