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Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

ABSTRACT: PURPOSE:Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution. EXPERIMENTAL DESIGN:We interrogated whole-exome sequencing (WES) from "trios" of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios. RESULTS:Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype. CONCLUSIONS:From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.

SUBMITTER: Amin-Mansour A

PROVIDER: S-EPMC7341441 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

Amin-Mansour Ali A George Suzanne S Sioletic Stefano S Carter Scott L SL Rosenberg Mara M Taylor-Weiner Amaro A Stewart Chip C Chevalier Aaron A Seepo Sara S Tracy Adam A Getz Gad G Hornick Jason L JL Nucci Marisa R MR Quade Bradley B Demetri George D GD Raut Chandrajit P CP Garraway Levi A LA Van Allen Eliezer M EM Wagner Andrew J AJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20190604 16

<h4>Purpose</h4>Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution.<h4>Experimental design</h4>We interrogated whole-exo ...[more]

PMID: 31164371

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Project description:BACKGROUND:Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. METHODS:We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. RESULTS:We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13-15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p?=?0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. CONCLUSIONS:Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.

Project description:BackgroundRetroperitoneal soft tissue sarcomas (STS) include a number of histologies but are rare, with approximately 3000 cases in the USA per year. Retroperitoneal STS have a high incidence of local and distant recurrence. The purpose of this study was to review the University of Maryland Medical Center's (UMMC) treatment experience of retroperitoneal STS, where the patient population served represents a diverse socioeconomic and ethnic catchment.MethodsIRB approval was obtained. We constructed a de-identified database of patients diagnosed with retroperitoneal liposarcomas (LPS) or leiomyosarcomas (LMS) treated at UMMC between 2000 and 2013. A total of 49 patients (Pts) with retroperitoneal STS met our eligibility criteria. Kaplan-Meier plots were used to graphically portray progression-free survival (PFS) and overall survival (OS). The log-rank test was used to compare time-to-event distributions.ResultsThe median OS for all patients (Pts) was 6.3 years, and the 2-year OS rate was 81%. The median PFS for all Pts was 1.8 years, and the 2-year PFS rate was 45%. There was no difference in OS and PFS among LMS and LPS patients; the median OS for LMS was 3.8 years vs. LPS 6.4 years (p = 0.33), and the median PFS for LMS was 1.2 years vs. LPS 2.5 years (p = 0.28). There was a significant difference between histology and race (p = 0.001). LPS were primarily Caucasian 86% vs. 14% black, whereas LMS were primarily black 52% vs. 33% Caucasian. OS was influenced by functional status, gender, American Joint Committee on Cancer (AJCC) stage, grade, histology, tumor size, and extent of resection. PFS was influenced by AJCC stage, grade, and extent of resection. Neither adjuvant chemotherapy (1 Pt) nor neoadjuvant/adjuvant radiation therapy (18 Pts) influenced OS or PFS. There was a non-significant difference that Pts who could undergo resection of local recurrence had improved 2-year OS, with 100% LMS and LPS compared to 2-year OS of 71% (LMS) and 78% (LPS) not undergoing resection of local recurrence.ConclusionsThis study suggests a higher incidence of leiomyosarcoma in the African-American population. This study confirms the prognostic importance of grade, tumor size, AJCC stage, histology, and extent of resection in patient outcomes, at a large substantially diverse academic medical center. Future research into the biological features of liposarcoma and leiomyosarcoma Pts imparting these characteristics will be important to define.

Dataset Information

Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

Publications

Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

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