Germline mutations in the RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, NF1 
or VHL genes are identified in about 30% of patients with pheochromocytoma or 
paraganglioma and somatic mutations in RET, VHL or MAX genes are reported in 17% 
of sporadic tumors. In the present study, using mutation screening of the NF1 
gene, mapping of chromosome aberrations by single nucleotide polymorphism (SNP) 
array, microarray-based expression profiling and immunohistochemistry (IHC), we 
addressed the implication of NF1 somatic alterations in pheochromocytomas and 
paragangliomas. We studied 53 sporadic tumors, selected because of their 
classification with RET/NF1/TMEM127-related tumors by genome wide expression 
studies, as well as a second set of 11 independent tumors selected on their low 
individual levels of NF1 expression evaluated by microarray. Direct sequencing 
of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 
somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with 
loss of the wild-type allele in 84% (21/25) of cases. Gene expression signature 
of NF1-related tumors highlighted the downregulation of NF1 and the major 
overexpression of SOX9. Among the second set of 11 tumors, two sporadic tumors 
carried somatic mutations in NF1 as well as in another susceptibility gene. 
These new findings suggest that NF1 loss of function is a frequent event in the 
tumorigenesis of sporadic pheochromocytoma and strengthen the new concept of 
molecular-based targeted therapy for pheochromocytoma or paraganglioma.