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Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.

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.

SUBMITTER: Inoue S

PROVIDER: S-EPMC6923389 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.

Inoue Satoshi S Hirota Yasushi Y Ueno Toshihide T Fukui Yamato Y Yoshida Emiko E Hayashi Takuo T Kojima Shinya S Takeyama Reina R Hashimoto Taiki T Kiyono Tohru T Ikemura Masako M Taguchi Ayumi A Tanaka Tomoki T Tanaka Yosuke Y Sakata Seiji S Takeuchi Kengo K Muraoka Ayako A Osuka Satoko S Saito Tsuyoshi T Oda Katsutoshi K Osuga Yutaka Y Terao Yasuhisa Y Kawazu Masahito M Mano Hiroyuki H

Nature communications 20191219 1

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 de ...[more]

PMID: 31857578

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Project description:BackgroundUterine leiomyomas and adenomyosis are both common and often associated with abnormal uterine bleeding (AUB), including the symptom of heavy menstrual bleeding (HMB). Understanding the prevalence of adenomyosis in women with uterine leiomyomas could inform clinicians and patients in a way that may improve therapeutic approaches.ObjectiveTo explore the prevalence of adenomyosis in a group of women who underwent hysterectomy for AUB-L, to determine the prevalence of submucous leiomyomas, and to examine the utility of preoperative ultrasound to detect the presence of adenomyosis.MethodsThe Kaiser Permanente Hysterectomy Database (KPHD) was searched for women aged 18-52 undergoing hysterectomy for leiomyoma-associated chronic AUB (AUB-L) in 2018 and 2019. A target sample of 400 comprised those with at least 3 years in the Health System. Radiologists evaluated preoperative pelvic ultrasound images to determine leiomyoma size and level 2 FIGO type (submucous or other), and the linked electronic medical record abstracted for clinical features, including histopathological evidence of adenomyosis.ResultsOf the 370 subjects that met the study criteria, adenomyosis was identified via histopathology in 170 (45.9%). There was no difference in the adenomyosis prevalence with (47.1%) and without (43.0%) at least one submucous leiomyoma. Subgroup analysis of ultrasound images by an expert radiologist for the presence of adenomyosis demonstrated a positive predictive value of 54.0% and a negative predictive value of 43.4%.ConclusionsAdenomyosis was present in almost half of this AUB-L cohort undergoing hysterectomy and was equally prevalent in those with and without submucous leiomyomas as determined by sonographic evaluation. The imaging findings are in accord with prior investigators and demonstrate that 2-D ultrasound is insensitive to the presence of adenomyosis when the uterus is affected by leiomyomas. Further research is necessary to determine the impact of various adenomyosis phenotypes on the presence and severity of the symptom of HMB.

Project description:BackgroundUterine artery embolisation is well established as a treatment for symptomatic fibroids, however, there remain some uncertainties. We have carried out a focused literature review on three particularly challenging aspects - post-procedure fertility, symptomatic adenomyosis and large volume fibroids and uteri, to enable operators to utilise evidence-based guidance in patient selection, consent, and management.ReviewLiterature searches were performed of the PubMed/Medline, Google scholar, EMBASE and Cochrane databases. The outcomes of our analysis of studies which recorded fertility rates in women desiring pregnancy following UAE for symptomatic fibroids found an overall mean pregnancy rate of 39.4%, live birth rate of 69.2% and miscarriage rate of 22%. The major confounding factor was patient age with many studies including women over 40 years who already have lower fertility compared to younger cohorts. Miscarriage rates and pregnancy rates in the studies analysed were comparable to the age matched population. Treatment of pure adenomyosis and adenomyosis with co-existing uterine fibroids with UAE has been shown to produce symptomatic improvement with better outcomes in those with combined disease. Although the effectiveness is not as high as it is in pure fibroid disease, UAE provides a viable and safe alternative for patients seeking symptom relief and uterine preservation. Our analysis of studies assessing the outcomes of UAE in patients with large volume uteri and giant fibroids (> 10 cm) demonstrate no significant difference in major complication rates demonstrating that fibroid size should not be a contraindication to UAE.ConclusionOur findings suggest uterine artery embolisation can be offered to women desiring pregnancy with fertility and miscarriage rates comparable to that of the age-matched general population. It is also an effective therapeutic option for symptomatic adenomyosis as well as for the treatment of large fibroids > 10 cm in diameter. Caution is advised in those with uterine volumes greater than 1000cm3. It is however clear that the quality of evidence needs to be improved on with an emphasis on well-designed randomised controlled trials addressing all three areas and the consistent use of validated quality of life questionnaires for outcome assessment to enable effective comparison of outcomes in different studies.

Project description:The purpose of this study was to implore the association among clinical features, long-term fertility outcomes and the anatomical location of adenomyosis identified by ultrasound. We collected data of non-pregnant patients between 20 and 40 years old who had undergone surgical exploration for benign gynecological conditions at our institution between January 2010 and December 2017. A total of 158 women met the inclusion criteria and were allocated into three groups according to the ultrasound-determined adenomyosis anatomical location: anterior (Group A), posterior (Group B), both posterior and anterior (Group C). 44.3% (70/158) adenomyosis was located at the posterior side. History of miscarriage and parity were significantly higher in Group C (p = 0.036 and 0.001 respectively). Group C also had a higher concurrence rate of ovarian endometrioma (OEM) (80.4%, p = 0.002), pelvic adhesion (80.4%, P = 0.003) and the revised American Fertility Society (rAFS) Score (median64, range2-100, P < 0.001), while a significantly lower rate of concurrent peritoneal endometriosis (P = 0.01). Group B showed a relative higher rate of coexistent heavy menstrual bleeding (28.6%, p = 0.04) and oviduct obstruction (24.3%, P = 0.038). Group A had a higher proportion of coexistent leiomyoma (53.1%, P = 0.002). There were no significant differences between group A, B, and C in terms of pain symptoms, endometrial polyps, operation time, and endometriosis fertility index score and other basic characters (p > 0.05). During the follow-up, 59.2% (61/103) patients had clinical pregnancies, and 26.2% (16/61) of them experienced pregnancy loss. Total in vitro fertilization and embryo transfer pregnancy rate was 64.6% (42/65) and spontaneous pregnancy rate was 50.0% (19/38). The Kaplan-Meier curves demonstrated significant lower cumulative pregnancy rate in Group C than Group A and Group B (p = 0.01). Severe obstetric complications such as placenta previa, placenta accreta, preeclampsia, and preterm birth were only found in women with adenomyosis located in the posterior side. In conclusion, types of adenomyosis based on sonographic location had different clinical features and pregnancy outcome. Patients with adenomyosis lesion in both anterior and posterior sides had higher combination of OEM, pelvic adhesion and rAFS score.

Dataset Information

Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.

Publications

Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations.

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