PLoS ONE：筛选FMR1基因突变更易检测卵巢癌和乳腺癌风险

研究人员开展一项基因突变研究，这些突变提高妇女患上乳腺癌和卵巢癌的几率。他们的研究发现可能有助于开发出更便宜和更容易的方法来筛选乳腺癌和卵巢癌。此外，这些令人吃惊的研究发现可能也解释着携带这些乳腺癌突变的人胚胎如何能够存活下来。相关研究于近期刊登在PLoS ONE期刊上。

已知妇女的乳腺癌和卵巢癌易感基因BRCA1和BRCA2(BRCA1/2)能够被用来预测她们患上这两种癌症的风险。当基因BRCA1/2没有发生突变时，她们在一生当中患上乳腺癌的几率是12%，患上卵巢癌的几率是1.4%。然而，当基因BRCA1/2发生突变时，她们患上乳腺癌的几率增加至12%，患上卵巢癌的几率增加至15-40%。

在当前这项研究中，参与研究的99名妇女携带BRCA1/2突变，而且她们几乎全部还携带一种非常特异性的基因型：低水平的FMR1。相反，作为对照组的300多名妇女不携带BRCA1/2突变，而且她们当中除了只有大约25%的妇女具有较低水平的FMR1之外，其他人都表现出正常分布的FMR1基因型。研究人员作出结论，因为基因BRCA1/2突变是仅在携带低水平FMR1的妇女体内发现的，所以不携带低水平FMR1基因型的妇女将没有发生基因BRCA1/2突变的风险，也就不与乳腺癌和卵巢癌相关联。

低水平FMR1基因型与乳腺癌和卵巢癌相关联，提示着人们能够开发出一种更便宜的FMR1基因测试来替代当前昂贵的基因BRCA1/2突变筛选方法来确定妇女患上这两种癌症的风险。

研究人员注意到对为什么如此多的携带基因BRCA1/2突变的妇女也携带低水平FMR1基因型的最为可能的解释就是，基因BRCA1/2突变对人胚胎是致命性的，除了这种基因突变之外，只有那些携带低水平FMR1基因型的胚胎才能够存活下来。

doi: 10.1371/journal.pone.0044753
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BRCA1/2 Mutations Appear Embryo-Lethal Unless Rescued by Low (CGG n<26) FMR1 Sub-Genotypes: Explanation for the “BRCA Paradox”?

Andrea Weghofer1,2, Muy-Kheng Tea3, David H. Barad1,4, Ann Kim1, Christian F. Singer3, Klaus Wagner5, Norbert Gleicher

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG n<26) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG n<26) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called “BRCA paradox” by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.