Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium
Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium
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DOI：
10.1016/j.celrep.2018.07.037
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发表时间：
2018-08-14
期刊：
影响因子：
8.8
通讯作者：
Enomoto, Takayuki
中科院分区：
文献类型：
--
作者：
Suda, Kazuaki;Nakaoka, Hirofumi;Enomoto, Takayuki
子宫内膜异位症的特征是异位内膜样上皮和间质，其分子特征仍有待充分阐明。我们对107例卵巢上皮增生和82例正常子宫内膜上皮进行了激光显微切割测序。在卵巢癌和正常上皮样本中，在卵巢癌相关性卵巢癌中频繁突变的基因中发现了许多体细胞突变。KRAS在上皮细胞增生中经常发生突变，突变等位基因频率（MAF）较高，伴有臂水平等位基因失衡。MAF分析，结合多区域测序，阐明了子宫内膜异位症和子宫内膜基因组的时空演变。我们对109个单个子宫内膜腺体进行了测序，发现每个腺体都携带不同的癌症相关突变，表明子宫内膜上皮细胞基因组结构的异质性。子宫内膜异位症上皮中癌症相关基因突变的MAF显著增加表明已经携带癌症相关突变的子宫内膜细胞的逆行流动，在异位部位具有选择性优势，导致子宫内膜异位症的发展。
Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.