title: Mitochondrial cytochrome c oxidase subunit II variations predict adverse prognosis in cytogenetically normal acute myeloid leukaemia.
abstract: Alterations in the two catalytic genes cytochrome c oxidase subunits I and II (COI and COII) have recently been suggested to have an adverse impact on prognosis in patients with acute myeloid leukaemia (AML). In order to explore this in further detail, we sequenced these two mitochondrial genes in diagnostic bone marrow or blood samples in 235 patients with AML. In 37 (16%) patients, a non-synonymous variation in either COI or COII could be demonstrated. No patients harboured both COI and COII non-synonymous variations. Twenty-four (10%) patients had non-synonymous variations in COI, whereas 13 (6%) patients had non-synonymous variations in COII. The COI and COII are essential subunits of cytochrome c oxidase that is the terminal enzyme in the oxidative phosphorylation complexes. In terms of disease course, we observed that in patients with a normal cytogenetic analysis at disease presentation (CN-AML) treated with curative intent, the presence of a non-synonymous variation in the COII was an adverse prognostic marker for both overall survival and disease-free survival (DFS) in both univariate (DFS; hazard ratio (HR) 4.4, P = 0.006) and multivariate analyses (DFS; HR 7.2, P = 0.001). This is the first demonstration of a mitochondrial aberration playing an adverse prognostic role in adult AML, and we argue that its role as a potentially novel adverse prognostic marker in the subset of CN-AML should be explored further.
authors.affiliation: Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Silkjaer
authors.forename: Charlotte Guldborg
authors.initials: CG
authors.lastname: Nyvold
authors.forename: Caroline
authors.initials: C
authors.lastname: Juhl-Christensen
authors.forename: Peter
authors.initials: P
authors.lastname: Hokland
authors.forename: Jan Maxwell
authors.initials: JM
authors.lastname: Nørgaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000201:enzymology / Q000473:pathology; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; C581860:cytochrome c oxidase subunit I, human
keywords: acute myeloid leukaemia; cytochrome c oxidase subunit II; mitochondria; mitochondrial DNA; prognosis