The Molecular Landscape of ETMR at Diagnosis and Relapse [methylation]

ETMRs are aggressive pediatric embryonal brain tumors with universally dismal outcome. We collected 193 ETMR samples and an additional 23 matched relapses to investigate the genomic landscape of this distinct entity. We found that patients having tumors without C19MC amplification, the proposed driver, frequently harbor DICER1 germline mutations or other miRNA-related aberrations such as somatic miR-17-92 miRNA cluster amplifications. Despite these distinct genetic aberrations, no molecular subgrouping was observed. 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. 193 unique samples and 23 matched recurrences were profiled using either Illumina 450K arrays or EPIC arrays and both copy numbers and methylation clustering was investigated.

多层菊形团胚胎性肿瘤（ETMR）是一类侵袭性儿童胚胎性脑肿瘤，整体预后极差。本研究收集了193例ETMR样本与23例匹配的复发样本，以解析该独特病种的基因组特征全景。我们发现，未携带已被提出的驱动变异C19MC扩增的患者，常携带有DICER1生殖系突变，或其他与微小RNA（miRNA，microRNA）相关的异常，例如体细胞性miR-17-92 miRNA簇扩增。尽管存在上述差异化遗传异常，本研究未观察到明确的分子亚型划分。全基因组测序结果显示，单核苷酸变异（SNV，Single Nucleotide Variant）的整体复发率较低，但普遍存在与R环（R-loop）相关的染色体不稳定性；我们证实，该染色体不稳定性可由DICER1功能缺失诱发。对比原发肿瘤与匹配的复发样本可见，结构变异（SV，Structural Variant）具有高度保守性，而单核苷酸变异的保守性则相对较低。此外，大量新获得的单核苷酸变异与一种全新的顺铂治疗相关突变特征存在关联。最后，本研究证实，利用拓扑异构酶抑制剂与多聚ADP核糖聚合酶（PARP，Poly(ADP-ribose) Polymerase）靶向干预R环，或可成为针对这一致命疾病的有效治疗策略。本研究通过Illumina 450K芯片或EPIC芯片，对193例独特样本及23例匹配的复发样本进行了组学表征，并对拷贝数与甲基化聚类展开了分析。