Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma.
Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma.
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DOI：
10.1038/srep42980
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发表时间：
2017-03-03
影响因子：
4.6
通讯作者：
Patel V
中科院分区：
文献类型：
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作者：
Chow YP;Tan LP;Chai SJ;Abdul Aziz N;Choo SW;Lim PV;Pathmanathan R;Mohd Kornain NK;Lum CL;Pua KC;Yap YY;Tan TY;Teo SH;Khoo AS;Patel V
在这项研究中，我们首先对10个未经治疗和临床注释的新鲜冷冻鼻咽癌（NPC）活检组织和匹配血液的DNA进行了全外显子组测序，以鉴定可能适合靶向治疗策略的体细胞突变基因。我们共鉴定出323个突变，这些突变要么是非同义的（n = 238），要么是同义的（n = 85）。此外，我们的分析还发现，在关键的癌症通路（DNA修复、细胞周期调节、细胞凋亡、免疫应答、脂质信号通路）中，基因发生了突变，其中脂质信号通路的基因富集程度最高。接下来，我们使用定制设计的HaloPlex靶富集面板和额外的88个NPC样本，扩展了对cosmos中列出的37个突变基因和前5个突变癌症基因的优先子集的分析。我们的分析在66/88个样本中的37/42个基因中发现了160个非同义突变。其中，有99/160个潜在药物通路内的突变被进一步选中进行验证。桑格测序显示，99个变异中有77个是真阳性，准确率为78%。总之，我们的研究表明，约72% （n = 71/98）的NPC样本在四种癌症途径（EGFR-PI3K-Akt-mTOR， NOTCH, NF-κB， DNA修复）中的一种中存在突变，这可能是对匹配靶向治疗反应的潜在有用的预测性生物标志物。
In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.