A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.
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DOI：
10.1002/humu.22213
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发表时间：
2013-01
期刊：
影响因子：
3.9
通讯作者：
Spurdle, Amanda B.
中科院分区：
文献类型：
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作者：
Thompson, Bryony A.;Goldgar, David E.;Paterson, Carol;Clendenning, Mark;Walters, Rhiannon;Arnold, Sven;Parsons, Michael T.;Walsh, Michael D.;Gallinger, Steven;Haile, Robert W.;Hopper, John L.;Jenkins, Mark A.;LeMarchand, Loic;Lindor, Noralane M.;Newcomb, Polly A.;Thibodeau, Stephen N.;Young, Joanne P.;Buchanan, Daniel D.;Tavtigian, Sean V.;Spurdle, Amanda B.
临床意义不确定的错配修复(MMR)基因序列变异常见于疑似Lynch综合征家系，这对研究者和临床医生都构成了挑战。多因素似然模型方法提供了MMR变异致病性的定量测量，但首先需要从适当的、表征良好的参考数据集中输入不同MMR变异相关特征的似然比(LRs)。使用微卫星不稳定性(MSI)和未选择的已知致病变异状态的结直肠癌先证者的体细胞BRAF肿瘤数据，使用结肠癌家族登记(CFR)资源得出肿瘤特征的LR。这些肿瘤LR结合家系内的变异分离，以及基于序列保守性和位置的先验致病概率的估计，分析了最初在澳大利亚结肠癌CFR家族中发现的44个未分类的变异。此外，基于生物信息学剪接预测，对变异体的子集进行了体外剪接分析。对于BRAF突变阴性MSI-H表型的结直肠肿瘤，支持致病性的LR估计为~12倍。对于44个变异中的31个，致病性的后验概率表明临床治疗将发生改变。我们的发现为分类提供了一个有效的多因素似然模型，该模型仔细考虑了基因测试的确证模式。
Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
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MLH1中C.1852_1853AA> GC的分类的证据作为Lynch综合征的中性变体。
影响因子：
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作者：
Castillejo A;Guarinos C;Martinez-Canto A;Barbera VM;Egoavil C;Castillejo MI;Perez-Carbonell L;Sanchez-Heras AB;Segura A;Ochoa E;Lazaro R;Ruiz-Ponte C;Bujanda L;Andreu M;Castells A;Carracedo A;Llor X;Clofent J;Alenda C;Paya A;Jover R;Soto JL
通讯作者：
Soto JL
影响因子：
9.8
作者：
Easton, Douglas F.;Deffenbaugh, Amie M.;Goldgar, David E.
通讯作者：
Goldgar, David E.
影响因子：
4.8
作者：
Guerrette, S;Acharya, S;Fishel, R
通讯作者：
Fishel, R
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
12.6
作者：
通讯作者：
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