The presence of markedly higher tumor tissue contents of epinephrine in patients with MEN 2 and NF1 than in those with mutations of VHL, SDHB, and SDHD genes represented the clearest distinguishing feature.
2A), plasma concentrations of metanephrine almost completely distinguished patients with MEN 2 and NF1 from those with mutations of VHL, SDHD, and SDHB genes (Fig.
Among the patients with SDHB and SDHD mutations there were 11 who had tumors with adrenal locations.
Plasma concentrations of methoxytyramine and dopamine showed additional patterns useful for distinguishing patients with SDHB and SDHD gene mutations from those with other mutations (Fig.
The 10% of patients with VHL, SDHB, or SDHD mutations who exhibited slight increases of metanephrine above the upper reference intervals (Fig.
Discriminant analysis indicated that measurements ofplasma metanephrine considered alone could be used to correctly classify 97% of patients into 2 groups: 1 group with MEN 2 and NF1 and the other with mutations of VHL, SDHB, and SDHD (Table 3).
Measurements of plasma methoxytyramine provided the best single biomarker for further distinguishing VHL patients from patients with mutations of SDHB and SDHD genes, correctly classifying 78% patients into either of these 2 groups (Table 3).
As illustrated by 3-dimensional plots of plasma concentrations of normetanephrine, metanephrine and methoxytyramine, data from patients with MEN 2 and NF1 clustered together within a group distinct from patients with mutations of VHL, SDHB, and SDHD genes (Fig.
In contrast, for patients with VHL, SDHB, or SDHD gene mutations, plasma concentrations of metanephrine showed no relationships with either of the 2 other biomarkers; positive relationships were observed only for plasma concentrations of normetanephrine vs methoxytyramine (VHL, r = 0.
Findings of distinct profiles for catecholamine O-methylated metabolites among different groups of patients with hereditary tumors are supported by additional measurements of catecholamines in tumor tissue and novel data are presented showing that plasma methoxytyramine provides a particularly sensitive biomarker for indicating tumoral dopamine production in patients with mutations of SDHB and SDHD genes.
In contrast to MEN 2 and NF1 groups, tumors from patients with VHL, SDHB, and SDHD mutations are characterized by low tissue levels of epinephrine.
The present study reports for the first time that more than two-thirds of patients with either SDHB or SDHD mutations have increases in plasma methoxytyramine and that in the former patients this finding reflects the tumor contents of dopamine.