Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations
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DOI：
10.1002/humu.22972
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发表时间：
2016-07-01
期刊：
影响因子：
3.9
通讯作者：
Rogan, Peter K.
中科院分区：
文献类型：
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作者：
Caminsky, Natasha G.;Mucaki, Eliseos J.;Rogan, Peter K.
遗传性乳腺癌和卵巢癌（HBOC）的BRCA1和BRCA2检测不能识别所有致病变异。对检测结果不明确的HBOC患者的20个完整基因（N = 287）进行测序，包括ATM、BARD1、BRCA1、BRCA2、CDH1、CHEK2、EPCAM、MLH1、MRE11A、MSH2、MSH6、MUTYH、NBN、PALB2、PMS2、PTEN、RAD51B、STK11、TP53和XRCC2的非编码和侧链序列，共鉴定出38,372个独特变异。我们应用信息理论（IT）来预测和优先考虑在调控区、编码区和内含子区具有不确定意义的非编码变异，这些变异基于这些基因结合位点的变化。除了mRNA剪接，IT还提供了一个共同的框架来评估突变后转录因子（TFBSs）、剪接调节（SRBSs）和rna结合蛋白（RBBSs）结合位点的潜在亲和力变化。我们对影响10个剪接位点（4个自然剪接位点，6个隐剪接位点）、148个SRBS、36个TFBS和31个RBBS强度的变异进行了优先排序。根据对mRNA二级（2度）结构的预测影响和对假外显子激活的预测影响，对三个变体进行了优先排序。此外，还发现了4个移码、2个帧内缺失和5个停止增益突变。当与谱系信息相结合时，完整的基因序列分析可以将注意力集中在广泛的功能突变类型中有限的一组变体上，用于下游功能和共分离分析。(C) 2016 Wiley期刊公司
BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize noncoding variants of uncertain significance in regulatory, coding, and intronic regions based on changes in binding sites in these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes in transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) binding sites following mutation. We prioritized variants affecting the strengths of 10 splice sites (four natural, six cryptic), 148 SRBS, 36 TFBS, and 31 RBBS. Three variants were also prioritized based on their predicted effects on mRNA secondary (2 degrees) structure and 17 for pseudoexon activation. Additionally, four frameshift, two in-frame deletions, and five stop-gain mutations were identified. When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and co-segregation analysis. (C) 2016 Wiley Periodicals, Inc.