Classifying Variants of CDKN2A Using Computational and Laboratory Studies
Classifying Variants of CDKN2A Using Computational and Laboratory Studies
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DOI：
10.1002/humu.21504
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发表时间：
2011-08-01
期刊：
影响因子：
3.9
通讯作者：
Greenblatt, Marc S.
中科院分区：
文献类型：
--
作者：
Miller, Peter J.;Duraisamy, Sekhar;Greenblatt, Marc S.
CDKN2A肿瘤抑制因子的变异与家族性黑色素瘤（FM）有关，尽管许多变异的联系很弱。错义变异对蛋白质功能和致病性的影响往往不清楚。多种方法（如实验室、计算、流行病学）已被开发来分析错义变异是否具有致病性。目前还不清楚如何将这些数据类型集成到变体分类策略中。我们使用细胞周期阻滞试验研究了51个CDKN2A错义变体。有一系列连续的结果，从完全的野生型效果到部分活动到完全失去逮捕。细胞周期阻滞活性可重复降低30%与FM关联相关。我们使用贝叶斯方法分析错义CDKN2A种系变异，结合多种数据类型并得出致病性概率。当使用该方法可以评估等于或多于两种数据类型时，25个fm相关变异中有22个和15个不确定意义的变异中有8个被分类为可能致病的概率为95%。其他10种变异被归类为不确定（概率为5-95%）。对于大多数变异，没有足够的数据来得出结论。贝叶斯模型似乎是对癌症易感基因中的错义变异进行分类的一种有效方法。[j] .农业科学学报，2011。(C) 2011 Wiley-Liss, Inc。
Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often unclear. Multiple methods (e. g., laboratory, computational, epidemiological) have been developed to analyze whether a missense variant is pathogenic or not. It is not yet clear how to integrate these data types into a strategy for variant classification. We studied 51 CDKN2A missense variants using a cell cycle arrest assay. There was a continuum of results ranging from full wild-type effect through partial activity to complete loss of arrest. A reproducible decrease of 30% of cell cycle arrest activity correlated with FM association. We analyzed missense CDKN2A germline variants using a Bayesian method to combine multiple data types and derive a probability of pathogenicity. When equal to or more than two data types could be evaluated with this method, 22 of 25 FM-associated variants and 8 of 15 variants of uncertain significance were classified as likely pathogenic with >95% probability. The other 10 variants were classified as uncertain (probability 5-95%). For most variants, there were insufficient data to draw a conclusion. The Bayesian model appears to be a sound method of classifying missense variants in cancer susceptibility genes. Hum Mutat 32:900-911, 2011. (C) 2011 Wiley-Liss, Inc.