Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non-microdeletion patients

✍ Scribed by Thomas De Raedt; Ophélia Maertens; Magdalena Chmara; Hilde Brems; Ine Heyns; Raf Sciot; Elisa Majounie; Meena Upadhyaya; Sofie De Schepper; Frank Speleman; Ludwine Messiaen; Joris Robert Vermeesch; Eric Legius

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 716 KB
• Volume: 45
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20353

✦ Synopsis

Abstract

Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome characterized by the presence of multiple benign neurofibromas. In 95% of NF1 individuals, a mutation is found in the NF____1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF____1 gene and several flanking genes. We studied the frequency of loss of heterozygosity (LOH) in the NF____1 region as a mechanism of somatic NF____1 inactivation in neurofibromas from NF1 patients with and without a microdeletion. There was a statistically significant difference between these two patient groups in the proportion of neurofibromas with LOH. None of the 40 neurofibromas from six different NF____1 microdeletion patients showed LOH, whereas LOH was observed in 6/28 neurofibromas from five patients with an intragenic NF____1 mutation (P = 0.0034, Fisher's exact). LOH of the NF____1 microdeletion region in NF____1 microdeletion patients would de facto lead to a nullizygous state of the genes located in the deletion region and might be lethal. The mechanisms leading to LOH were further analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal microdeletion was found; in three, a mitotic recombination was responsible for the observed LOH; and in one, a chromosome loss with reduplication was present. These data show an important difference in the mechanisms of second hit formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor syndrome in which the type of germline mutation influences the type of second hit in the tumors. © 2006 Wiley‐Liss, Inc.