The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families
The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families
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DOI：
10.1158/0008-5472.can-08-0599
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Nathanson, Katherine L.
中科院分区：
文献类型：
--
作者：
Palma, Maurizia Dalla;Domchek, Susan M.;Nathanson, Katherine L.
对BRCA1和BRCA2突变筛查的需求正在增加，因为它们的识别将影响医疗管理。然而，在美国的高危人群中，BRCA1和BRCA2中不同突变类型的贡献，以及应该对哪些人进行大规模基因组重排检测，都尚未得到很好的确定。我们定义了美国非德系犹太人和德系犹太人后裔的高风险临床人群中BRCA基因的点突变和基因组重排的患病率和频谱，使用了美国基因测试人群的代表性样本集。通过宾夕法尼亚大学高风险诊所确定的251个先知者，都进行了BRCA1和BRCA2的商业测试，使用Myriad If模型和可用的DNA样本估计BRCA突变>= 10%的患病率，进行了研究。个人没有。有害的观点。筛选BRCA1和BRCA2基因重排突变。在136个非德系犹太人先证者中，鉴定出36个（26%）BRCA点突变和8个（6%）基因组重排（7个BRCA1和1个BRCA2）。115名德系犹太人先证者中有47名（40%）有点突变；在没有突变的组中没有发现基因组重排。在非德系犹太人先证者中，基因组重排占所有已识别BRCA突变的18%；估计的突变流行率（Myriad II模型）不能预测它们的存在。虽然这些发现应该在更大的样本集中得到证实，但我们的数据表明，在所有估计突变患病率>= 10%的非德系犹太妇女中，应该考虑进行基因组重排测试。
The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation >= 10% using the Myriad If model and a DNA sample available, were studied. Individuals without. deleterious point. mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should he confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence >= 10%.