Krinio Giannikou, MSc, PhD

Research Associate
Medical Physics and Biophysics
Pulmonary and Critical Care Medicine
Distinct oncogenic signatures in malignant PEComa and leiomyosarcoma identified by integrative RNA-seq and H3K27ac ChIP-seq analysis

Principal Investigator: David J. Kwiatkowski

Authors: Krinio Giannikou1,2, Ahmad-Abdel Azim1*, Elio Adib1,2*, Inga-Marie Schaefer3, Nikolas Kesten2, Len Taing2, Zachary Zhu1, Jason L. Hornick3, Michelle S. Hirsch3, Henry W. Long1, Andrew J. Wagner4, Matthew L. Hemming4,#, David J. Kwiatkowski1,# 1 Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, USA 3 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 4 Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA * Equal second co-authors # senior co-authors
Lay Abstract

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.

Scientific Abstract

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.

Clinical Implications
We identified genes whose expression and regulation differ greatly between PEComa and LMS and may serve as biomarkers to distinguish these tumor types. Our studies also have the potential to identify novel therapeutic targets beyond mTORC1 inhibitors/rapalogs for PEComas

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