Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone.
Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone.
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DOI：
10.1002/path.5176
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Latif F
中科院分区：
文献类型：
--
作者：
Ali NM;Niada S;Brini AT;Morris MR;Kurusamy S;Alholle A;Huen D;Antonescu CR;Tirode F;Sumathi V;Latif F
未分化多形性骨肉瘤（UPSb）是一种罕见的原发性骨肉瘤，缺乏特定的分化线。关于导致肿瘤发生或恶性转化的基因改变的信息很少。UPSb和其他恶性骨肉瘤，包括去分化软骨肉瘤和骨肉瘤，由于重叠的特征，可能具有挑战性。为了探索UPSb肿瘤的基因组和转录组学格局，我们对UPSb肿瘤进行了全外显子组测序（WES）和RNA测序（RNA- seq）。所有肿瘤均缺乏IDH1/2 132或172密码子的热点突变，因此排除去分化软骨肉瘤的诊断。在4/14（29%）的样本中发现复发性TP53体细胞突变。此外，组蛋白染色质重塑基因（包括H3F3A、ATRX和DOT1L）的复发性突变在5/14的样本中被发现（36%），突出了染色质重塑途径失调在UPSb肿瘤发生中的潜在作用。这里发现的大多数染色质重塑基因的复发突变都是在COSMIC中报道的，包括H3F3A G35和K36热点残基。拷贝数改变分析确定了UPSb或软组织UPS先前改变的基因的增益和损失。通过RNA-Seq鉴定了8个体细胞基因融合体，其中两个，CLTC-VMP1和FARP1-STK24，先前在多种癌症中报道过。对5个基因融合体进行了基因组表征。利用RNA-Seq数据进行分层聚类分析，明确地将来自骨肉瘤和其他肉瘤的UPSb肿瘤聚类，从而在分子上区分UPSb与其他肉瘤。RNA-Seq表达谱分析和定量RT-PCR显示FGF23表达升高，FGF23可能是UPSb的潜在分子生物标志物。据我们所知，这项研究首次对UPSb肿瘤进行了全面的WES和RNA-Seq分析，揭示了新的蛋白质编码复发性基因突变、基因融合，并鉴定了潜在的UPSb分子生物标志物，从而拓宽了对致病机制的理解，并强调了开发新型靶向治疗方法的可能性。
Undifferentiated pleomorphic sarcoma of bone (UPSb), is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole-exome sequencing (WES) and RNA Sequencing (RNA-Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in TP53 were identified in 4/14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in 5/14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G35 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA-Seq, two of which, CLTC-VMP1 and FARP1-STK24, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA-Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA-Seq expression profiling analysis and quantitative RT-PCR showed an elevated expression in FGF23 which can be a potential molecular biomarker in UPSb. To our knowledge, this study represents the first comprehensive WES and RNA-Seq analysis of UPSb tumours revealing novel protein-coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics.
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影响因子：
64.5
作者：
Jan, YW;Matter, M;Ruoslahti, E
通讯作者：
Ruoslahti, E
影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
影响因子：
14.9
作者：
Babiceanu M;Qin F;Xie Z;Jia Y;Lopez K;Janus N;Facemire L;Kumar S;Pang Y;Qi Y;Lazar IM;Li H
通讯作者：
Li H
影响因子：
30.8
作者：
Behjati, Sam;Tarpey, Patrick S.;Presneau, Nadege;Scheipl, Susanne;Pillay, Nischalan;Van Loo, Peter;Wedge, David C.;Cooke, Susanna L.;Gundem, Gunes;Davies, Helen;Nik-Zainal, Serena;Martin, Sancha;McLaren, Stuart;Goodie, Victoria;Robinson, Ben;Butler, Adam;Teague, Jon W.;Halai, Dina;Khatri, Bhavisha;Myklebost, Ola;Baumhoer, Daniel;Jundt, Gernot;Hamoudi, Rifat;Tirabosco, Roberto;Amary, M. Fernanda;Futreal, P. Andrew;Stratton, Michael R.;Campbell, Peter J.;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.
影响因子：
3.3
作者：
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通讯作者：
Cheng, Liang