Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
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DOI：
10.1002/humu.21202
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发表时间：
2010-03
期刊：
影响因子：
3.9
通讯作者：
Bernstein, Jonine L.
中科院分区：
文献类型：
--
作者：
Borg, Ake;Haile, Robert W.;Malone, Kathleen E.;Capanu, Marinela;Diep, Ahn;Torngren, Therese;Teraoka, Sharon;Begg, Colin B.;Thomas, Duncan C.;Concannon, Patrick;Mellemkjaer, Lene;Bernstein, Leslie;Tellhed, Lina;Xue, Shanyan;Olson, Eric R.;Liang, Xiaolin;Dolle, Jessica;Borresen-Dale, Anne-Lise;Bernstein, Jonine L.
在乳腺癌高危女性中进行BRCA 1和BRCA 2筛查，可识别明确定义的有害突变和临床意义未知的序列变异（VUS）。我们研究了一个基于人群的样本，年轻女性对侧乳腺癌（CBC，n=705）或单侧乳腺癌（UBC，n=1398）。我们确定了470个独特的序列变异，其中113个是有害的突变。其余357个VUS包括185个独特的错义变化，60%仅观察到一次，而3%的发生频率> 10%。CBC女性（15.3%）的有害突变发生率是UBC女性（5.2%）的三倍，而CBC和UBC女性的VUS发生率相似。蛋白质比对算法定义了16种罕见的VUS，发生在高度保守的残基和/或赋予相当大的生化差异，大多数位于BRCA 2 DNA结合结构域。我们证实了BRCA 1和BRCA 2 VUS的多重性，发生在广泛的等位基因频率。虽然一些VUS在保守残基上造成化学差异，表明有害作用，但大多数与CBC风险增加无关。
BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.
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