The Center for Human Reproduction, New York, New York, United States of America.
PLoS One. 2012;7(9):e44753. doi: 10.1371/journal.pone.0044753. Epub 2012 Sep 12.
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.
BRCA1/2 突变和最近描述的 FMR1 结构基因突变都与卵巢储备过早减少有关。它们在分布上是否相互关联，以及 BRCA1/2 和 FMR1 对卵巢的观察到的影响是否相互独立，目前尚不清楚。因此，在一项前瞻性比较队列研究中，我们调查了 99 名 BRCA1/2 突变阳性妇女和 410 名女性对照者的 FMR1 结构基因突变、正常（norm）、杂合子（het）和纯合子（hom）以及各自的亚基因型（高/低）的分布情况，以确定研究和对照患者的分布模式是否存在差异。与对照组相比，BRCA1/2 携带者除了 CGG（n<26）等位基因的低（CGG（n<26））亚基因型外，几乎完全不存在所有的 FMR1 结构基因型。BRCA1/2 阳性患者和对照组之间的交叉制表证实了与 FMR1 分布相关的显著组间关系（P<0.0001）。这些结果最可能的解释是，BRCA1/2 突变是胚胎致死的，除非被大约四分之一的女性中存在的低（CGG（n<26））FMR1 亚基因型所挽救。因此，具有低 FMR1 亚基因型的女性应反映出增加的 BRCA1/2 相关癌症风险，而其余大约 75%的女性应面临几乎没有这种风险。如果得到证实，这一观察结果为更有效和成本效益更高的 BRCA1/2 癌症筛查提供了机会。该研究还表明，与 BRCA 突变相关的先前报道的卵巢储备过早减少的风险是由 FMR1 介导的，并通过提出广泛认为的 BRCA1/2 相关肿瘤风险实际上是由 FMR1 介导的可能性，为所谓的“BRCA 悖论”提供了一种可能的解释。
