Felix K F Kommoss1, Damian Stichel2,3, Daniel Schrimpf2,3, Mark Kriegsmann1, Basile Tessier-Cloutier4, Aline Talhouk4, Jessica N McAlpine5, Kenneth T E Chang6, Dominik Sturm7,8,9, Stefan M Pfister7,8,9, Laura Romero-Pérez10, Thomas Kirchner11, Thomas G P Grünewald10, Rolf Buslei12, Hans-Peter Sinn1, Gunhild Mechtersheimer1, Peter Schirmacher1, Dietmar Schmidt13, Hans-Anton Lehr14, Felix Sahm2, David G Huntsman4, C Blake Gilks4, Friedrich Kommoss14, Andreas von Deimling2,3, Christian Koelsche15. 1. Department of Pathology, Institute of Pathology, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany. 2. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 3. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada. 5. Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada. 6. Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore. 7. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. 8. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. 9. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. 10. Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. 11. Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. 12. Institute of Pathology, Sozialstiftung Bamberg, Bamberg, Germany. 13. Institute of Pathology, Viersen, Germany. 14. Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, Germany. 15. Department of Pathology, Institute of Pathology, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany. Christian.Koelsche@med.uni-heidelberg.de.
Abstract
PURPOSE: Uterine neoplasms comprise a broad spectrum of lesions, some of which may pose a diagnostic challenge even to experienced pathologists. Recently, genome-wide DNA methylation-based classification of central nervous system tumors has been shown to increase diagnostic precision in clinical practice when combined with standard histopathology. In this study, we describe DNA methylation patterns of a diverse set of uterine neoplasms and test the applicability of array-based DNA methylation profiling. METHODS: A multicenter cohort including prototypical epithelial and mesenchymal uterine neoplasms was collected. Tumors were subject to pathology review and array-based DNA methylation profiling (Illumina Infinium HumanMethylation450 or EPIC [850k] BeadChip). Methylation data were analyzed by unsupervised hierarchical clustering and t-SNE analysis. RESULTS: After sample retrieval and pathology review the study cohort consisted of 49 endometrial carcinomas (EC), 5 carcinosarcomas (MMMT), 8 uterine leiomyomas (ULMO), 7 uterine leiomyosarcomas (ULMS), 15 uterine tumor resembling ovarian sex cord tumors (UTROSCT), 17 low-grade endometrial stromal sarcomas (LGESS) and 9 high-grade endometrial stromal sarcomas (HGESS). Analysis of methylation data identified distinct methylation clusters, which correlated with established diagnostic categories of uterine neoplasms. MMMT clustered together with EC, while ULMO, ULMS and UTROSCT each formed distinct clusters. The LGESS cluster differed from that of HGESS, and within the branch of HGESS, we observed a notable subgrouping of YWHAE- and BCOR-rearranged tumors. CONCLUSION: Herein, we describe distinct DNA methylation signatures in uterine neoplasms and show that array-based DNA methylation analysis holds promise as an ancillary tool to further characterize uterine neoplasms, especially in cases which are diagnostically challenging by conventional techniques.
PURPOSE:Uterine neoplasms comprise a broad spectrum of lesions, some of which may pose a diagnostic challenge even to experienced pathologists. Recently, genome-wide DNA methylation-based classification of central nervous system tumors has been shown to increase diagnostic precision in clinical practice when combined with standard histopathology. In this study, we describe DNA methylation patterns of a diverse set of uterine neoplasms and test the applicability of array-based DNA methylation profiling. METHODS: A multicenter cohort including prototypical epithelial and mesenchymal uterine neoplasms was collected. Tumors were subject to pathology review and array-based DNA methylation profiling (Illumina Infinium HumanMethylation450 or EPIC [850k] BeadChip). Methylation data were analyzed by unsupervised hierarchical clustering and t-SNE analysis. RESULTS: After sample retrieval and pathology review the study cohort consisted of 49 endometrial carcinomas (EC), 5 carcinosarcomas (MMMT), 8 uterine leiomyomas (ULMO), 7 uterine leiomyosarcomas (ULMS), 15 uterine tumor resembling ovarian sex cord tumors (UTROSCT), 17 low-grade endometrial stromal sarcomas (LGESS) and 9 high-grade endometrial stromal sarcomas (HGESS). Analysis of methylation data identified distinct methylation clusters, which correlated with established diagnostic categories of uterine neoplasms. MMMT clustered together with EC, while ULMO, ULMS and UTROSCT each formed distinct clusters. The LGESS cluster differed from that of HGESS, and within the branch of HGESS, we observed a notable subgrouping of YWHAE- and BCOR-rearranged tumors. CONCLUSION: Herein, we describe distinct DNA methylation signatures in uterine neoplasms and show that array-based DNA methylation analysis holds promise as an ancillary tool to further characterize uterine neoplasms, especially in cases which are diagnostically challenging by conventional techniques.
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