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.
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