A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history.
A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history.
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DOI：
10.1186/bcr2223
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Vreeswijk MP
中科院分区：
文献类型：
--
作者：
Gómez García EB;Oosterwijk JC;Timmermans M;van Asperen CJ;Hogervorst FB;Hoogerbrugge N;Oldenburg R;Verhoef S;Dommering CJ;Ausems MG;van Os TA;van der Hout AH;Ligtenberg M;van den Ouweland A;van der Luijt RB;Wijnen JT;Gille JJ;Lindsey PJ;Devilee P;Blok MJ;Vreeswijk MP
BRCA 1/BRCA 2基因中的未分类变异（UV）是咨询乳腺癌和/或卵巢癌家族的常见问题。关于癌症家族史的信息通常是可用的，但很少用于评估UV。本研究的目的是确定哪种是可以预测UV是否有害的临床参数的最佳组合，用于UV的分类。我们开发了具有最佳临床特征组合的逻辑回归模型，该模型将BRCA致病性变体的阳性对照（115个家族）与最初被分类为UV且后来被认为是中性的BRCA变体的阴性对照群体（38个家族）区分开来。这些模型包括BRCAPRO评分、Myriad评分、家族中卵巢癌的数量、诊断时的年龄以及患有卵巢肿瘤和/或乳腺肿瘤的人数。BRCA 1和BRCA 2模型的受试者工作特征曲线下面积分别为0.935和0.836。对于每种模型，选择最小受试者工作特征距离（BRCA 1和BRCA 2的特异性分别为90%和78%）作为截止值，以预测哪些UV是有害的，来自59个荷兰家庭的12个UV的研究人群。根据我们的模型，BRCA 1中的p.S1655F、p.R1699W和p.R1699Q变体以及BRCA 2中的p.Y2660D、p.R2784Q和p.R3052W变体被归类为有害的。BRCA 1中p.L246V变体以及BRCA 2中p.Y42C、p.E462G、p.R2888C和p.R3052Q变体的预测与已发表的中性信息一致。BRCA 2中的p.R2784W变体仍然不确定。本研究表明，这些开发的模型是有用的分类紫外线在临床遗传学实践。
Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs. We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families). The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain. The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
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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：
6.4
作者：
Osorio, A;de la Hoya, M;Benítez, J
通讯作者：
Benítez, J
影响因子：
11.2
作者：
Judkins, T;Hendrickson, BC;Scholl, T
通讯作者：
Scholl, T
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
DOI：
10.1093/jnci/94.11.844
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Euhus, DM;Smith, KC;Tomlinson, G
通讯作者：
Tomlinson, G