The BRCA1 suppressor hypothesis: An explanation for the tissue-specific tumor development in BRCA1 patients
The BRCA1 suppressor hypothesis: An explanation for the tissue-specific tumor development in BRCA1 patients
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DOI：
10.1016/s1535-6108(02)00041-7
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发表时间：
2002-03-01
期刊：
影响因子：
50.3
通讯作者：
Amon, A
中科院分区：
文献类型：
--
作者：
Elledge, SJ;Amon, A
肿瘤抑制基因BRCA1在细胞对DNA损伤和同源重组的反应中是必需的，尽管它在这些过程中发挥的确切功能尚不清楚(Moynahan等人，1999；Scully和Livingston，2000)。与BRCA1在细胞内发挥中心管家作用的想法一致，缺乏BRCA1的小鼠在胚胎发育中很早就死亡(E7。5或更早)是由于极端的基因组不稳定和p53/p21途径的激活(Gowen等人，1996；Hakem等人，1996；Ludwig等人，1997)。尽管BRCA1在双链断裂修复中起着明显的核心作用，但BRCA1功能的丧失似乎只影响到人类中非常特定的一小部分组织。虽然携带BRCA1基因胚系突变的患者可能会稍微增加患其他类型癌症的可能性，但仅在这些人中观察到乳腺癌和卵巢癌的易感性显著增加(在Welcsh等人，1998；Scully和Livingston，2000；Rosen等人，2001)中观察到的易感性显著增加。到目前为止，BRCA1的大多数突变都是单碱基对的删除、插入或大的基因组重排，可能会由于由此导致的框架移位而导致BRCA1功能的完全丧失(Neuhausen和Ostrander，1997；Blackwood和Weber，1998)，排除了这些BRCA1突变是弱亚型等位基因的可能性。事实上，与这些截断相关的表型预计至少与迄今为止在小鼠身上进行的BRCA1突变一样有害。
The tumor suppressor gene BRCA1 is required for the cellular response to DNA damage and homologous recombination, although the exact function it plays in these processes is unclear (Moynahan et al., 1999; Scully and Livingston, 2000). Consistent with the idea that BRCA1 plays a central housekeeping role within cells, mice lacking BRCA1 die very early in embryogenesis (E7. 5 or earlier) due to extreme genomic instability and activation of the p53/p21 pathway (Gowen et al., 1996; Hakem et al., 1996; Ludwig et al., 1997). Despite its apparent central role in double-strand break repair, loss of BRCA1 function appears to affect only a very specific and small subset of tissues in humans. Although a slight increase in predisposition of other cancer types may exist in patients carrying a germline mutation in the BRCA1 gene, a dramatic increase in predisposition is observed only for cancer of the breast and ovary in these individuals (reviewed in Welcsh et al., 1998; Scully and Livingston, 2000; Rosen et al., 2001). Most mutations in BRCA1 thus far represent single base pair deletions, insertions or large genomic rearrangements likely causing a complete loss of function of BRCA1 due to the resulting frameshifts (Neuhausen and Ostrander, 1997; Blackwood and Weber, 1998), excluding the possibility that these BRCA1 mutations are weak hypomorphic alleles. The phenotypes associated with these truncations are in fact expected to be at least as deleterious as the BRCA1 mutations made thus far in mice.