Dunning A M, Chiano M, Smith N R, Dearden J, Gore M, Oakes S, Wilson C, Stratton M, Peto J, Easton D, Clayton D, Ponder B A
CRC Human Cancer Genetics Research Group, Addenbrooke's Hospital, Cambridge, UK.
Hum Mol Genet. 1997 Feb;6(2):285-9. doi: 10.1093/hmg/6.2.285.
Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.
大多数年轻女性乳腺癌和卵巢癌的多病例家族被认为是由易感基因BRCA1和BRCA2中的高外显率突变所致。然而，这些突变在人群中并不常见，它们可能仅占所有乳腺癌发病率的百分之几。原则上，更大比例的乳腺癌可能是由具有较低个体风险的常见变异引起的。BRCA1基因存在几种常见的多态性，这些多态性会导致氨基酸替换。我们在大量乳腺癌和卵巢癌病例以及匹配的对照组中检测了其中四种多态性的频率：Gln356Arg、Pro871Leu、Glu1038Gly和Ser1613Gly。由于强连锁不平衡，这四个位点仅产生三种频率>1.3%的单倍型。最常见的单倍型由等位基因Gln356Pro871Glu1038Ser1613和Gln356Leu871Gly1038Gly1613定义，频率分别为0.57和0.32，患者组和对照组之间这些频率无显著差异。因此，BRCA1基因最常见的多态性对乳腺癌或卵巢癌风险没有显著贡献。然而，我们的数据表明，Arg356等位基因在乳腺癌患者中的基因型分布可能与对照组不同（对照组中Arg356纯合子更常见，P = 0.01），这表明它可能对乳腺癌具有保护作用。如果这一发现能够得到证实，可能会为深入了解BRCA1蛋白对其功能至关重要的结构特征提供线索。
