Abstract ETMR are rare tumors of infancy characterized by undifferentiated neuroepithelial tumor cells, multilayered ependymoblastic rosettes and LIN28A expression. 90% of ETMR have alterations in the C19MC microRNA cluster; and a fraction of those lacking such C19MC alterations harbor DICER1 mutations. In this study, we aimed to histologically and molecularly characterize 12 ETMR cases lacking C19MC-alterations. Histologic and immunohistochemical analyses revealed a variety of morphological phenotypes including ependymoblastoma-like tumors and medulloepithelioma-like tumors as well as less cellular cases with abundant neuropil (formerly termed ETANTR). Panel NGS sequencing detected DICER1 mutations in two cases only. Interestingly, one further case had a heterozygous mutation in DGCR8, another gene implicated in microRNA-processing. Methylation-based classification showed that DICER1 mutant cases cluster with typical C19MC-altered ETMR, but all others were annotated to a separate “ETMR, non-C19MC-altered” methylation subtype. In this subtype, one case had a probably pathogenic heterozygous ARID2 variant, three other tumors had homozygous TP53 mutations. Cytogenetic copy number status of the C19MC-intact ETMR was analyzed by high-resolution genome-wide molecular inversion probe (MIP) array. In a comparison with typical C19MC-altered ETMR, gains on chromosomal arms 3p and 9q and focal losses on 17p (including TP53) - in addition to lack of C19MC focal gains - were significantly more frequent in C19MC-intact cases. Focal copy-neutral “losses-of-heterozygosity” (cnLOH) were similarly rare in both groups, but the only three cases with whole chromosomal cnLOH were in the C19MC-intact ETMR, two of them on chromosome 6. In summary, DICER1 mutant ETMR showed similar epigenetic profiles as C19MC-altered ETMR, and a fraction of C19MC-intact cases carried TP53 mutations. The tumor-driving events in most ETMR lacking C19MC-alterations or DICER1 mutations remain elusive.
Goschzik et al. (Fri,) studied this question.