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

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

“…8 Selected cases were also analyzed using a DeltaVision deconvolution microscope (Applied Precision, South El Monte, CA, USA) as previously described. 13 …”

Whole-Genome Sequencing and Target Validation Analysis of Müllerian Adenosarcoma: A Tumor With Complex but Specific Genetic Alterations

“…Some commonalities have been identified in terms of copy number variations (CNVs) and mutations, but considerable heterogeneity is present, and no dominant or driver mutation has been identified. Studies to date suggest that MAS and its variants are genetically heterogeneous and CNVs are more frequent with SO (9,15). Unlike other uterine sarcomas, MAS does not demonstrate specific non-random chromosomal translocations or fusion gene abnormalities.…”

“…Typical MAS is low grade; however, two histologic features with prognostic significance have been described: MAS with stromal overgrowth [SO: pure sarcoma component comprising ≥25% of the tumor (7)] and high-grade sarcomatous transformation (8). SO is present in 33-53% of MAS, and is associated with older age, higher rates of recurrence and death, higher stage at presentation, and lower overall survival (6,7,(9)(10)(11)(12)(13). Treatment of MAS typically consists of hysterectomy; occasionally, more conservative resection is performed (4,10).…”

“…The genomic landscape and molecular pathogenesis of MAS and its variants remain unclear. Prior studies have employed a variety of methods, including targeted sequencing using cancer-related gene panels, whole-exome sequencing, fluorescence in situ hybridization, conventional cytogenetics, and immunohistochemistry (IHC), to evaluate the molecular changes in varied sample size of MAS cases (8,9,(14)(15)(16)(17). Some commonalities have been identified in terms of copy number variations (CNVs) and mutations, but considerable heterogeneity is present, and no dominant or driver mutation has been identified.…”

Uterine Adenosarcoma

“…In contrast, in another study, alterations of the TP53 pathway were quite frequent in high-grade cases - associated with an aggressive clinical behavior [19]. Others have demonstrated frequent chromosome 12q amplifications - including loci harboring potential pharmacological targets that may be of relevance in the future [20]. …”