OpenCRAVAT: Informatics Tools for High-Throughput Analysis of Cancer Mutations

项目总结 癌症测序项目已经确定了大量DNA突变，这些突变在癌症中具有重要意义 目前还不清楚。为了更好地了解这些突变的影响，我们团队开发了一个软件 用于计算分析癌症突变的工具，可同时分析数百万个突变。此工具 作为一个漏斗，帮助研究人员找到最有可能提供信息的少量突变 在测序项目中发现了大量的突变。该软件允许用户设计 组合多个突变评估度量的方法，并生成更多突变的优先列表 很可能具有重要的生物学意义。这些评估指标包括分子后果、生物信息学 识别致病基因和驱动基因突变的分数，人类群体中突变的频率，之前 在肿瘤组织类型中的出现，文献的指针，以及注释的蛋白质结构和 网络。一个网络版本的管道-癌症相关变异分析工具包(CRAVAT)已经发布 被广泛采用(2020年平均每月提交3000多个工作岗位)。我们已经吸引了一个用户社区 横跨基础和临床癌症研究人员，他们都依赖于高通量的肿瘤测序 工作。2019年，我们推出了OpenCRAVAT，它的特点是开源代码库和开放的 工具和资源的应用程序商店，可用于更好地了解突变的重要性和影响。 应用程序商店由用户社区驱动；根据用户请求和应用程序确定新应用程序的优先级 商店包括许多由外部工具开发者直接贡献的应用程序。应用商店目前 聚合了来自70多个组织的工具，这些工具可以组合在一起来识别其突变 分子影响在肿瘤的发生、预后和治疗选择中起重要作用。最初采用我们的 OpenCRAVAT工具令人振奋，在最初的两年里有超过10,000个本地包下载。我们预计 鉴于DNA的重要性日益增加，OpenCRAVAT将被更大的社区采用 癌症研究中的测序数据。我们将继续确保我们的工具可以与其他 信息学工具和服务，可以在云计算等不同的计算环境中运行 和本地安装，以维护数据隐私。

PROJECT SUMMARY Cancer sequencing projects have identified a very large number of DNA mutations whose importance in cancer is not yet understood. To better understand the impact of these mutations, our team has produced a software tool for computational analysis of cancer mutations that can analyze millions of mutations at one time. This tool works as a funnel to help researchers to find the small number of mutations that are most likely to be informative from the very large number of mutations discovered in a sequencing project. The software allows users to design ways to combine multiple mutation evaluation metrics, and generate a prioritized list of mutations that are more likely to be biologically important. These evaluation metrics include the molecular consequence, bioinformatic scores to identify pathogenic and driver mutations, frequency of the mutation in human populations, previous occurrence in tumor tissue types, pointers to literature, and visualization of annotated protein structures and networks. A web-based version of the pipeline - Cancer Related Analysis of Variants Toolkit (CRAVAT) has been widely adopted (3000+ jobs submitted/month on average in 2020). We have attracted a user community that spans both basic and clinical cancer researchers, all of whom rely on high-throughput tumor sequencing in their work. In 2019, we introduced OpenCRAVAT, which is distinguished by an open source codebase and an open app store of tools and resources that can be used to better understand the importance and impact of mutations. The app store is driven by the user community; new apps are prioritized based upon user requests and the app store includes many apps that were contributed directly by outside tool developers. The app store currently aggregates tools from over 70 organizations, and these tools can be combined to identify mutations whose molecular impact contributes to tumorigenesis, prognosis and treatment selection. Initial adoption of our OpenCRAVAT tool is encouraging, with over 10,000 local package downloads in the first two years. We expect that OpenCRAVAT will be adopted by a much larger community, given the increasing importance of DNA sequencing data in cancer research. We will continue to ensure that our tools are interoperable with other informatics tools and services, and can be run in different computational environments such as cloud computing and local installation to maintain data privacy.