High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing.
High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing.
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DOI：
10.1158/2159-8290.cd-11-0184
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发表时间：
2012-01
期刊：
影响因子：
28.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Wagle N;Berger MF;Davis MJ;Blumenstiel B;Defelice M;Pochanard P;Ducar M;Van Hummelen P;Macconaill LE;Hahn WC;Meyerson M;Gabriel SB;Garraway LA
了解每个肿瘤中存在的“可操作的”体细胞基因组改变(例如，点突变、小插入/缺失和指导治疗选择的拷贝数改变)应有助于癌症治疗的个体化方法。然而，除了有限数量的癌基因点突变外，系统基因组图谱的临床实施很少实现。为了应对这一挑战，我们使用了一种有针对性的大规模并行测序方法来检测福尔马林固定的石蜡包埋(FFPE)肿瘤样本中的肿瘤基因组变化。与临床上使用的其他方法相比，该方法实现了近400倍的平均序列覆盖率，并同时检测到单核苷酸序列变异、小插入/缺失和染色体拷贝数改变。在每个被测试的肿瘤样本中都检测到了可能可操作的基因组改变，包括那些预测对现有和实验治疗的敏感性或耐药性的改变。因此，对临床肿瘤材料进行有针对性的深度测序可能会使突变驱动的临床试验成为可能，并最终实现“个性化”癌症治疗。
Knowledge of “actionable” somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic profiling has rarely been achieved beyond limited numbers of oncogene point mutations. To address this challenge, we utilized a targeted, massively parallel sequencing approach to detect tumor genomic alterations in formalin-fixed, paraffin embedded (FFPE) tumor samples. Nearly 400-fold mean sequence coverage was achieved, and single nucleotide sequence variants, small insertions/deletions, and chromosomal copy number alterations were detected simultaneously with high accuracy compared to other methods in clinical use. Putatively actionable genomic alterations, including those that predict sensitivity or resistance to established and experimental therapies, were detected in each tumor sample tested. Thus, targeted deep sequencing of clinical tumor material may enable mutation-driven clinical trials and, ultimately, ”personalized” cancer treatment.