Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker. Issue 8 (11th October 2019)

• Record Type: Journal Article
• Authors: Ghosal, Suman; Das, Shaoli; Pang, Ying; Gonzales, Melissa K.; Huynh, Thanh‐Truc; Yang, Yanqin; Taieb, David; Crona, Joakim; Shankavaram, Uma T.; Pacak, Karel
• Is Part Of: International journal of cancer. Volume 146:Issue 8(2020)
• Page Start: 2326
• Page End: 2335
• Publication Date: 2019-10-11
• Subjects: lincRNA -- pheochromocytoma -- paraganglioma -- molecular subtypes -- biomarkers; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32654
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in‐depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA‐Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine‐learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis‐free survival. The results were validated in independent samples using RT‐PCR. From a pan‐cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT‐PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non‐metastatic PCPGs. Kaplan–Meier analysis identified five lincRNAs as prognostic markers for metastasis‐free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk‐score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis‐free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs. Abstract : What's new? LincRNAs are differentially expressed in the rare neuro‐endocrine tumors pheochromocytomas and paragangliomas (PCPG) compared to normal adrenal medulla. However, the profiles of lincRNAs in PCPG remain to be fully elucidated. Using published RNA‐Seq data and machine‐learning models, here the authors found lincRNA expression signatures that can classify PCPG molecular subtypes with high precision. They identified and validated several lincRNA markers of metastatic PCPG and developed a prognostic model combining lincRNA profiles and clinical factors to predict metastasis‐free survival. PCPGs thus exhibit specific lincRNA expression profiles that correspond to the established molecular subgroups and can provide potential markers for aggressive/metastatic PCPGs.