Genomic Signatures Predict Poor Outcome in Undifferentiated Pleomorphic Sarcomas and Leiomyosarcomas

Sara Martoreli Silveira,Cristovam Scapulatempo Neto,Fabio Albuquerque Marchi,Sandra Aparecida Drigo,Mateus De Camargo Barros Filho,Rolando Andre Rios Villacis,Silvia Regina Rogatto,Ademar Lopes,Isabela Werneck Da Cunha

doi:10.1371/journal.pone.0067643

Sara Martoreli Silveira, Cristovam Scapulatempo Neto + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0067643

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Abstract

Undifferentiated high-grade pleomorphic sarcomas (UPSs) display aggressive clinical behavior and frequently develop local recurrence and distant metastasis. Because these sarcomas often share similar morphological patterns with other tumors, particularly leiomyosarcomas (LMSs), classification by exclusion is frequently used. In this study, array-based comparative genomic hybridization (array CGH) was used to analyze 20 UPS and 17 LMS samples from untreated patients. The LMS samples presented a lower frequency of genomic alterations compared with the UPS samples. The most frequently altered UPS regions involved gains at 20q13.33 and 7q22.1 and losses at 3p26.3. Gains at 8q24.3 and 19q13.12 and losses at 9p21.3 were frequently detected in the LMS samples. Of these regions, gains at 1q21.3, 11q12.2-q12.3, 16p11.2, and 19q13.12 were significantly associated with reduced overall survival times in LMS patients. A multivariate analysis revealed that gains at 1q21.3 were an independent prognostic marker of shorter survival times in LMS patients (HR = 13.76; P = 0.019). Although the copy number profiles of the UPS and LMS samples could not be distinguished using unsupervised hierarchical clustering analysis, one of the three clusters presented cases associated with poor prognostic outcome (P = 0.022). A relative copy number analysis for the ARNT, SLC27A3, and PBXIP1 genes was performed using quantitative real-time PCR in 11 LMS and 16 UPS samples. Gains at 1q21-q22 were observed in both tumor types, particularly in the UPS samples. These findings provide strong evidence for the existence of a genomic signature to predict poor outcome in a subset of UPS and LMS patients.

Highlights

Sarcomas are a heterogeneous group of mesenchymal tumors that represent approximately 1% of cancers diagnosed in adults and 15% of childhood tumors [1]
undifferentiated high-grade pleomorphic sarcomas (UPSs), which have been previously known referred to as malignant fibrous histiocytomas (MFHs), represent 5% of Soft-tissue sarcomas (STSs) diagnosed in adults [3]
The majority of these studies did not report whether the tested samples were collected from patients who had received either chemotherapy or radiotherapy prior to surgery

Summary

Introduction

Sarcomas are a heterogeneous group of mesenchymal tumors that represent approximately 1% of cancers diagnosed in adults and 15% of childhood tumors [1]. The first group includes tumors with non-pleomorphic morphologies, which are usually associated with genomic translocations and certain specific mutations, and tumors with pleomorphic morphologies, which are associated with complex chromosomal alterations and genomic instability [2]. UPSs, which have been previously known referred to as malignant fibrous histiocytomas (MFHs), represent 5% of STSs diagnosed in adults [3]. These aggressive tumors frequently show local recurrence and can metastasize to distant sites [4]. A number of important signaling pathways required for the maintenance of mesenchymal stem cells (MSCs) have been associated with UPS cell tumorigenicity [6,7]

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