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: Keck Michaela-Kristina , Tietze Anna , Sievers Philipp , Bison Brigitte , Avula Shivaram , Brandner Sebastian , Cheesman Edmund , Faure-Conter Cécile , Fenouil Tanguy , Figarella-Branger Dominique , Gauchotte Guillaume , Goebell Einar , Gojo Johannes , Haberler Christine , Hakumäki Juhana , Hayden James T , Jabado Nada , Korhonen Laura S , Korshunov Andrey , Koscielniak Ewa , Kramm Christof M , Kranendonk Mariëtte E G , Lavarino Cinzia , Lequin Maarten , Loiseau Hugues , Ludlow Louise E , Maher Ossama , Meyronet David , Nyman Per , Øra Ingrid , Perwein Thomas , Pesola Jouni , Rauramaa Tuomas , Reddingius Roel , Samuel David , Schouten-van Meeteren Antoinette Y N , Schüller Ulrich , Sexton-Oates Alexandra , Solomon David , Varlet Pascale , Vasiljevic Alexandre , von Kalle Thekla , Wefers Annika K , Wesseling Pieter , White Christine , Zamecnik Josef , Zapotocky Michal , von Hoff* Katja , Jones* David T W 
Published: June 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 &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.