Abstract
BackgroundThe potential pathogenetic significance of mitochondrial DNA (mtDNA) mutations in tumorigenesis is controversial. We hypothesized that benign tumorigenesis of a slowly replicating tissue like the human parathyroid might constitute an especially fertile ground on which a selective advantage conferred by mtDNA mutation could be manifested and might contribute to the oxyphilic phenotype observed in a subset of parathyroid tumors.MethodsWe sought acquired mitochondrial DNA mutations by sequencing the entire 16.6 kb mitochondrial genome of each of thirty sporadic parathyroid adenomas (18 chief cell and 12 oxyphil cell), eight independent, polyclonal, parathyroid primary chief cell hyperplasias plus corresponding normal control samples, five normal parathyroid glands, and one normal thyroid gland.ResultsTwenty-seven somatic mutations were identified in 15 of 30 (9 of 12 oxyphil adenomas, 6 of 18 chief cell) parathyroid adenomas studied. No somatic mutations were observed in the hyperplastic parathyroid glands.ConclusionFeatures of the somatic mutations suggest that they may confer a selective advantage and contribute to the molecular pathogenesis of parathyroid adenomas. Importantly, the statistically significant differences in mutation prevalence in oxyphil vs. chief cell adenomas also suggest that mtDNA mutations may contribute to the oxyphil phenotype.
Highlights
The potential pathogenetic significance of mitochondrial DNA mutations in tumorigenesis is controversial
The mitochondrial genome has been identified as a possible target for somatic mutations that may promote tumorigenesis [2,3,4,5,6,7,8,9,10]
One patient with primary chief cell hyperplasia had a hisc[FT3ohi0gme]upcroheisee1fdcoelflsspoafrasne amdietonochmoand(Ari)ahaanvdetahneaumsupahlooprhgialince, lvleacsuaosslaotceidatceydtowpiltahsmpr,owtehiinchsyonntheelesicstraonnd mseicreotsicoonp, igclyecxoagmeninatnidonlipisid The chief cells of an adenoma (A) have an amphophilic, vacuolated cytoplasm, which on electron microscopic examination is composed of sparse mitochondria and the usual organelles associated with protein synthesis and secretion, glycogen and lipid [30]
Summary
The potential pathogenetic significance of mitochondrial DNA (mtDNA) mutations in tumorigenesis is controversial. We hypothesized that benign tumorigenesis of a slowly replicating tissue like the human parathyroid might constitute an especially fertile ground on which a selective advantage conferred by mtDNA mutation could be manifested and might contribute to the oxyphilic phenotype observed in a subset of parathyroid tumors. The mitochondrial genome has been identified as a possible target for somatic mutations that may promote tumorigenesis [2,3,4,5,6,7,8,9,10]. Mitochondrial abnormalities, including changes in structure, number, and respiratory enzyme components and transport systems, have been observed in many cancers. Homoplasmic somatic mutations of the mitochondrial genome have been identi-. The pathogenetic significance of the mutations detected in those tissues is unclear
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