MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.
MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.
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DOI：
10.1038/modpathol.2013.243
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发表时间：
2014-08
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最近在大多数子宫平滑肌瘤中发现的体细胞MED 12突变为研究平滑肌瘤的肿瘤发生提供了一个新的场所。我们特别感兴趣的是MED 12和HMGA 2基因产物在有或没有MED 12突变的平滑肌瘤和平滑肌肉瘤中的相关性。为了解决这些问题，在这项研究中，我们检查了一个大的队列中常见型平滑肌瘤（178例）和子宫平滑肌瘤（32例）的MED 12突变。我们发现74.7%（133/178）的平滑肌瘤有MED 12突变，这与几项独立研究一致。相比之下，只有9.7%（3/32）的平滑肌瘤携带MED 12突变。蛋白质印迹和免疫组化表达分析显示，那些复杂的MED 12突变的平滑肌瘤有显着低于匹配的子宫肌层的蛋白质产物。有趣的是，与匹配的子宫肌层相比，大多数没有MED 12突变的平滑肌瘤也具有非常低的MED 12表达水平。这些发现表明MED 12在良性和恶性子宫平滑肌肿瘤中的潜在功能作用。当我们进一步检查所有平滑肌瘤和平滑肌肉瘤中的HMGA 2表达时，我们发现HMGA 2过表达仅存在于那些没有MED 12突变的平滑肌瘤中，占总平滑肌瘤的10.1%（18/178）和非MED 12突变平滑肌瘤的40%（18/45）。25%（8/32）的平滑肌肉瘤中HMGA 2过表达，而在HMGA 2阳性的平滑肌肉瘤中未发现MED 12突变。这些发现强烈表明，MED 12突变和HMGA 2过表达是发生在平滑肌瘤中的独立的遗传事件，并且它们在子宫平滑肌瘤的肿瘤发生中可能起不同的作用。
Recent identification of somatic MED12 mutations in most uterine leiomyomas brings a new venue for the study of the tumorigenesis of leiomyomas. We are particularly interested in the correlation of MED12 and HMGA2 gene products in leiomyomas and leiomyosarcomas with and without MED12 mutations. To address these issues, in this study we examined MED12 mutations in a large cohort of usual type leiomyomas (178 cases) and uterine leiomyosarcomas (32 cases). We found that 74.7% (133/178) of leiomyomas had MED12 mutations, which was consistent with several independent studies. In contrast, only 9.7% (3/32) of leiomyosarcomas harbored MED12 mutations. Expression analysis by Western blot and immunohistochemistry revealed that those leiomyomas with complex MED12 mutations had significantly lower protein products than matched myometrium. Interestingly, most leiomyosarcomas without MED12 mutations also had very low levels of MED12 expression in comparison to the matched myometrium. These findings suggest a potential functional role of MED12 in both benign and malignant uterine smooth muscle tumors. When we further examined HMGA2 expression in all leiomyomas and leiomyosarcomas, we found HMGA2 overexpression was exclusively present in those leiomyomas with no MED12 mutation, accounting for 10.1 % (18/178) of total leiomyomas and 40 % (18/45) of non-MED12 mutant leiomyomas. Twenty-five % (8/32) of leiomyosarcomas had HMGA2 overexpression and no MED12 mutations were found in HMGA2 positive leiomyosarcoma. These findings strongly suggest that MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas.
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