Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors.
Neurofibromatosis type 1 is an autosomal dominantly inherited disease predisposing to a multitude of tumors, most characteristically benign plexiform neurofibromas and diffuse cutaneous neurofibromas. We investigated the presence and distribution of somatic mitochondrial DNA (mtDNA) mutations in neurofibromas and in nontumor tissue of neurofibromatosis type 1 patients. MtDNA alterations in the entire mitochondrial genome were analyzed by temporal temperature gradient gel electrophoresis followed by DNA sequencing. Somatic mtDNA mutations in tumors were found in 7 of 19 individuals with cutaneous neurofibromas and in 9 of 18 patients with plexiform neurofibromas. A total of 34 somatic mtDNA mutations were found. All mutations were located in the displacement loop region of the mitochondrial genome. Several plexiform neurofibromas from individual patients had multiple homoplasmic mtDNA mutations. In cutaneous neurofibromas, the same mtDNA mutations were always present in tumors from different locations of the same individual. An increase in the proportion of the mutant mtDNA was always found in the neurofibromas when compared with nontumor tissues. The somatic mtDNA mutations were present in the Schwann cells of the analyzed multiple cutaneous neurofibromas of the same individual. The observed dominance of a single mtDNA mutation in multiple cutaneous neurofibromas of individual patients indicates a common tumor cell ancestry and suggests a replicative advantage rather than random segregation for cells carrying these mutated mitochondria.
Kurtz
Andreas
A
Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
Lueth
Maria
M
Kluwe
Lan
L
Zhang
Tingguo
T
Foster
Rosemary
R
Mautner
Victor-Felix
VF
Hartmann
Melanie
M
Tan
Duan-Jun
DJ
Martuza
Robert L
RL
Friedrich
Reinhard E
RE
Driever
Pablo Hernáiz
PH
Wong
Lee-Jun C
LJ
D001483:Base Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D016514:Genes, Neurofibromatosis 1; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000378:metabolism
D004272:DNA, Mitochondrial