Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.
Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.
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DOI：
10.1186/bcr2810
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发表时间：
2011-01-18
期刊：
影响因子：
--
通讯作者：
Tavtigian SV
中科院分区：
文献类型：
--
作者：
Le Calvez-Kelm F;Lesueur F;Damiola F;Vallée M;Voegele C;Babikyan D;Durand G;Forey N;McKay-Chopin S;Robinot N;Nguyen-Dumont T;Thomas A;Byrnes GB;Breast Cancer Family Registry;Hopper JL;Southey MC;Andrulis IL;John EM;Tavtigian SV
CHEK2中的蛋白质截断变异和一些错义替换都会增加患乳腺癌的风险。然而，还没有大规模的研究使用完整的开放阅读框突变筛查来评估CHEK2中罕见的错义替换对乳腺癌风险的贡献。这种缺失的部分原因是缺乏有效的统计方法来总结可归因于大量个别罕见的错义替换的风险。以前，我们将用于分析BRCA1和BRCA2中未分类错义替换的错义替换的电子评估应用于使用病例对照突变筛查研究中观察到的罕见错义替换数据来评估候选基因的问题。该方法包括将病例和/或对照中观察到的罕见错义替换分层为一系列等级，按先验从最小到最有可能对进化有害的顺序排序，然后对趋势进行Logistic回归检验，以比较病例和对照中分级错义替换的频率分布。在这里，我们使用这种方法来分析CHEK2突变筛查数据，这些数据来自1303名女性乳腺癌患者和1109名未受影响的女性对照。我们发现了与罕见的、进化上不太可能的CHEK2错义替换相关的风险证据。其他发现是：(1)最严重级别的CHEK2错义替换(表示为C65)的风险估计大致相当于CHEK2蛋白质截断变体的风险估计；(2)罕见错义替换池所解释的人群归因分数和家族相对风险与蛋白质截断变体池所解释的相似；以及(3)特殊功率计算表明，扩大病例对照突变筛查以检查整个生化途径将需要大约2,000例病例和对照才能达到可接受的统计能力。这项研究表明，CHEK2含有许多罕见的序列变异，这些变异会增加患乳腺癌的风险，其中很大一部分是错义替换。这项研究验证了我们对罕见错义替换的分析方法，并提供了一种方法，将来自蛋白质截断变体和罕见错义替换的数据结合到每个基因测试的一个自由度中。
Both protein-truncating variants and some missense substitutions in CHEK2 confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in CHEK2 to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions. Previously, we adapted an in silico assessment of missense substitutions used for analysis of unclassified missense substitutions in BRCA1 and BRCA2 to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered a priori from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze CHEK2 mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls. We found evidence of risk associated with rare, evolutionarily unlikely CHEK2 missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of CHEK2 missense substitutions (denoted C65) is approximately equivalent to that of CHEK2 protein-truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) post hoc power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power. This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.
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DOI：
10.1093/jnci/djq055
发表时间：
2010-04-07
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Bernstein, Jonine L.;Haile, Robert W.;Concannon, Patrick
通讯作者：
Concannon, Patrick
影响因子：
45.3
作者：
Bruinooge, SS
通讯作者：
Bruinooge, SS
影响因子：
3.8
作者：
Bernstein, JL;Teraoka, SN;Concannon, P
通讯作者：
Concannon, P
影响因子：
3.5
作者：
Brennan, Paul;Mckay, James;Hung, Rayjean J.
通讯作者：
Hung, Rayjean J.
所谓的低渗透率乳腺癌基因，ATM，BRIP1，PALB2和CHEK2是否对拥有较强家庭历史的女性高风险？
DOI：
10.1186/bcr2099
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Byrnes GB;Southey MC;Hopper JL
通讯作者：
Hopper JL