The Molecular Landscape of ETMR at Diagnosis and Relapse

ETMRs are aggressive pediatric embryonal brain tumors with universally dismal outcome1. We collected 193 primary ETMRs and 23 matched relapses to investigate the genomic landscape of this distinct entity. We found that patients having tumors without C19MC amplification, the proposed driver(3–5), frequently harbor DICER1 germline mutations or other miRNA-related aberrations including somatic miR-17–92 amplifications. Whole-genome sequencing revealed an overall low recurrence of SNVs, but prevalent R-loop-associated chromosomal instability, of which we show that this can be induced by loss of DICER1 function. Comparing primary tumors and matched relapses revealed a strong conservation of SVs but low conservation of SNVs. Moreover, many newly acquired SNVs are associated to a new cisplatin treatment related mutational signature. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.