No 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.

The clinical phenotype linked with mutations in ABCB1, encoding P‐glycoprotein, has never been reported. Here, we describe twin sisters with biallelic mutations in ABCB1 who showed recurrent reversible encephalopathy accompanied by acute febrile or afebrile illness. Whole‐exome sequencing was performed on one of the twin and her healthy parents, and revealed compound heterozygous loss‐of‐function variants in ABCB1. The patient brains displayed substantial loss of xenobiotic clearance ability, as demonstrated by [11C]verapamil positron emission tomography (PET) study, linking this phenotype with ABCB1 function. The endogenous cytokine clearance from the brain was also decreased in LPS‐treated ABCB1 knockout mice compared to controls. The results provide insights into the physiological requirement of ABCB1 in maintaining homeostasis of various compounds for normal brain function.