title: Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup.
abstract: Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas.
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Jen-Chieh
authors.identifier: 0000-0001-7739-5934
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Public Health, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Lu
authors.affiliation: Integrated Laboratory, Center of Translational Medicine, Graduate Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun A
authors.initials: CA
authors.lastname: Changou
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Cher-Wei
authors.initials: CW
authors.lastname: Liang
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Pathology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
authors.forename: Hsien-Neng
authors.initials: HN
authors.lastname: Huang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lauria
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Department of Pathology, Cardinal Tien Hospital Yung-Ho Branch, New Taipei City, Taiwan.
authors.forename: Chin-Yao
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ying-Cheng
authors.initials: YC
authors.lastname: Chiang
authors.affiliation: Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuan-Ting
authors.identifier: 0000-0002-3657-1652
authors.initials: KT
authors.lastname: Kuo
mesh_terms: D018195:Adenosarcoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D020223:Chromosome Painting; D000072837:Chromothripsis; D056915:DNA Copy Number Variations; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009095:Mullerian Ducts / Q000737:chemistry / Q000473:pathology*; D016612:Paraffin Embedding; D010641:Phenotype; D014594:Uterine Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor