title: Somatic complex I disruptive mitochondrial DNA mutations are modifiers of tumorigenesis that correlate with low genomic instability in pituitary adenomas.
abstract: Mitochondrial DNA (mtDNA) mutations leading to the disruption of respiratory complex I (CI) have been shown to exhibit anti-tumorigenic effects, at variance with those impairing only the function but not the assembly of the complex, which appear to contribute positively to cancer development. Owing to the challenges in the analysis of the multi-copy mitochondrial genome, it is yet to be determined whether tumour-associated mtDNA lesions occur as somatic modifying factors or as germ-line predisposing elements. Here we investigated the whole mitochondrial genome sequence of 20 pituitary adenomas with oncocytic phenotype and identified pathogenic and/or novel mtDNA mutations in 60% of the cases. Using highly sensitive techniques, namely fluorescent PCR and allele-specific locked nucleic acid quantitative PCR, we identified the most likely somatic nature of these mutations in our sample set, since none of the mutations was detected in the corresponding blood tissue of the patients analysed. Furthermore, we have subjected a series of 48 pituitary adenomas to a high-resolution array comparative genomic hybridization analysis, which revealed that CI disruptive mutations, and the oncocytic phenotype, significantly correlate with low number of chromosomal aberrations in the nuclear genome. We conclude that CI disruptive mutations in pituitary adenomas are somatic modifiers of tumorigenesis most likely contributing not only to the development of oncocytic change, but also to a less aggressive tumour phenotype, as indicated by a stable karyotype.
authors.affiliation: Dip. di Scienze Mediche e Chirurgiche, U.O. Genetica Medica, Bologna, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kurelac
authors.forename: Alan
authors.initials: A
authors.lastname: MacKay
authors.forename: Maryou B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: Erica
authors.initials: E
authors.lastname: Di Cesare
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Isabella
authors.initials: I
authors.lastname: Morra
authors.forename: Antonio
authors.initials: A
authors.lastname: Melcarne
authors.forename: Luca
authors.initials: L
authors.lastname: Morandi
authors.forename: Francesco Maria
authors.initials: FM
authors.lastname: Calabrese
authors.forename: Marcella
authors.initials: M
authors.lastname: Attimonelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D010641:Phenotype; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D016415:Sequence Alignment
chemical_list: D004272:DNA, Mitochondrial; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C112633:PTTG1IP protein, human; D042967:Electron Transport Complex I