ETMR-28. EVALUATING THERAPEUTIC APPROACHES IN EMBRYONAL TUMORS WITH PLAGL1 AND PLAGL2 AMPLIFICATION AND UNRAVELING MOLECULAR PARALLELS IN EPIGENETICALLY RELATED TUMORS WITH PLAG1-ALTERATIONS
Authors: Michaela-Kristina Keck, Anna Tietze, Philipp Sievers, Brigitte Bison, Shivaram Avula, Sebastian Brandner, Edmund Cheesman, Cécile Faure-Conter, Tanguy Fenouil, Dominique Figarella-Branger, Guillaume Gauchotte, Einar Goebell, Johannes Gojo, Christine Haberler, Juhana Hakumäki, James T Hayden, Nada Jabado, Laura S Korhonen, Andrey Korshunov, Ewa Koscielniak, Christof M Kramm, Mariëtte E G Kranendonk, Cinzia Lavarino, Maarten Lequin, Hugues Loiseau, Louise E Ludlow, Ossama Maher, David Meyronet, Per Nyman, Ingrid Øra, Thomas Perwein, Jouni Pesola, Tuomas Rauramaa, Roel Reddingius, David Samuel, Antoinette Y N Schouten-van Meeteren, Ulrich Schüller, Alexandra Sexton-Oates, David Solomon, Pascale Varlet, Alexandre Vasiljevic, Thekla von Kalle, Annika K Wefers, Pieter Wesseling, Christine White, Josef Zamecnik, Michal Zapotocky, Katja von Hoff*, David T W Jones*
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Embryonal tumors with PLAGL1 and PLAGL2 amplification (ET, PLAGL) display substantial clinical heterogeneity regarding applied treatment and outcomes. As a recently-defined entity, the spectrum of tumor-driving PLAG-family alterations is not yet fully elucidated. METHODS We analyzed clinical and MRI data from patients with ET, PLAGL. Second, we identified and analyzed tumors with epigenetic similarities. RESULTS 18 patients with ET, PLAGL revealed diverse clinical behavior. Patients with PLAGL1-amplified tumors (ET, PLAGL1) were older (median 8 years), had a higher rate of complete resections (6/9) and fewer relapses (3/9). Patients with PLAGL2-amplified tumors (ET, PLAGL2) were younger (median 1.9 years), often incompletely resected (6/9) and prone to earlier relapse/progression. Five-year PFS was 89% and 17% (ET, PLAGL1/ET, PLAGL2), with no predictive value of initial surgical extent on PFS/OS. Postoperative treatment included chemotherapy (17/18, various protocols) alone (n=8) or combined with RT (n=9). The three survivors with ET, PLAGL2 underwent induction and high-dose chemotherapy. All five patients with less intensive chemotherapy relapsed. Most first and all subsequent ET, PLAGL2 relapses were distant, questioning the value of initial local radiotherapy. Two ET, PLAGL1 relapses occurred &amp;gt;8 years after diagnosis (one after, one without previous RT). Through methylation-based t-SNE we identified 143 tumors with epigenetic similarities to ET, PLAGL. Filtering revealed a core set of 27 tumors, of which seven displayed evidence of PLAG1-fusion events and one PLAG1-amplification. RNAseq analysis (n=4) revealed distinct gene fusions involving PLAG1, with similar genes upregulated (RET, CYP2W1 and imprinted genes) as in ET, PLAGL. Like ET, PLAGL, PLAG1-fused tumors, occurred in young children with different diagnoses and localizations. CONCLUSION PLAG1-fused tumors are epigenetically similar to ET, PLAGL, show similarities in gene expression, and need to be differentiated from neuroepithelial tumor with PLAGL1-fusion. Future investigations will examine differences in clinical behavior and the utility of PLAG1/L1/L2 IHC for diagnosis.