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Abstract：
Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study.
We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.
Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1-7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.
The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome-phenome archive (accession: EGAS00001002477).
We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.
Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1-7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.
The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome-phenome archive (accession: EGAS00001002477).
摘要：
最近的研究表明，癌症是由于肿瘤DNA中驱动体细胞事件的阳性选择而产生的，负面选择只扮演次要角色，如果有的话。然而,这些研究涉及非重复序列的改变,没有考虑在本研究中研究的显示错配修复缺陷导致的微卫星不稳定性(MSI)的肿瘤中具有非常高的病理生理相关性的重复序列中的突变.
我们对47例MSI结直肠癌（CRC）进行了全外显子组测序，并在53例MSICRC的独立队列中证实了结果。我们使用了微卫星内突变事件的概率模型，同时调整预先存在的模型来分析非重复DNA序列。研究了MSICRC中的阴性选择的编码改变在CRC细胞系和164名MSICRC患者的第三组中的功能和临床影响。
观察到DNA重复序列中体细胞突变的阳性和阴性选择，引导我们确定与MSI驱动的致瘤过程相关的预期真正的驱动基因。几个编码负选择的MSI相关突变事件(n=5)显示对肿瘤细胞具有有害作用。在尽管阴性选择仍观察到有害MSI突变的肿瘤中，它们与MSICRC患者的生存率较差相关(风险比，3；95%CI，1.1-7.9；P=0.03），提示它们的抗癌作用应被其他未知的致癌过程所抵消，这些过程会导致预后不良。
本结果确定了在MSI驱动的肿瘤发生中起作用的阳性和阴性驱动体细胞突变，表明MSICRC中的基因组不稳定性在实现肿瘤细胞转化中起着双重作用。外显子组测序数据已保存在欧洲基因组-表型档案中(登录号:EGAS00001002477)。
我们对47例MSI结直肠癌（CRC）进行了全外显子组测序，并在53例MSICRC的独立队列中证实了结果。我们使用了微卫星内突变事件的概率模型，同时调整预先存在的模型来分析非重复DNA序列。研究了MSICRC中的阴性选择的编码改变在CRC细胞系和164名MSICRC患者的第三组中的功能和临床影响。
观察到DNA重复序列中体细胞突变的阳性和阴性选择，引导我们确定与MSI驱动的致瘤过程相关的预期真正的驱动基因。几个编码负选择的MSI相关突变事件(n=5)显示对肿瘤细胞具有有害作用。在尽管阴性选择仍观察到有害MSI突变的肿瘤中，它们与MSICRC患者的生存率较差相关(风险比，3；95%CI，1.1-7.9；P=0.03），提示它们的抗癌作用应被其他未知的致癌过程所抵消，这些过程会导致预后不良。
本结果确定了在MSI驱动的肿瘤发生中起作用的阳性和阴性驱动体细胞突变，表明MSICRC中的基因组不稳定性在实现肿瘤细胞转化中起着双重作用。外显子组测序数据已保存在欧洲基因组-表型档案中(登录号:EGAS00001002477)。
