Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness

SIMPLE SUMMARY: Although the genetic event that initiates liposarcoma is relatively well studied, understanding how the tumor progresses and displays differential severities will shed new insights into the diagnosis and prognosis determination of patients with liposarcoma. We analyzed the genome and transcriptome of liposarcoma samples and found that the overexpression of the histone gene cluster is an important determinant for dedifferentiated liposarcoma in predicting genome instability and cell proliferation. The overexpression of histone genes was caused by increased HMGA2 with amplification of chromosome 12q13-14. This dedifferentiated liposarcoma-specific genetic signature may serve as a biomarker for prognosis prediction. ABSTRACT: Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.