The molecular landscape of ETMR at diagnosis and relapse

Abstract

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][4][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.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…Recent data demonstrate that this amplification is present in 90% of ETMR, with the majority of remaining tumours showing disruption of the microRNA machinery by other mechanisms, mostly compound heterozygous mutations of the microRNA‐processing gene DICER1 , amplification of a microarray cluster on chromosome 13 (miR‐17‐92) or structural alterations of the C19MC locus not associated with an amplification . Regardless of C19MC amplification status, ETMRs form a single methylation class that is sufficiently distinct for robust tumour classification . A further DNA methylation‐based sub‐classification of ETMR is currently not possible .…”

“…Regardless of C19MC amplification status, ETMRs form a single methylation class that is sufficiently distinct for robust tumour classification . A further DNA methylation‐based sub‐classification of ETMR is currently not possible . However, it has been recognized that the histologically similar intraocular medulloepithelioma represents a distinct entity with a distinct DNA methylation profile .…”

“…However, it has been recognized that the histologically similar intraocular medulloepithelioma represents a distinct entity with a distinct DNA methylation profile . Copy number analysis will reveal a C19MC microRNA cluster amplification in around 90% of cases and may identify cases with the rare mutually exclusive amplification of the miR‐17‐92 cluster . C19MC amplifications are frequently associated with TTYH1 fusions but other fusion partners have also been identified .…”

“…Copy number analysis will reveal a C19MC microRNA cluster amplification in around 90% of cases and may identify cases with the rare mutually exclusive amplification of the miR‐17‐92 cluster . C19MC amplifications are frequently associated with TTYH1 fusions but other fusion partners have also been identified . The DNA methylation profile offers some guidance for additional molecular testing for cases without C19MC or miR‐17‐92 cluster amplification.…”

“…The DNA methylation profile offers some guidance for additional molecular testing for cases without C19MC or miR‐17‐92 cluster amplification. For these cases a high rate of germline DICER1 alterations can be expected and genetic counselling for DICER1 syndrome should be considered .…”