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 bylaser 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 ofthe 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.
Highlights
Five to fifteen percent of women of reproductive age suffer from endometriosis, which is histologically characterized by an extrauterine growth of endometrial-like epithelium and stroma and which causes pelvic pain, dysmenorrhea, and infertility (Giudice, 2010; Hickey et al, 2014)
Whole-Exome Sequencing in a Discovery Cohort We performed whole-exome sequencing for 13 endometriotic and 11 normal uterine endometrial epithelium samples, together with sequencing their matched normal blood samples (Figures 1A and 1B; Table S1)
In the five subjects for which both endometriotic and uterine endometrial epithelium samples were sequenced, mutation profiles were discordant between their endometriosis and normal uterine endometrium (Figure 1B; Tables S2 and S3)
Summary
Five to fifteen percent of women of reproductive age suffer from endometriosis, which is histologically characterized by an extrauterine growth of endometrial-like epithelium and stroma and which causes pelvic pain, dysmenorrhea, and infertility (Giudice, 2010; Hickey et al, 2014). Endometriosis has been clinically recognized for nearly 150 years, yet the origin of the disease is still disputed. Several hypotheses, such as retrograde menstruation, coelomic metaplasia, and Mu€llerian remnants, have been proposed to account for the etiology and pathogenesis of endometriosis, but none have yet to be conclusively confirmed (Vercellini et al, 2014). Focusing on the possibility that ovarian endometriosis could be the precursor of certain histological types of ovarian cancers, somatic mutations on genes frequently mutated in clear-cell and endometrioid ovarian cancers, such as PTEN, PIK3CA, and ARID1A, have been detected in ovarian endometriosis with or without concurrent ovarian cancers (Sato et al, 2000; Wiegand et al, 2010; Vestergaard et al, 2011; Yamamoto et al, 2011; Anglesio et al, 2015; Cell Reports 24, 1777–1789, August 14, 2018 a 2018 The Author(s).
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