Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?
Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?
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DOI：
10.1186/bcr1826
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Brown MA
中科院分区：
文献类型：
--
作者：
Lovelock PK;Spurdle AB;Mok MT;Farrugia DJ;Lakhani SR;Healey S;Arnold S;Buchanan D;kConFab Investigators;Couch FJ;Henderson BR;Goldgar DE;Tavtigian SV;Chenevix-Trench G;Brown MA
在乳腺癌易感基因BRCA 1中鉴定的许多DNA序列变异在其潜在致病性方面仍然未分类。多因子似然分析和功能方法都被提出作为阐明这些变异可能的临床意义的手段，但这些方法对所有序列变异进行分类的比较价值的分析受到限制。我们比较了多因素似然分析的结果与四个BRCA 1序列变体A1708 E，G1738 R，R1699 Q和A1708 V的几个功能分析。我们的研究结果表明，多因素似然分析，其中包括序列保守，共遗传，分离，肿瘤免疫组化分析，可能会提高分类的变异。对于A1708 E，以前被证明是功能受损，雌激素受体，细胞角蛋白5/6，和细胞角蛋白14肿瘤表达数据的分析显着加强了致病性的预测，致病性的后验概率为99%。对于G1738 R，在这项研究中被证明是功能缺陷的，免疫组织化学分析证实了先前研究的两种肿瘤的不一致的“BRCA 1样”表型的发现，这种变体的后验概率为96%。R1699 Q和A1708 V的后验概率分别为54%和69%，仅中度提示风险增加。有趣的是，功能分析的结果表明，这两种变体都只有部分功能活性。R1699 Q是有缺陷的焦点形成在响应DNA损伤，并显示中间转录反式激活活性，但没有表现出中心体扩增的证据。与此相反，A1708 V显示了一个中间的转录反式激活活性和正常的焦点形成响应DNA损伤，但诱导中心体扩增。这些数据强调了需要进行一系列功能研究，以识别功能部分受损的变体。研究结果还提高了A1708 V和R1699 Q可能与低或中度癌症风险相关的可能性。虽然数据汇集策略可以为多因素分析提供更多信息，以改善对这些变异的临床意义的解释，但很可能需要发展当前的多因素可能性方法并考虑替代统计方法，以确定这些个体罕见变异是否确实赋予乳腺癌低或中度风险。
Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. These data highlight the need for a range of functional studies to be performed in order to identify variants with partially compromised function. The results also raise the possibility that A1708V and R1699Q may be associated with a low or moderate risk of cancer. While data pooling strategies may provide more information for multifactorial analysis to improve the interpretation of the clinical significance of these variants, it is likely that the development of current multifactorial likelihood approaches and the consideration of alternative statistical approaches will be needed to determine whether these individually rare variants do confer a low or moderate risk of breast cancer.
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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
作者：
Phelan, CM;Dapic, V;Monteiro, ANA
通讯作者：
Monteiro, ANA
DOI：
10.1089/10906570260199375
发表时间：
2002-06-01
期刊：
GENETIC TESTING
影响因子：
--
作者：
Deffenbaugh, AM;Frank, TS;Neuhausen, SL
通讯作者：
Neuhausen, SL
影响因子：
9.8
作者：
Goldgar, DE;Easton, DF;Couch, FJ
通讯作者：
Couch, FJ
影响因子：
10.3
作者：
Lakhani, SR;Jacquemier, J;Easton, DF
通讯作者：
Easton, DF