Gene expression and regulation in endocrine cancers

在美国，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）是增长最快的癌症诊断之一，但通过常规临床、实验室和影像学检查很难区分良性和恶性肿瘤。因此，即使是看似良性的内分泌肿瘤患者，也经常选择接受手术来获得明确的诊断，希望能排除癌症。大多数内分泌癌患者预后较好。然而，10%至40%（取决于肿瘤类型）的肿瘤具有侵袭性，在最初治疗时往往无法可靠地确定。能够可靠地对复发和死亡高风险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，如果确定了不同的分子表型，预后标记物也可以帮助确定哪些患者可能对标准治疗有反应，哪些患者对标准治疗没有反应。我们正在使用人类肿瘤组织样本的泛基因组（mRNA和microRNA表达以及全局甲基化）分析方法来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。我们已经完成了对肾上腺肿瘤的分析，并确定了mRNA表达和microRNA表达水平以及dna甲基化的关键变化，这些变化可作为出色的诊断标记。基于这些发现，我们刚刚开展了一项临床试验，以测试它们在临床活检样本中对肾上腺肿瘤患者的诊断效用。我们还利用泛基因组数据确定了肾上腺皮质癌细胞中关键失调控基因（KIAA0101, IL13RA2, TOP2A）的功能。我们发现这些基因不仅在体外调节恶性细胞表型（细胞增殖、侵袭和迁移）的特征，而且在肾上腺皮质癌（如IL13RA2）的体内异种移植研究中是极好的治疗靶点。我们正在整合泛基因组数据，以了解内分泌癌中基因表达失调的主要机制。

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 are using a pan-genomic (mRNA and microRNA expression, and global methylation) profiling approach 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 expression and microRNA expression levels, and DNA-methylation that serve as excellent diagnostic markers. Based on these findings, we just opened a clinical trial to test their diagnostic utility in patients with adrenal neoplasm in clinical biopsy samples. We have also used the pan-genomic data to determine the function of the key deregulated genes (KIAA0101, IL13RA2, TOP2A) in adrenocortical carcinoma cells. We have found these genes not only regulate the hallmarks of malignant cell phenotype (cell proliferation, invasion and migration) in vitro but are excellent therapeutic targets in vivo xenograft studies of adrenocoritcal carcinoma (e.g. IL13RA2). We are in the process of integrating the pan-genomic data to understand the main mechanisms of gene expression dysregulation in endocrine cancers.