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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011275-04
Application #
8763426
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2013
Total Cost
$1,541,934
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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Boufraqech, Myriem; Zhang, Lisa; Jain, Meenu et al. (2014) miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer 21:517-31
Jain, Meenu; Zhang, Lisa; Boufraqech, Myriem et al. (2014) ZNF367 inhibits cancer progression and is targeted by miR-195. PLoS One 9:e101423
Peng, Hongzhuang; Talebzadeh-Farrooji, Mehdi; Osborne, Michael J et al. (2014) LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase. Cancer Res 74:1390-403
Lee, Paul; Linderman, Joyce D; Smith, Sheila et al. (2014) Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 19:302-9

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