Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.
Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.
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DOI：
10.1038/ncomms8557
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发表时间：
2015-07-03
影响因子：
16.6
通讯作者：
Takita J
中科院分区：
文献类型：
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作者：
Seki M;Nishimura R;Yoshida K;Shimamura T;Shiraishi Y;Sato Y;Kato M;Chiba K;Tanaka H;Hoshino N;Nagae G;Shiozawa Y;Okuno Y;Hosoi H;Tanaka Y;Okita H;Miyachi M;Souzaki R;Taguchi T;Koh K;Hanada R;Kato K;Nomura Y;Akiyama M;Oka A;Igarashi T;Miyano S;Aburatani H;Hayashi Y;Ogawa S;Takita J
横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤。在这里，我们研究了60 RMS使用全外显子组/转录组测序，拷贝数（CN）和DNA甲基化组分析，以解开遗传/表观遗传基础的RMS。根据甲基化模式，RMS可分为四种不同的亚型，这些亚型与突变/CN谱、组织学表型和临床行为显著相关。A1和A2亚型，特别是A1，在很大程度上对应于肺泡组织学，具有频繁的PAX 3/7融合和细胞周期调节因子的改变。相比之下，主要显示胚胎组织学，E1和E2亚型的特征在于高频率的CN改变和/或等位基因不平衡、FGFR 4/RAS/AKT途径突变和PTEN突变/甲基化，并且在E2中，也通过p53失活。尽管胚胎型RMS的预后较好，但E2期患者的预后可能较差。我们的研究结果突出了甲基化状态和基因突变与RMS生物学行为的密切关系。 横纹肌肉瘤是一种常见的儿童软组织肿瘤。在这里，Seki和Nishimura分析了60个肉瘤的外显子组、转录组、拷贝数和DNA甲基化组，并确定了与遗传和临床特征相关的不同甲基化亚组。
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS. Rhabdomyosarcoma is a common childhood soft-tissue cancer. Here Seki and Nishimura analyse the exome, transcriptome, copy number and DNA methylome of 60 sarcomas and identify distinct methylation subgroups associated with genetic and clinical features.