R-loop–associated genomic instability may be a therapeutic vulnerability in ETMRs.
Major Finding: R-loop–associated genomic instability may be a therapeutic vulnerability in ETMRs.
Concept: Combination treatment with TOP1 and PARP1 inhibitors exhibited synergy in ETMR cells.
Impact: This work provides insight into molecular mechanisms driving ETMRs and may lead to new therapies.
Embryonal tumors with multilayered rosettes (ETMR) are aggressive malignant brain tumors that most often occur in children younger than five years of age. ETMRs are histologically diverse, but most are characterized by amplification and fusion of C19MC (an miRNA cluster) with TTYH1. Lambo and colleagues confirmed that ETMRs are molecularly distinct from other brain tumors, regardless of C19MC-amplification status. Sequencing of 82 ETMRs revealed the presence of a few other recurrent mutations in a small but notable proportion of tumors, including mutations in DICER1, CTNNB1 (encoding β-catenin), and TP53. Interestingly, DICER1 mutations were observed solely in tumors lacking C19MC amplifications, suggesting a possible driver role for DICER1 mutations. Genomic comparison of primary-tumor and relapse samples showed that the majority of single-nucleotide variants were acquired post treatment and were not conserved, suggesting they are not drivers. However, genomic structural variants arose early in disease progression, and breakpoints were highly conserved, implying a possible role in tumorigenesis. Further investigation revealed that breakpoints in ETMRs frequently occurred in proximity to R-loop–forming sequences, which are DNA sequences prone to forming R-loops, three-stranded nucleic-acid structures that can result from stalled RNA polymerases and may induce DNA damage if not resolved. The authors previously reported that ETMRs are sensitive to inhibition of topoisomerase I (TOP1), an enzyme that can resolve R-loops, and other studies have shown that PARP1 can rescue TOP1 function in cells treated with TOP1 inhibitors. Correspondingly, combination treatment with inhibitors of TOP1 and PARP1 exhibited synergy in ETMR cells, not only implying that such a drug combination—after thorough in vivo testing—may be of use in treating ETMRs, but also providing further evidence for the role of R-loops in this tumor type. Collectively, the results presented in this study shed light on the molecular mechanisms driving ETMRs, providing a basis for further research that may lead to new therapeutics for this tumor type, for which treatment options are currently limited.
Lambo S, Gröbner SN, Rausch T, Waszak SM, Schmidt C, Gorthi A, et al. The molecular landscape of ETMR at diagnosis and relapse. Nature 2019;576:274–80.
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