Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
N Engl J Med. 2013 Jul 4;369(1):43-53. doi: 10.1056/NEJMoa1302736. Epub 2013 Jun 5.
Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions.
We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women.
Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages.
Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).
子宫肌瘤虽是良性的，但却影响着数百万女性的健康。深入了解其中涉及的分子机制，可能为预防和治疗这些病变提供线索。
我们对 30 名女性的 38 个子宫肌瘤及其相应的子宫肌组织进行了全基因组测序和基因表达谱分析。
一些单独的肿瘤结节中观察到相同的变异，提示这些结节具有共同的起源。类似于染色体重排的复杂染色体重排是子宫肌瘤的一个常见特征。这些重排最好通过多次染色体断裂和随机重组的单一事件来解释。这些重排导致组织特异性变化，与子宫肌瘤的起始有关，如 HMGA2 和 RAD51B 基因座的易位以及 COL4A5-COL4A6 基因座的异常，并且发生在正常 TP53 等位基因的存在下。在某些情况下，单个肿瘤细胞谱系中已经发生了多次单独的事件。
类似于染色体重排的染色体破碎和重组（单个基因组事件导致多个基因组区域的局部缺失和重排）是子宫平滑肌瘤染色体异常的主要原因；我们提出，当通过这些事件形成组织特异性的肿瘤促进变化时，肿瘤发生。染色体重排先前与侵袭性癌症有关；它在子宫肌瘤中的常见发生表明，它在良性肿瘤的发生和进展中也具有作用。我们观察到，多个单独的肿瘤可以从单个子宫平滑肌瘤细胞谱系中播种。（由芬兰科学院卓越中心计划和其他计划资助）。
