Back to Search
Start Over
Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup
- Source :
- Modern Pathology. 29:1070-1082
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- Subjects :
- Adult
0301 basic medicine
medicine.medical_specialty
Pathology
DNA Copy Number Variations
Gene Dosage
Copy number analysis
Biology
Molecular Inversion Probe
Chromosome Painting
Pathology and Forensic Medicine
Young Adult
03 medical and health sciences
0302 clinical medicine
CDKN2A
Chromosome instability
Biomarkers, Tumor
medicine
Humans
Genetic Predisposition to Disease
Copy-number variation
Mullerian Ducts
Chromosome 12
Aged
Chromothripsis
Paraffin Embedding
Adenosarcoma
Cytogenetics
Middle Aged
Immunohistochemistry
Phenotype
030104 developmental biology
030220 oncology & carcinogenesis
Uterine Neoplasms
Female
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 08933952
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Modern Pathology
- Accession number :
- edsair.doi.dedup.....f798e1e3fda069cc11b2e402125362f2