Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
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子宫腺肌病是一种与KRAS基因突变相关的寡克隆性疾病。
DOI：
10.1038/s41467-019-13708-y
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发表时间：
2019-12-19
影响因子：
16.6
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Inoue, Satoshi;Hirota, Yasushi;Mano, Hiroyuki
子宫肿块是一种良性疾病，常与子宫内膜异位症和/或平滑肌瘤共同发生，并损害生活质量。子宫腺肌症的基因组特征尚不清楚。在这里，我们对子宫腺肌症（70个个体和192个多地区样本）以及同时发生的平滑肌瘤和子宫内膜异位症进行了新一代测序，发现26/70（37.1%）的子宫腺肌症病例中存在复发性KRAS突变。多区域测序显示子宫腺肌症的低克隆性，在正常子宫内膜和/或同时发生的子宫内膜异位症中也检测到一些突变。KRAS突变在子宫腺肌症合并子宫内膜异位症、低孕激素受体（PR）表达或孕激素（dienogest； DNG）预处理的病例中更为常见。在KRAS突变的永生化细胞中，DNG的抗增殖作用通过PR的表观遗传沉默而减弱。我们的基因组分析表明，腺肌病病变经常包含可能降低DNG疗效的KRAS突变，并且子宫腺肌症和子宫内膜异位症可能具有相同的分子病因，解释了它们的共同发生。这些发现可能导致保留子宫手术后的遗传指导治疗和/或复发风险评估。
Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG's anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.