Accelerating Discovery of Functional Mutant Alleles in Cancer.
Accelerating Discovery of Functional Mutant Alleles in Cancer.
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DOI：
10.1158/2159-8290.cd-17-0321
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发表时间：
2018-03
期刊：
影响因子：
28.2
通讯作者：
Taylor BS
中科院分区：
文献类型：
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作者：
Chang MT;Bhattarai TS;Schram AM;Bielski CM;Donoghue MTA;Jonsson P;Chakravarty D;Phillips S;Kandoth C;Penson A;Gorelick A;Shamu T;Patel S;Harris C;Gao J;Sumer SO;Kundra R;Razavi P;Li BT;Reales DN;Socci ND;Jayakumaran G;Zehir A;Benayed R;Arcila ME;Chandarlapaty S;Ladanyi M;Schultz N;Baselga J;Berger MF;Rosen N;Solit DB;Hyman DM;Taylor BS
癌症中的大多数突变是罕见的，这使得治疗上重要的突变的鉴定变得复杂，从而限制了癌症患者基因组谱分析的临床影响。在这里，我们分析了24,592例癌症，包括10,336例前瞻性测序的晚期疾病患者，以确定在没有选择的情况下比预期更频繁出现的突变残基。我们确定了1,165个具有统计学意义的热点突变，其中80%发生在1/1000或更少的患者中。在55个反复出现的框内插入缺失中，我们验证了新的AKT 1重复诱导通路过度活化并赋予AKT抑制剂敏感性。随着样本量的增加，癌症基因表现出不同的热点发现率，很少接近饱和。因此，26%的可治疗致癌基因热点是新的。在将一部分受影响的患者直接与分子靶向治疗相匹配后，我们观察了放射学和临床反应。群体规模的突变等位基因发现说明了癌症驱动突变的识别远未完成。
Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in cancer patients. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.