Pheochromocytomas are tumors that are derived from neural crest cells, which also give rise to the sympathetic nervous system. Inherited cases of pheochromocytoma are associated with mutations in a group of very dissimilar genes, presenting an intriguing puzzle as to how disruption of such different genes could cause the same disease. Further, noninherited somatic pheochromocytomas rarely exhibit mutations in the same genes that have been linked to the familial cancer. Dr. William G. Kaelin, Jr. from the Dana-Farber Cancer Institute and Brigham and Women's Hospital and colleagues found that all the genetic lesions associated with inherited pheochromocytomas result in a reduction of programmed cell death, called apoptosis, during development.
The researchers show that mutations in each of the disparate genes that cause familial pheochromocytoma, NF1, c-RET, SDH, and VHL, ultimately can interfere with the normal activity of EglN3, an enzyme that is required for apoptosis during development. Reduced apoptosis results in sympathetic neuronal progenitors that can elude developmental apoptosis and have a high risk of becoming cancerous later on. These results explain why NF1, c-RET, SDH, and VHL mutations are rare in somatic pheochromocytomas because mutations in these genes would no longer cause problems after the developmental window during which apoptosis occurs had passed. The authors speculate that escape from developmental apoptosis may play a role in other pediatric tumors that involve neural crest-derived cells, like neuroblastoma and medulloblastoma.
The researchers include Sungwoo Lee, Eijiro Nakamura, Haifeng Yang, Wenyi Wei and Susanne Schlisio of the Dana-Farber Cancer Institute and Brigham and Women's Hospital at Harvard Medical School in Boston, Massachusetts; Michelle S. Linggi of the Vanderbilt University Medical School in Nashville, Tennessee; Mini P. Sajan and Robert V. Farese of the James A. Haley Veterans Hospital and the University of South Florida College of Medicine in Tampa, Florida; Robert S. Freeman of the University of Rochester in Rochester, New York; Bruce D. Carter of the Center for Molecular Neuroscience at Vanderbilt University Medical School in Nashville, Tennessee; and William G. Kaelin, Jr. of the Howard Hughes Medical Institute in Chevy Chase, Maryland and the Dana-Farber Cancer Institute and Brigham and Women's Hospital at Harvard Medical School in Boston, Massachusetts. This work was supported by grants from NIH and Murray Foundation.
Lee et al.: "Neuronal Apoptosis linked to EglN3 Prolyl Hydroxylase and Familial Pheochromocytoma Genes: Developmental Culling and Cancer" Publishing in Cancer Cell, Vol. 8, August 2005, pages 155-167. DOI 10.1016/j.ccr.2005.06.015 www.cancercell.org