Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma.
Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma.
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DOI：
10.18632/oncotarget.25463
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发表时间：
2018-06-08
期刊：
影响因子：
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通讯作者：
Yamanaka R
中科院分区：
文献类型：
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作者：
Takashima Y;Sasaki Y;Hayano A;Homma J;Fukai J;Iwadate Y;Kajiwara K;Ishizawa S;Hondoh H;Tokino T;Yamanaka R
外显子组测序用于体细胞突变检测和拷贝数变异分析是目前分子医学中评估人类肿瘤的有效方法。我们在离子质子半导体测序仪上进行了靶扩增外显子测序分析，包括靶向浓缩和下一代测序。对27例原发性中枢神经系统淋巴瘤(PCNSL)及其相应的非癌组织进行多重PCR扩增，获得409个肿瘤相关基因编码区的靶向覆盖率。平均每个样本的体细胞突变总数为13.3个，包括单核苷酸突变和插入/缺失突变。其中，每个样本中非同义替换的比例平均为74.8%。27例标本中，PIM1、MYD88、CD79B、DST、IRF4、ERBB3、MYH11、DCC和KMT2D是最常见的突变。此外，MYH11的体细胞突变与PCNSL患者的预后不良有关。在节段性基因组岛的深度测序中，拷贝数变异也被复制和/或删除。除了这些候选的预后标记物外，RTK-RAS-MAPK信号和PTEN-PI3K-AKT促凋亡通路的分析表明，体细胞激活和异常可能分别参与了含有mTOR、c-Myc、FOXO1和P53的中枢通路。本研究为基于基因组诊断和预后的PCNSL分子靶向治疗奠定了基础。
Exome-sequencing for somatic mutation detection and copy number variation analysis are effective and valid methods for evaluating human cancers in current molecular medicine. We conducted target amplicon exome-sequencing analyses using PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Twenty-seven primary central nervous system lymphoma (PCNSL) specimens and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverages of the entire coding regions of 409 cancer-related genes. The average of the total numbers of somatic mutations including single-nucleotide variations and insertion/deletion mutations in each specimen was 13.3. Of these, the average of the ratios of nonsynonymous substitutions in each specimen was 74.8%. The most frequent mutations in 27 specimens were in PIM1, MYD88, CD79B, DST, IRF4, ERBB3, MYH11, DCC, and KMT2D. Furthermore, somatic mutations of MYH11 were related to poor prognoses in PCNSL patients. Copy number variations were also duplicated and/or deleted from deep-sequencing in segmental genomic islands. In addition to these prognostic marker candidates, analysis of RTK-RAS-MAPK signaling and the PTEN-PI3K-AKT proapoptotic pathway showed that somatic activations and aberrations, respectively, may be involved in a promising central oncopathway harboring mTOR, c-Myc, FOXO1, and p53. This study provides a foundation for molecular targeted therapies based on genome diagnostics and prognosis in PCNSL.