Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
Int J Cancer. 2014 Feb 15;134(4):1008-12. doi: 10.1002/ijc.28410. Epub 2013 Aug 29.
Uterine leiomyomas are extremely common tumors originating from the smooth muscle cells of myometrium. We recently reported recurrent somatic mutations in mediator complex subunit 12 (MED12) in the majority of these lesions, and analyzed chromosomal abnormalities in leiomyomas by whole-genome sequencing. The aim of our study was to examine in detail uterine leiomyoma exomes, to search for driver mutations in MED12 mutation-negative leiomyomas and to scrutinize MED12 mutation-positive leimyomas for additional contributing mutations. We analyzed whole exome sequencing data of 27 uterine leiomyomas (12 MED12 mutation-negative and 15 MED12 mutation-positive) and their paired normal myometrium. We searched for genes, which would be recurrently mutated. No such genes were identified in MED12 mutation-negative uterine leiomyomas. Similarly, MED12 mutation-positive leiomyomas displayed no additional recurrent changes. The complete lack of novel driver point mutations in the examined series highlights the unique role of MED12 mutations in genesis of uterine leiomyomas, and suggests that these mutations alone may be sufficient for tumor development. Additional factors that cannot be detected by exome sequencing, such as somatic structural rearrangements, epigenetic events and intronic variants, are likely to have a particular impact to the development of MED12 wild-type lesions.
子宫肌瘤是起源于子宫平滑肌细胞的非常常见的肿瘤。我们最近报道了这些病变中大多数存在中介体复合物亚基 12（MED12）的反复体细胞突变，并通过全基因组测序分析了子宫肌瘤的染色体异常。我们研究的目的是详细检查子宫肌瘤外显子组，在 MED12 突变阴性的子宫肌瘤中寻找驱动突变，并仔细研究 MED12 突变阳性的肌瘤中是否存在其他贡献突变。我们分析了 27 例子宫肌瘤（12 例 MED12 突变阴性和 15 例 MED12 突变阳性）及其配对的正常子宫平滑肌的全外显子组测序数据。我们寻找反复突变的基因。在 MED12 突变阴性的子宫肌瘤中未发现此类基因。同样，MED12 突变阳性的肌瘤也没有显示出额外的反复变化。在检查的系列中，完全没有新的驱动点突变，这突出了 MED12 突变在子宫肌瘤发生中的独特作用，并表明这些突变本身可能足以促进肿瘤的发展。其他无法通过外显子组测序检测到的因素，如体细胞结构重排、表观遗传事件和内含子变异，可能对 MED12 野生型病变的发展有特殊影响。
