Department of Medicine and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Hum Mutat. 2011 Aug;32(8):900-11. doi: 10.1002/humu.21504.
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.
CDKN2A 肿瘤抑制因子的变异与家族性黑色素瘤 (FM) 有关，尽管许多变异的关联性较弱。错义变异对蛋白质功能和致病性的影响往往不清楚。已经开发了多种方法（例如实验室、计算、流行病学）来分析错义变异是否具有致病性。目前尚不清楚如何将这些数据类型整合到变异分类策略中。我们使用细胞周期阻滞测定法研究了 51 种 CDKN2A 错义变异。结果从完全野生型效应到部分活性到完全阻滞丧失呈连续分布。细胞周期阻滞活性降低 30%具有重现性，与 FM 相关。我们使用贝叶斯方法分析错义 CDKN2A 种系变体，以组合多种数据类型并得出致病性的可能性。当使用这种方法可以评估等于或多于两种数据类型时，25 个与 FM 相关的变体中有 22 个和 15 个不确定意义的变体被归类为可能致病性，概率大于 95%。其他 10 个变体被归类为不确定（概率 5-95%）。对于大多数变体，没有足够的数据得出结论。贝叶斯模型似乎是一种可靠的方法，可以对癌症易感性基因中的错义变体进行分类。
