Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.
Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.
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DOI：
10.1038/ncomms15936
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发表时间：
2017-06-23
影响因子：
16.6
通讯作者：
Campbell PJ
中科院分区：
文献类型：
--
作者：
Behjati S;Tarpey PS;Haase K;Ye H;Young MD;Alexandrov LB;Farndon SJ;Collord G;Wedge DC;Martincorena I;Cooke SL;Davies H;Mifsud W;Lidgren M;Martin S;Latimer C;Maddison M;Butler AP;Teague JW;Pillay N;Shlien A;McDermott U;Futreal PA;Baumhoer D;Zaikova O;Bjerkehagen B;Myklebost O;Amary MF;Tirabosco R;Van Loo P;Stratton MR;Flanagan AM;Campbell PJ
骨肉瘤是一种影响儿童和成人的原发性骨恶性肿瘤。在这里，我们提出了迄今为止最大的骨肉瘤测序研究，包括112个儿童和成人肿瘤，涵盖所有主要的组织学亚型。我们研究的一个关键发现是在8/112（7%）的病例中发现胰岛素样生长因子（IGF）信号基因突变。我们在另外87例骨肉瘤中使用荧光原位杂交（FISH）验证了这一观察结果，在14%的肿瘤中观察到IGF1受体（IGF1R）扩增。这些发现可能为将来骨肉瘤中IGF1R抑制剂的患者选择提供信息。分析突变模式，我们确定了不同的重排档案，包括一个以染色体分裂和扩增为特征的过程。这个过程在离散的基因组区域反复运行，并产生驱动突变。它可能代表了一种与年龄无关的突变机制，有助于儿童和成人骨肉瘤的发展。骨肉瘤是一种影响儿童和成人的原发性骨恶性肿瘤。在这里，作者对儿童和成人骨肉瘤进行了测序，确定了胰岛素样生长因子信号基因的突变和以染色体扩增为特征的独特基因组重排谱。
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike. Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, the authors sequence childhood and adult osteosarcomas, identifying mutations in insulin-like growth factor signalling genes and distinct genomic rearrangement profiles characterized by chromothripsis-amplification.