Langston A A, Malone K E, Thompson J D, Daling J R, Ostrander E A
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
N Engl J Med. 1996 Jan 18;334(3):137-42. doi: 10.1056/NEJM199601183340301.
Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families. However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population. We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer.
We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history. Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays. Alterations were defined by DNA sequencing.
Germ-line BRCA1 mutations were identified in 6 of the 80 women. Four additional rare sequence variants of unknown functional importance were also identified. Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects.
Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer. The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer. These results represent a minimal estimate of the frequency of BRCA1 mutations in this population. Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken.
BRCA1基因的遗传性突变在一些家族中与乳腺癌和卵巢癌的高风险相关。然而，对于BRCA1突变在普通人群乳腺癌中的作用知之甚少。我们分析了参与一项基于人群的早发性乳腺癌研究的女性的DNA样本，以评估患有乳腺癌的年轻女性中胚系BRCA1突变的谱型和频率。
我们研究了80名在35岁之前被诊断出患有乳腺癌且未根据家族史进行选择的女性。通过涉及单链构象多态性分析和等位基因特异性检测的方法研究基因组DNA中的BRCA1突变。通过DNA测序确定变异情况。
在80名女性中有6名被鉴定出胚系BRCA1突变。还鉴定出另外4个功能重要性未知的罕见序列变异。在39名报告无乳腺癌或卵巢癌家族史的女性中发现了2个突变和3个罕见序列变异。在73名无关受试者的参考人群中未发现任何突变，仅发现1个罕见变异。
在这一队列的年轻乳腺癌女性中，约10%鉴定出BRCA1改变。携带突变的风险并不局限于有乳腺癌或卵巢癌家族史的女性。这些结果是该人群中BRCA1突变频率的最低估计值。在对普通人群中的女性进行检测之前，需要有识别BRCA1突变并了解其重要性的综合方法。
