The clinical utility of circulating neuroendocrine gene transcript analysis in well-differentiated paragangliomas and pheochromocytomas Journal Article


Authors: Pȩczkowska, M.; Cwikla, J.; Kidd, M.; Lewczuk, A.; Kolasinska-Ćwikła, A.; Niec, D.; Michałowska, I.; Prejbisz, A.; Januszewicz, A.; Chiarelli, J.; Bodei, L.; Modlin, I.
Article Title: The clinical utility of circulating neuroendocrine gene transcript analysis in well-differentiated paragangliomas and pheochromocytomas
Abstract: Context: Paragangliomas and pheochromocytomas (PPGLs) exhibit variable malignancy, which is difficult to determine by histopathology, amine measurements or tissue genetic analyses. Objective: To evaluate whether a 51-neuroendocrine gene blood analysis has clinical utility as a diagnostic and prognostic marker. Design: Prospective cohort study. Well-differentiated PPGLs (n = 32), metastatic (n = 4); SDHx mutation (n = 25); 12 biochemically active, Lanreotide treated (n = 4). Nine patients had multiple sampling. Age- and gender-matched controls and GEP-NETs (comparators). Methods: Circulating neuroendocrine tumor mRNA measured (qPCR) with multianalyte algorithmic analysis. Metabolic, epigenomic and proliferative genes as well as somatostatin receptor expression were assessed (averaged, normalized gene expression: mean ± s.e.m.). Amines were measured by HPLC and chromogranin A by ELISA. Analyses (2-tailed): Fisher's test, non-parametric (Mann-Whitney), receiver-operator curve (ROC) and multivariate analysis (MVA). All data are presented as mean ± s.e.m. Results: PPGL were NETest positive (100%). All exhibited higher scores than controls (55 ± 5% vs 8 ± 1%, P = 0.0001), similar to GEP-NETs (47 ± 5%). ROC analysis area under curve was 0.98 for differentiating PPGLs/controls (cut-off for normal: 26.7%). Mutation status was not directly linked to NETest. Genetic and molecular clustering was associated (P < 0.04) with NETest scores. Metastatic (80 ± 9%) and multicentric (64 ± 9%) disease had significantly (P < 0.04) higher scores than localized disease (43 ± 7%). Progressive disease (PD) had the highest scores (86 ± 2%) vs stable (SD, 41 ± 2%) (P < 0.0001). The area under the curve for PD from SD was 0.93 (cut-off for PD: 53%). Proliferation, epigenetic and somatostatin receptor gene expression was elevated (P < 0.03) in PD. Metabolic gene expression was decreased in SDHx mutations. Repeat NETest measurements defined clinical status in the 9 patients (6 SD and 3 PD). Amine measurement was non-informative. Multivariate analysis identified NETest >53% as an independent prognostic factor. Conclusion: Circulating NET transcript analysis is positive (100% diagnostic) in well-differentiated PCC/PGL, scores were elevated in progressive disease irrespective of mutation or biochemical activity and elevated levels were prognostic. © 2017 European Society of Endocrinology Printed in Great Britain.
Keywords: adolescent; adult; child; middle aged; young adult; genetics; prospective study; prospective studies; metabolism; paraganglioma; tumor marker; neuroendocrine tumor; pregnancy; pheochromocytoma; neuroendocrine tumors; somatostatin receptor; humans; human; female; receptors, somatostatin; biomarkers, tumor
Journal Title: European Journal of Endocrinology
Volume: 176
Issue: 2
ISSN: 0804-4643
Publisher: BioScientifica Ltd.  
Date Published: 2017-02-01
Start Page: 143
End Page: 157
Language: English
DOI: 10.1530/eje-16-0727
PUBMED: 27913608
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 2 March 2017 -- Source: Scopus
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  1. Lisa   Bodei
    206 Bodei