RRC ID 58370
Author Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E, Hayashi T, Kojima S, Takeyama R, Hashimoto T, Kiyono T, Ikemura M, Taguchi A, Tanaka T, Tanaka Y, Sakata S, Takeuchi K, Muraoka A, Osuka S, Saito T, Oda K, Osuga Y, Terao Y, Kawazu M, Mano H.
Title Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.
Journal Nat Commun
Abstract 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.
Volume 10(1)
Pages 5785
Published 2019-12-19
DOI 10.1038/s41467-019-13708-y
PII 10.1038/s41467-019-13708-y
PMID 31857578
PMC PMC6923389
MeSH Adenomyosis / complications Adenomyosis / genetics* Adenomyosis / therapy Adult Cell Proliferation / drug effects Cell Proliferation / genetics DNA Mutational Analysis Endometriosis / complications Endometriosis / genetics* Endometriosis / therapy Endometrium / pathology Endometrium / surgery Female High-Throughput Nucleotide Sequencing Humans Hysterectomy Middle Aged Mutation Myometrium / pathology Myometrium / surgery Nandrolone / analogs & derivatives* Nandrolone / pharmacology Nandrolone / therapeutic use Proto-Oncogene Proteins p21(ras) / genetics* Receptors, Progesterone / genetics Receptors, Progesterone / metabolism Treatment Outcome Young Adult
IF 12.121
Times Cited 2
Resource
DNA material CSII-CMV-RfA (RDB04386) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)