Teng D H, Bogden R, Mitchell J, Baumgard M, Bell R, Berry S, Davis T, Ha P C, Kehrer R, Jammulapati S, Chen Q, Offit K, Skolnick M H, Tavtigian S V, Jhanwar S, Swedlund B, Wong A K, Kamb A
Myriad Genetics, Inc., Salt Lake City, Utah 84108, USA.
Nat Genet. 1996 Jun;13(2):241-4. doi: 10.1038/ng0696-241.
Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.
家族性肿瘤抑制基因的遗传性突变等位基因使个体易患特定类型的癌症。除了参与遗传性癌症易感性外，这些肿瘤抑制基因还是家族性形式中发现的同类型散发性癌症体细胞突变的靶点。BRCA1是一个例外，它在很大一部分家族性乳腺癌和卵巢癌中起作用，但在散发性乳腺癌和卵巢癌中的突变率非常低。这一发现表明，其他基因可能是乳腺癌体细胞突变的主要靶点。最近发现的第二个家族性乳腺癌基因BRCA2（参考文献5 - 8），在乳腺癌中所占比例与BRCA1大致相当。与BRCA1一样，BRCA2表现为显性遗传的肿瘤抑制基因。继承一个突变等位基因的个体患乳腺癌的风险增加，他们所患肿瘤通过杂合缺失失去野生型等位基因。BRCA2编码序列巨大，由26个外显子组成，跨度为10443 bp。在这里，我们研究了散发性乳腺癌以及一组代表其他12种肿瘤类型的细胞系中BRCA2的突变率。令人惊讶的是，BRCA2突变在包括乳腺癌在内的癌症中并不常见。然而，在一个胰腺肿瘤细胞系中发现的一个可能的种系突变表明BRCA2在胰腺癌易感性中起作用。
