Burden of Nonsynonymous Mutations among TCGA Cancers and Candidate Immune Checkpoint Inhibitor Responses.
Burden of Nonsynonymous Mutations among TCGA Cancers and Candidate Immune Checkpoint Inhibitor Responses.
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DOI：
10.1158/0008-5472.can-16-0170
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Chanock SJ
中科院分区：
文献类型：
--
作者：
Colli LM;Machiela MJ;Myers TA;Jessop L;Yu K;Chanock SJ
免疫检查点抑制剂治疗代表了治疗癌症的一种有前景的方法，并且已被证明在黑色素瘤，非小细胞肺癌（NSCLC）和肾癌的子集中有效。最近的研究表明，非同义突变（NsM）的数量可用于选择最有可能从检查点抑制剂治疗中获益的黑色素瘤和NSCLC患者。据推测，更高的NsM负荷产生新的表位和基因产物，被免疫系统检测为外来的。我们对来自癌症基因组图谱（TCGA）项目中测序的26种癌症的7，757个肿瘤样本进行了NsM评估，以估计符合黑色素瘤和NSCLC特征的癌症子集（类型及其分数）。对从5种癌症中抽取的另外一组独立的613个肿瘤进行复制分析。对已发表的黑色素瘤和NSCLC检查点抑制剂应答数据的受试者操作特征（ROC）曲线进行分析，估计临界值为192 NsM，灵敏度为74%，特异性为59.3%，可区分潜在的临床获益。在7,757份TCGA样本中，16.2%的样本显示NsM计数超过阈值192。值得注意的是，超过30%的膀胱癌、结肠癌、胃癌和子宫内膜癌的NsM计数高于192，这也在黑色素瘤和NSCLC中得到证实。我们的数据可以为可能的临床试验提供肿瘤类型（和亚型）的优先级，以研究有效使用免疫检查点抑制剂的进一步适应症，特别是在成人癌症中。
Immune checkpoint inhibitor treatment represents a promising approach towards treating cancer and has been shown to be effective in a subset of melanoma, non-small cell lung cancer (NSCLC) and kidney cancers. Recent studies have suggested that the number of non-synonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment. It is hypothesized that a higher burden of NsMs generates novel epitopes and gene products, detected by the immune system as foreign. We conducted an assessment of NsM across 7,757 tumor samples drawn from 26 cancers sequenced in the Cancer Genome Atlas (TCGA) Project to estimate the subset of cancers (both types and fractions thereof) that fit the profile suggested for melanoma and NSCLC. An additional independent set of 613 tumors drawn from 5 cancers were analyzed for replication. An analysis of the Receiver Operator Characteristic (ROC) curves of published data on checkpoint inhibitor response in melanoma and NSCLC data estimates a cutoff of 192 NsM with 74% sensitivity and 59.3% specificity to discriminate potential clinical benefit. Across the 7,757 samples of TCGA, 16.2% displayed an NsM count that exceeded the threshold of 192. It is notable that more than 30% of bladder, colon, gastric, and endometrial cancers have NsM counts above 192, which was also confirmed in melanoma and NSCLC. Our data could inform the prioritization of tumor types (and subtypes) for possible clinical trials to investigate further indications for effective use of immune checkpoint inhibitors, particularly in adult cancers.