8bf968b0-879a-47a1-8fe5-9a9e447bd696
title
Chromosome 11 monosomy in conjunction with a mutated  SDHD  initiation codon in nonfamilial paraganglioma cases.
de6821a0-8031-41ff-9a5e-9df9924f01fd
abstract
Paragangliomas of the head and neck region are a group of rare, usually benign, slow-growing tumors developing from paraganglionic chemoreceptors in most patients. Mutations in a subunit of the  mitochondrial enzyme II complex (succinate dehydrogenase [SDHD])  were shown to be responsible for the formation of paragangliomas. In addition, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23 ( PGL1 ), was observed recently. We analyzed DNA derived from tumor sections of three unrelated paraganglioma patients (one case with multiple paragangliomas, two cases with single tumors; all of them sporadic cases) for mutations in the  SDHD  gene by direct sequencing. Microsatellite-based LOH was performed, and events of chromosomal loss were validated by fluorescence in situ hybridization (FISH) on paraffin-embedded tumor and normal tissue by using centromeric satellite DNA. Sequence analysis revealed mutations in  SDHD  exon 1 in all patients, affecting the initiation codon ( M1V ). Another alteration was detected in exon 2 but was lacking in tumor DNA and therefore classified as polymorphism ( H50R ). LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested. A common genetic mechanism appears to be the pathophysiologic basis for sporadic tumor development because the proposed two-hit model comprising both LOH and point mutation is manifest in our patients. Loss of chromosome 11 regions, including the deletion of  PGL1  and  PGL2  loci, may result in a more severe phenotype, as exemplified by the development of multiple tumors in one of the patients.