Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can 
occur either sporadically or in the context of hereditary tumor syndromes. 
Whereas the genetic background of hereditary pheochromocytomas is becoming 
rather well-defined, very little is known about the more common sporadic form of 
the disease which constitutes ∼70% of all cases. In this study, we elucidate 
some of the molecular mechanisms behind sporadic pheochromocytoma by performing 
a comprehensive analysis of copy number alterations, gene expression, promoter 
methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, 
SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with 
hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses 
of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an 
altered copy number in at least one of the known susceptibility genes, often in 
association with an altered messenger RNA (mRNA) expression. Specifically, 11 
sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which 
significantly correlated with a reduced NF1 mRNA expression. Subsequent 
sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic 
DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with 
NF1 loss. Our results thus suggest that the NF1 gene constitutes the most 
frequent (24%) target of somatic mutations so far known in sporadic 
pheochromocytomas.