Integrative data fusion for comprehensive assessment of a novel CHEK2 variant using combined genomics, imaging, and functional–structural assessments via protein informatics,Molecular Omics

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Integrative data fusion for comprehensive assessment of a novel CHEK2 variant using combined genomics, imaging, and functional–structural assessments via protein informatics
Molecular Omics ( IF 3.0 ) Pub Date : 2018-12-18 , DOI: 10.1039/c8mo00137e
Stephanie L. Hines _{1,

2,

3,

4,

5} , Ahmed N. Mohammad _{1,

2,

3,

4,

5} , Jessica Jackson _{1,

2,

3,

4} , Sarah Macklin _{1,

2,

3,

4} , Thomas R. Caulfield _{2,

3,

4,

6,

7}

Affiliation

The CHEK2 gene and its encoded protein Chk2 have a well-known role in cancers, especially those related to breast cancer mediated through the BRCA1 gene. Additionally Chk2 has a crucial role in DNA repair, apoptosis and the cell cycle, which is why classification of variants of uncertain significance (VUS) is an area highly sought for a better elucidation of the “genomic effect” that results. Because it can often take years before enough clinical data is accumulated, and the costly and expensive functional analysis for individual variants presents a significant hurdle, it is important to identify other tools to help aid in clarifying the impact of specific variants on a protein's function and eventually the patient's health outcome. Here we describe a newly identified CHEK2 variant and analyze with an integrated approach combining genomics (whole exome analysis), clinical study, radiographic imaging, and protein informatics to identify and predict the functional impact of the VUS on the protein's behavior and predicted impact on the related pathways. The observed and analyzed defects in the protein were consistent with the expected clinical effect. Here, we support the use of personalized protein modeling and informatics and further our goal of developing a large-scale protein deposition archive for all protein-level VUS.

中文翻译：

整合的数据融合，可通过蛋白质信息学结合基因组学，影像学和功能结构评估，对新型CHEK2变体进行全面评估

该CHEK2基因及其编码蛋白Chk2的在癌症中一个著名的角色，尤其是那些与通过BRCA1基因介导的乳腺癌。另外，Chk2在DNA修复，细胞凋亡和细胞周期中也起着至关重要的作用，这就是为什么对不确定性显着性（VUS）的变体进行分类是为什么要更好地阐明产生的“基因组效应”这一领域的原因。由于积累足够的临床数据通常需要花费数年的时间，并且单个变体的功能分析昂贵且昂贵，因此存在很大的障碍，因此，重要的是找出其他工具，以帮助阐明特定变体对蛋白质功能和功能的影响。最终患者的健康状况。在这里，我们描述了一个新识别的CHEK2通过整合基因组学（整个外显子组分析），临床研究，放射成像和蛋白质信息学的集成方法进行变异和分析，以识别和预测VUS对蛋白质行为的功能影响以及对相关途径的影响。观察和分析的蛋白质缺陷与预期的临床效果一致。在这里，我们支持使用个性化蛋白质建模和信息学，并进一步实现为所有蛋白质级VUS开发大规模蛋白质沉积档案的目标。

更新日期：2019-02-13

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