Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium

Kazuaki Suda, Hirofumi Nakaoka, Kosuke Yoshihara, Tatsuya Ishiguro, Ryo Tamura, Yutaro Mori, Kaoru Yamawaki, Sosuke Adachi, Tomoko Takahashi, Hiroaki Kase, Kenichi Tanaka, Tadashi Yamamoto, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto
Cell reports · 2018 · vol. 24(7) , pp. 1777–1789 · doi:10.1016/j.celrep.2018.07.037 · PMID:30110635 · W2885069342
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This study identified numerous cancer-associated somatic mutations in both endometriotic and normal endometrial epithelium, with KRAS mutations and allelic imbalances being frequent in endometriosis, suggesting retrograde flow of mutated endometrial cells and selection at ectopic sites.

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Abstract

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.

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Condition tags

endometriosis

MeSH descriptors

Endometrial Neoplasms Endometriosis Epithelial Cells Gene Expression Regulation, Neoplastic Mutation Proto-Oncogene Proteins p21(ras) Alleles Carcinogenesis Carcinogenesis Carcinogenesis Carcinogenesis Class Ia Phosphatidylinositol 3-Kinase Class I Phosphatidylinositol 3-Kinases Class I Phosphatidylinositol 3-Kinases Class I Phosphatidylinositol 3-Kinases Clone Cells Endometrial Neoplasms Endometrial Neoplasms Endometrial Neoplasms Endometriosis

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