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.
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Acknowledgements
We want to thank the Microarray Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) for providing excellent technical support. This work was supported by the German Cancer Aid (Grant: 70112499). The laboratory of TGPG was supported by the Dr. Leopold and Carmen Ellinger foundation and the German Cancer Aid (Grant: 70112257).
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AvD, FKFK and CK conceptualized the project, FKFK and CK wrote the original draft. FKFK and CK coordinated data generation. CK, FS and AvD supervised RNA sequencing and DNA methylation array analysis, DSchr and DSt analyzed data. FKFK, MK, BT-C, AT, JNM, KTC, DS, SMP, LR-P, TK, TGPG, RB, HS, GM, PS, DS, HL, CBG, DGH, FK, AvD and CK provided tumor samples and corresponding metadata. All authors reviewed and approved of the final manuscript.
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PS: grants from MSD, BMS, Roche, Astra Zeneca, Novartis, Sanofi-Aventis, Chugai, Illumina and Thermo Fisher; personal fees from MSD, BMS, Roche, Astra Zeneca, AbbVie, Ipsen and Novartis. FS: lecturing honoraria from Illumina, Medac and Agilent; board member of AbbVie. SMP and AvD: patent pending for a “DNA-methylation based method for classifying tumors”. AvD: issued patent for IDH1R132H and BRAFv600E antibodies. All other authors declare no conflict of interest.
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This study was performed in accordance with the ethical standards of the institutional research committee and the Declaration of Helsinki.
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Kommoss, F.K.F., Stichel, D., Schrimpf, D. et al. DNA methylation-based profiling of uterine neoplasms: a novel tool to improve gynecologic cancer diagnostics. J Cancer Res Clin Oncol 146, 97–104 (2020). https://doi.org/10.1007/s00432-019-03093-w
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DOI: https://doi.org/10.1007/s00432-019-03093-w