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Cell Rep. 2018 Aug 14;24(7):1777-1789. doi: 10.1016/j.celrep.2018.07.037.

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

Author information

1
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
2
Division of Human Genetics, National Institute of Genetics, Mishima 411-8540, Japan.
3
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. Electronic address: yoshikou@med.niigata-u.ac.jp.
4
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
5
Department of Obstetrics and Gynecology, Nagaoka Chuo General Hospital, Nagaoka 940-8653, Japan.
6
Niigata Medical Center Hospital, Niigata 950-2022, Japan.
7
COI-s Biofluid Biomarker Center, Institute of Research Collaboration and Promotion, Niigata University, Niigata 950-2181, Japan.
8
Department of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
9
Division of Human Genetics, National Institute of Genetics, Mishima 411-8540, Japan. Electronic address: itinoue@nig.ac.jp.
10
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. Electronic address: enomoto@med.niigata-u.ac.jp.

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.

KEYWORDS:

clonal evolution; endometrial gland; endometriosis; epithelial cell; genomic heterogeneity; multiregional sequencing; next-generation sequencing; ovarian cancer; somatic mutation; uterine endometrium

PMID:
30110635
DOI:
10.1016/j.celrep.2018.07.037
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