Abstract
High-level amplification of MDM2 and other genes in the 12q13–15 locus is a hallmark genetic feature of well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS, respectively). Detection of this genomic aberration in plasma cell-free DNA may be a clinically useful assay for non-invasive distinction between these liposarcomas and other retroperitoneal tumors in differential diagnosis, and might be useful for the early detection of disease recurrence. In this study, we performed shallow whole genome sequencing of cell-free DNA extracted from 10 plasma samples from 3 patients with DDLPS and 1 patient with WDLPS. In addition, we studied 31 plasma samples from 11 patients with other types of soft tissue tumors. We detected MDM2 amplification in cell-free DNA of 2 of 3 patients with DDLPS. By applying a genome-wide approach to the analysis of cell-free DNA, we also detected amplification of other genes that are known to be recurrently affected in DDLPS. Based on the analysis of one patient with DDLPS with longitudinal plasma samples available, we show that tracking MDM2 amplification in cell-free DNA may be potentially useful for evaluation of response to treatment. The patient with WDLPS and patients with other soft tissue tumors in differential diagnosis were negative for the MDM2 amplification in cell-free DNA. In summary, we demonstrate the feasibility of detecting amplification of MDM2 and other DDLPS-associated genes in plasma cell-free DNA using technology that is already routinely applied for other clinical indications. Our results may have clinical implications for improved diagnosis and surveillance of patients with retroperitoneal tumors.
Highlights
Non-invasive sampling of tumor-derived genetic material through liquid biopsies may be beneficial for an improved management of patients with soft tissue tumors
All three patients with DDLPS had diagnostic fluorescence in situ hybridization (FISH) performed on the primary tumor specimens, which showed that all 3 tumors carried MDM2 amplification (Table 1)
In this study we demonstrate that MDM2 amplification can be detected by shallow whole genome sequencing of plasma cell-free DNA from patients with DDLPS
Summary
Non-invasive sampling of tumor-derived genetic material through liquid biopsies may be beneficial for an improved management of patients with soft tissue tumors. Profiling ctDNA has the potential to improve diagnosis, evaluation of response to treatment and long-term surveillance of patients with soft tissue tumors. Our group and others have previously showed that tumor-derived copy number aberrations can be detected in plasma of patients with leiomyosarcoma (LMS) and leiomyoma (LM) [2,3,4]. In LMS patients, we showed that the levels of ctDNA correspond with response to treatment, and that a combination approach that integrates detection of point mutations and copy number alterations substantially increases the number of molecular markers that can be tracked in plasma [2]
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