Exome-wide Sequencing Shows Low Mutation Rates and Identifies Novel Mutated Genes in Seminomas
Exome-wide Sequencing Shows Low Mutation Rates and Identifies Novel Mutated Genes in Seminomas
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DOI：
10.1016/j.eururo.2014.12.040
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发表时间：
2015-07-01
期刊：
影响因子：
23.4
通讯作者：
Rozen, Steven G.
中科院分区：
文献类型：
--
作者：
Cutcutache, Ioana;Suzuki, Yuka;Rozen, Steven G.
背景：睾丸生殖细胞肿瘤是年轻男性最常见的癌症，而睾丸间质细胞瘤是这些癌症中最常见的类型。目前还没有对乳腺癌中突变基因或这些肿瘤中非沉默体细胞突变的总体比率进行外显子组范围的检查。目的：目的是分析乳腺癌中的体细胞突变，以确定哪些基因受到影响，并确定非沉默突变的比率。设计、设置和参与者：从8名患者手术获得8例乳腺癌和匹配的正常样本。干预：从组织样品中提取DNA，并在大规模并行Illumina DNA测序仪上对外显子组进行测序。结果测量和统计分析：分析DNA测序读取数据以检测体细胞突变，包括单核苷酸取代和短插入和缺失。通过独立测序验证检测到的突变，并进一步检查亚克隆性。结果和限制：非同义体细胞突变的平均率为0.31突变/Mb。我们在96个基因中检测到了非沉默体细胞突变，这些基因以前不知道在乳腺癌中会发生突变，其中一些可能是驱动突变。许多突变出现在亚克隆群体中。此外，两种肿瘤中的两个基因KIT和KRAS受到影响，每个基因都具有之前在其他癌症中观察到的突变，并且可能是致癌的。结论：我们的研究是关于精原细胞瘤外显子组测序的第一份报告，检测到了96个新基因的体细胞突变，其中一些可能是可靶向的驱动因素。此外，我们的研究结果表明，乳腺癌的突变率比以前认为的高五倍，但与其他常见癌症相比仍然很低。在其他癌症中也可以看到类似的低发病率，这些癌症也有很好的化疗缓解率。患者摘要：我们检查了睾丸生殖细胞癌最常见的类型--睾丸腺瘤的DNA序列。我们的研究确定了96个新的基因，其中突变发生在恶性肿瘤的发展过程中，其中一些可能有助于癌症的发展或进展。该研究还表明，肿瘤发展过程中的DNA突变率高于以前的想法，但仍低于其他常见的实体器官癌症。在其他癌症中也观察到这种低比率，如乳腺癌，在化疗后显示出极好的疾病缓解率。(C)2015年欧洲泌尿外科协会。由Elsevier B. V.出版，这是CC BY-NC-ND许可下的开放获取文章。
Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors.Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations.Design, setting, and participants: Eight seminomas and matched normal samples were surgically obtained from eight patients.Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations.Outcome measurements and statistical analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality.Results and limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic.Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy.Patient summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy. (C) 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.