Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.
Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.
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DOI：
10.1200/jco.20.03060
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发表时间：
2021-09-10
期刊：
影响因子：
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通讯作者：
Khan J
中科院分区：
文献类型：
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作者：
Shern JF;Selfe J;Izquierdo E;Patidar R;Chou HC;Song YK;Yohe ME;Sindiri S;Wei J;Wen X;Rudzinski ER;Barkauskas DA;Lo T;Hall D;Linardic CM;Hughes D;Jamal S;Jenney M;Chisholm J;Brown R;Jones K;Hicks B;Angelini P;George S;Chesler L;Hubank M;Kelsey A;Gatz SA;Skapek SX;Hawkins DS;Shipley JM;Khan J
横纹肌肉瘤是儿童最常见的软组织肉瘤。尽管进行了积极的治疗，但转移性或复发性疾病患者的5年生存率仍然很低，而且除了PAX-FOXO1融合状态外，没有基因组标记可用于风险分层。我们提出了一项国际联盟的研究，旨在确定DIVER突变的发生率及其与临床结果的关系。从参加儿童肿瘤学小组试验(1998-2017)的患者以及参加恶性间充质肿瘤和RMS2005(1995-2016)试验的英国患者收集的肿瘤样本接受定制捕获测序。鉴定突变、缺失、基因缺失和扩增，并进行生存分析。641例患者的DNA可用于分析。每个肿瘤发现一个突变的中位数。在FOXO1融合阴性的病例中，50%的病例发现任何RAS通路成员的突变，21%的病例没有发现可能的驱动突变。BCOR(15%)、NF1(15%)和TP53(13%)突变的发生率高于先前报道，并且在融合阴性和FOXO1融合阳性病例中，TP53突变与较差的预后相关。有趣的是，RAS亚型突变主要发生在1岁以下的婴儿(%的病例)。MYOD1基因突变与先前描述的组织学类型、年龄较大、头颈部原发部位和生存惨淡有关。最后，我们提供了一个可搜索的配套数据库(ClinOmics)，其中包含所有基因组变异，以及包括生存数据在内的临床注释。这是迄今为止临床注释横纹肌肉瘤最大的基因组特征，提供了预后遗传特征，完善了风险分层，并将纳入前瞻性试验。
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data. This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.