Principal Investigator: David J. Kwiatkowski
Perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two rare cancers that can affect multiple organs. These two types of cancers can be challenging to distinguish because they can look the same down the microscope in a subset of cases. In this study, we aimed to better understand these tumors at the epigenetic level. Epigenetics is the study of how genes are expressed in different types of cells. For example, in cancer cells, genes involved in cell growth are inappropriately over-expressed. Little is known regarding the epigenetic changes unique to PEComa and LMS. We applied cutting-edge sequencing approaches to study the epigenetics and gene expression patterns of PEComa and LMS. We discovered that although these tumors show many similarities, they also have distinct features. We discovered a set of genes whose expression was largely specific for each tumor type. These gene markers may serve as useful clinical tools for the distinction of these two overlapping tumor types. Our analyses will help to facilitate diagnosis and provide a deeper understanding of PEComa and LMS development.
Background: Perivascular epithelioid cell tumor (PEComa) and leiomyosarcoma (LMS) are two sarcomas with overlapping morphologic and immunophenotypic features which can make diagnosis challenging.
Aim: Characterize the transcriptional and epigenetic features of these two sarcomas to identify distinguishing features.
Methods: We performed RNA-seq on 19 PEComas and compared to 259 TCGA sarcomas including 104 LMS. H3K27ac ChIP-seq was conducted on 9 PEComas and 12 LMS, and compared to 4 other sarcoma subtypes publicly available.
Results: RNA-Seq and H3K27ac ChIP-Seq data showed major similarity between PEComa and LMS, which were distinct from other sarcomas. However, there were a set of highly expressed and H3K27ac marked genes that were highly different (>17x fold higher expression by DESeq2 (FDR<0.0001)) between PEComa and LMS: DAPL1; MLANA; SULT1C2; GPR143, and CHI3L1 for PEComa; and MYOCD; WDFC2; DES; MYH11, and CNN1 for LMS. GSEA analysis demonstrated greatest enrichment in the KEGG Lysosome pathway in PEComa, and in Myogenesis-Smooth Muscle Contraction in LMS. PEComas showed a higher degree of immune infiltration (specifically, macrophages) compared to LMS. Selected genes (N=11) were validated by immunohistochemistry in PEComa and LMS (N=26).
Conclusions: Our studies revealed novel markers including lysosomal/melanocytic and myogenic genes for PEComa and LMS, respectively, that may be useful to distinguish these two pathologic entities.