MED12 mutations in uterine fibroids-their relationship to cytogenetic subgroups
MED12 mutations in uterine fibroids-their relationship to cytogenetic subgroups
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DOI：
10.1002/ijc.27424
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发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Bullerdiek, Joern
中科院分区：
文献类型：
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作者：
Markowski, Dominique Nadine;Bartnitzke, Sabine;Bullerdiek, Joern
在所有子宫肌瘤中，约有20%的子宫肌瘤有反复的染色体改变，但大多数缺乏细胞遗传学改变。最近，在大多数肌瘤中发现了基因介体亚复合体12(MED12)的突变，但目前尚不清楚它们是否与细胞遗传学亚型共存，例如编码高迁移率组AT-挂钩(HMGA)蛋白的基因重排。在来自50名患者的80个细胞遗传学特征的肌瘤中，我们不仅能够证实MED12突变的频繁发生，而且能够将肌瘤发生的两条相互排斥的途径分层，要么通过影响12q14的克隆染色体异常反映HMGA2重排，要么通过影响MED12外显子2的突变反映HMGA2重排。平均而言，后一种突变与明显较小的肿瘤大小相关。然而，与其他MED12突变相比，核苷酸c.130或c.131的G>；A突变与肌瘤的大小显著相关，从而解释了前一种突变在临床可检测到的肌瘤中的高发生率。有趣的是，带有MED12突变的肌瘤中，编码无翅型MMTV整合位点家族成员4(WNT4)的基因表达水平显著升高。基于这些发现和文献数据，我们假设雌激素和突变的MED12协同激活Wnt通路，该通路反过来激活已知引起小鼠子宫肌瘤样病变的β-连环素。在一种罕见的子宫内膜息肉的组织学亚型中出现肌瘤型突变，这表明这种机制并不局限于子宫肌瘤。
Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14 similar to 15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates beta-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a fibroid-type mutation in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.