Easton D, Ford D, Peto J
Section of Epidemiology, Institute of Cancer Research, Belmont, Surrey.
Cancer Surv. 1993;18:95-113.
Four genes are now known to be responsible for inherited susceptibility to breast cancer: the BRCA1 gene on chromosome 17q21, the ataxia-telangiectasia (AT) gene (11q22-q23), the TP53 gene (17p13.1) and the androgen receptor (AR) (Xq11.2-q12). These genes, however, differ dramatically in terms of the risk of breast cancer that they confer, the proportion of breast cancer incidence that they account for and the other cancers and other phenotypes with which they are associated. Genetic linkage studies have shown that some high risk breast cancer families, particularly those where breast cancer occurs in association with ovarian cancer, are due to a gene on chromosome 17q known as BRCA1. The BRCA1 gene is estimated to confer a breast cancer risk of about 70% by age 70, and may account for about 2% of overall breast cancer incidence, although a higher proportion of younger cases. Germline mutations in the TP53 gene are responsible for a high proportion of LI-Fraumeni families, in which breast cancer occurs in association with childhood sarcomas and other cancers. In such families, the risk of breast cancer is over 50% by age 50, and the risk of all cancers is nearly 100%; germline TP53 mutations are, however, probably responsible for much less than 1% of all breast cancer. By contrast, heterozygotes for the AT gene carry a much more moderate risk of breast cancer. This gene, however, is much more common in the population and may account for 7% or more of breast cancer incidence. Finally, germline mutations in the androgen receptor are known to cause male breast cancer, but this has only been demonstrated in two families. Evidence from linkage and population based studies suggests that these genes may account for about one half of the observed familial clustering of breast cancer; other breast cancer susceptibility genes therefore remain to be identified.
位于17号染色体q21区域的BRCA1基因、共济失调毛细血管扩张症（AT）基因（11号染色体q22 - q23区域）、TP53基因（17号染色体p13.1区域）以及雄激素受体（AR）基因（X染色体q11.2 - q12区域）。然而，这些基因在其所赋予的乳腺癌风险、它们在乳腺癌发病率中所占比例以及与之相关的其他癌症和其他表型方面存在显著差异。基因连锁研究表明，一些高危乳腺癌家族，尤其是那些乳腺癌与卵巢癌并发的家族，是由17号染色体q区域上一个名为BRCA1的基因所致。据估计，BRCA1基因在70岁时赋予约70%的乳腺癌风险，可能占总体乳腺癌发病率的约2%，尽管在年轻病例中所占比例更高。TP53基因的种系突变是导致高比例的李-弗劳梅尼家族发病的原因，在这些家族中，乳腺癌与儿童肉瘤及其他癌症并发。在这类家族中，50岁时患乳腺癌的风险超过50%，患所有癌症的风险接近100%；然而，种系TP53突变可能仅导致不到1%的所有乳腺癌病例。相比之下，AT基因的杂合子携带者患乳腺癌的风险要温和得多。不过，该基因在人群中更为常见，可能占乳腺癌发病率的7%或更多。最后，已知雄激素受体的种系突变会导致男性乳腺癌，但仅在两个家族中得到证实。来自连锁研究和基于人群的研究证据表明，这些基因可能占所观察到的乳腺癌家族聚集现象的约一半；因此，其他乳腺癌易感基因仍有待确定。
