title: Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations.
abstract: Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplication (masked haploidization), which manifests as a near-homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome-wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two-tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype.
authors.affiliation: Department of Pathology, Leiden University Medical Center, RC, Leiden, Netherlands.
authors.forename: Willem E
authors.initials: WE
authors.lastname: Corver
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Kees
authors.initials: K
authors.lastname: Molenaar
authors.forename: Melanie
authors.initials: M
authors.lastname: Schrumpf
authors.forename: Brendy
authors.initials: B
authors.lastname: van den Akker
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Dina
authors.initials: D
authors.lastname: Ruano Neto
authors.forename: Jan
authors.initials: J
authors.lastname: Oosting
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D058534:Class I Phosphatidylinositol 3-Kinases; D004272:DNA, Mitochondrial / Q000235:genetics*; D056726:Genetic Association Studies; D006238:Haploidy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D009154:Mutation; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D007521:Isocitrate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020930:MAP Kinase Kinase Kinases