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Targeted genomic analysis of Müllerian adenosarcoma
Brooke E Howitt1, Lynette M Sholl, P Dal Cin
1Women's and Perinatal Pathology Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
The Journal of Pathology
|September 19, 2014
Summary
Genomic analysis of Müllerian adenosarcoma (MA) reveals copy number variations, not mutations, distinguish tumors with sarcomatous overgrowth (SO). These findings may lead to new diagnostic and prognostic tools for this rare cancer.
Area of Science:
- Gynecologic Oncology
- Cancer Genomics
- Pathology
Background:
- Müllerian adenosarcoma (MA) is a rare female genital tract tumor with malignant stroma and benign epithelium.
- Sarcomatous overgrowth (SO) is the sole histological predictor of poorer prognosis in MA.
- Current diagnostic and prognostic tools for MA lack specific molecular or immunohistochemistry (IHC) markers.
Purpose of the Study:
- To investigate genomic mutations and copy number variations (CNVs) in MA.
- To elucidate the pathobiology of MA and identify potential diagnostic and prognostic biomarkers.
- To correlate genomic findings with histological subtypes, specifically the presence or absence of SO.
Main Methods:
- DNA extraction from 20 MA samples (18 subjects), including areas with and without SO.
- Targeted next-generation sequencing (NGS) of 275 cancer genes for mutations and CNVs.
- Analysis of 91 introns across 30 genes for cancer-associated rearrangements.
- Immunohistochemistry (IHC) for CDK4, MDM2, and HMGA2 expression.
Main Results:
- No significant difference in the mean number of mutations between MA with and without SO.
- MA with SO showed significantly higher mean numbers of gene-level CNVs compared to MA without SO (24.6 vs. 5; p=0.0002).
- Frequent amplifications of MDM2 and CDK4 (28%) and MYBL1 (22%) were observed, with MYBL1 amplification predominantly in SO.
- Alterations in the PIK3CA/AKT/PTEN pathway were present in 72% of cases.
- TP53 mutations were rare (2 cases, both with SO); ATRX mutations were associated with SO (3 cases, 17%).
- No chromosomal rearrangements were detected.
Conclusions:
- Recurrent genomic alterations, particularly CNVs, are identified in MA.
- Specific CNVs, such as MDM2, CDK4, and MYBL1 amplifications, are associated with MA, and some correlate with sarcomatous overgrowth.
- These genomic findings represent potential novel diagnostic and prognostic markers for MA, warranting further investigation.
