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Characterization and plasma measurement of the WE-14 peptide in patients with pheochromocytoma.

Guillemot J, Guérin M, Thouënnon E, Montéro-Hadjadje M, Leprince J, Lefebvre H, Klein M, Muresan M, Anouar Y, Yon L - PLoS ONE (2014)

Bottom Line: Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors.However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays.These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France ; Normandy University, Normandy, France ; Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France ; Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.

ABSTRACT
Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

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EM66 levels in the plasma of patients with pheochromocytoma.(A) Scattergram of EM66 concentrations in plasma samples of healthy volunteers (controls, ×, n = 21), and patients with pheochromocytoma before surgical removal of the tumor (preop, +, n = 37). (B) Distribution of EM66 preoperative concentrations of patients reported in (A), depending on the adrenal (PHEO, ▴, n = 26) or extra-adrenal (PGL, ▾, n =  11) location of the tumor, the benign (•, n = 32) or malignant (▪, n = 5), and the sporadic (♦, n = 24) or hereditary (•, n = 13) nature of the neoplasm. The grey zone corresponds to the distribution of control values and indicates the cut-off level for EM66 test assay. See legends of Figure 2 for other designations.
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pone-0088698-g005: EM66 levels in the plasma of patients with pheochromocytoma.(A) Scattergram of EM66 concentrations in plasma samples of healthy volunteers (controls, ×, n = 21), and patients with pheochromocytoma before surgical removal of the tumor (preop, +, n = 37). (B) Distribution of EM66 preoperative concentrations of patients reported in (A), depending on the adrenal (PHEO, ▴, n = 26) or extra-adrenal (PGL, ▾, n =  11) location of the tumor, the benign (•, n = 32) or malignant (▪, n = 5), and the sporadic (♦, n = 24) or hereditary (•, n = 13) nature of the neoplasm. The grey zone corresponds to the distribution of control values and indicates the cut-off level for EM66 test assay. See legends of Figure 2 for other designations.

Mentions: In the plasma of healthy volunteers (n = 21), EM66 concentrations ranged from 0.615–4.953 ng/ml with a median value of 2.584 ng/ml (Figure 5A). The concentrations of EM66 in preoperative patients (n = 37) ranged from 1.411–51.260 ng/ml with a median value of 7.329 ng/ml (Figure 5A). Statistical analysis revealed that the median value of EM66 concentrations was significantly higher in patients than in healthy volunteers (p<0.001) (Figure 5A). EM66 concentrations were not significantly different between patients with pheochromocytomas or paraganglioma [7.323 (1.411–46.789) vs 7.329 (2.306–51.257) ng/ml, respectively] (Figure 5B), while for these two groups, the EM66 median values were significantly higher compared to healthy volunteers (p<0.001) (Figures 5A-B). Patients with benign pheochromocytomas did not show any significant difference in plasma EM66 concentrations compared to patients with malignant tumors [7.378 (2.306–51.257) vs 3.226 (1.411–26.611) ng/ml, respectively] (Figure 5B). Finally, EM66 concentrations were not significantly different between patients with sporadic or hereditary pheochromocytoma [7.829 (1.411–46.789) vs 6.950 (2.306–51.257) ng/ml, respectively] (Figure 5B), while for the two groups the EM66 median values were significantly higher than that in healthy volunteers (p<0.001, p<0.01, respectively) (Figures 5A-B). A positive correlation was found between WE-14 and EM66 or between CgA and EM66 concentrations in plasma of patients with pheochromocytoma (r  =  0.509 and r  =  0.470, respectively; p<0.01, n = 37) (data not shown). No correlation was found between tumor size and EM66 levels (r  =  0.286) (data not shown).


Characterization and plasma measurement of the WE-14 peptide in patients with pheochromocytoma.

Guillemot J, Guérin M, Thouënnon E, Montéro-Hadjadje M, Leprince J, Lefebvre H, Klein M, Muresan M, Anouar Y, Yon L - PLoS ONE (2014)

EM66 levels in the plasma of patients with pheochromocytoma.(A) Scattergram of EM66 concentrations in plasma samples of healthy volunteers (controls, ×, n = 21), and patients with pheochromocytoma before surgical removal of the tumor (preop, +, n = 37). (B) Distribution of EM66 preoperative concentrations of patients reported in (A), depending on the adrenal (PHEO, ▴, n = 26) or extra-adrenal (PGL, ▾, n =  11) location of the tumor, the benign (•, n = 32) or malignant (▪, n = 5), and the sporadic (♦, n = 24) or hereditary (•, n = 13) nature of the neoplasm. The grey zone corresponds to the distribution of control values and indicates the cut-off level for EM66 test assay. See legends of Figure 2 for other designations.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3921219&req=5

pone-0088698-g005: EM66 levels in the plasma of patients with pheochromocytoma.(A) Scattergram of EM66 concentrations in plasma samples of healthy volunteers (controls, ×, n = 21), and patients with pheochromocytoma before surgical removal of the tumor (preop, +, n = 37). (B) Distribution of EM66 preoperative concentrations of patients reported in (A), depending on the adrenal (PHEO, ▴, n = 26) or extra-adrenal (PGL, ▾, n =  11) location of the tumor, the benign (•, n = 32) or malignant (▪, n = 5), and the sporadic (♦, n = 24) or hereditary (•, n = 13) nature of the neoplasm. The grey zone corresponds to the distribution of control values and indicates the cut-off level for EM66 test assay. See legends of Figure 2 for other designations.
Mentions: In the plasma of healthy volunteers (n = 21), EM66 concentrations ranged from 0.615–4.953 ng/ml with a median value of 2.584 ng/ml (Figure 5A). The concentrations of EM66 in preoperative patients (n = 37) ranged from 1.411–51.260 ng/ml with a median value of 7.329 ng/ml (Figure 5A). Statistical analysis revealed that the median value of EM66 concentrations was significantly higher in patients than in healthy volunteers (p<0.001) (Figure 5A). EM66 concentrations were not significantly different between patients with pheochromocytomas or paraganglioma [7.323 (1.411–46.789) vs 7.329 (2.306–51.257) ng/ml, respectively] (Figure 5B), while for these two groups, the EM66 median values were significantly higher compared to healthy volunteers (p<0.001) (Figures 5A-B). Patients with benign pheochromocytomas did not show any significant difference in plasma EM66 concentrations compared to patients with malignant tumors [7.378 (2.306–51.257) vs 3.226 (1.411–26.611) ng/ml, respectively] (Figure 5B). Finally, EM66 concentrations were not significantly different between patients with sporadic or hereditary pheochromocytoma [7.829 (1.411–46.789) vs 6.950 (2.306–51.257) ng/ml, respectively] (Figure 5B), while for the two groups the EM66 median values were significantly higher than that in healthy volunteers (p<0.001, p<0.01, respectively) (Figures 5A-B). A positive correlation was found between WE-14 and EM66 or between CgA and EM66 concentrations in plasma of patients with pheochromocytoma (r  =  0.509 and r  =  0.470, respectively; p<0.01, n = 37) (data not shown). No correlation was found between tumor size and EM66 levels (r  =  0.286) (data not shown).

Bottom Line: Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors.However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays.These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France ; Normandy University, Normandy, France ; Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France ; Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada.

ABSTRACT
Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

Show MeSH
Related in: MedlinePlus