KRAS mutations in uterine endometrium are associated with gravidity and parity.
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ABSTRACT:
SUBMITTER: Inoue S
PROVIDER: S-EPMC7214428 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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KRAS mutations in uterine endometrium are associated with gravidity and parity.
Inoue Satoshi S Yoshida Emiko E Fukui Yamato Y Ueno Toshihide T Kawazu Masahito M Takeyama Reina R Ikemura Masako M Osuga Yutaka Y Terao Yasuhisa Y Hirota Yasushi Y Mano Hiroyuki H
Cell death & disease 20200511 5
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Project description: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.
| S-EPMC6923389 | biostudies-literature
Project description:The influence of hormonal changes caused by pregnancy has been well studied in relation to colorectal cancer risk, but the association remains undefined. The purpose of this investigation was to examine in a case-control study the relationship between differences in gravidity and parity and colorectal cancer risk and if the association varied by microsatellite instability (MSI), a feature more common in women.The study population included incident colorectal cancer patients (n = 1014), aged 50-74 years, diagnosed in 1998-2002 in Washington state and controls (n = 1064) randomly selected from population lists. All study subjects completed telephone interviews to ascertain prior pregnancies, live births, and other covariates. Case tissue samples were obtained for MSI analyses. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for age, family history of colorectal cancer, body mass index (BMI), education, endoscopy screening, oral contraceptive use, hormone therapy use, smoking, and alcohol consumption.There was an approximate 30%-50% reduction in risk of colon cancer associated with gravidity, which was attenuated in the analysis with parity. Increasing gravidity and parity were associated with a suggestion of a decreasing trend in risk for rectal cancer (p for trend = 0.07). Compared with women who had equal numbers of pregnancies and live births, women who were nulligravid and nulliparous had a 40%-60% increased risk of colon cancer. There was a suggestion of a reduced risk of both colon and rectal cancer associated with one more pregnancy than live birth. There was a suggestion of an increased risk of MSI-high tumors with nulligravidity and nulliparity.These results confirm the importance of pregnancy events in the etiology of colon and rectal cancer.
| S-EPMC2851134 | biostudies-literature
Project description:ObjectivesDespite a hypothesised connection of reproductive history with hypertension and mortality, the nature of this association is poorly characterised. We evaluated the association of parity and gravidity with blood pressure, hypertension and all-cause mortality.DesignProspective cohort study.SettingHealth Effects of Arsenic Longitudinal Study cohort in rural Bangladesh.ParticipantsThere were 21 634 Bangladeshi women recruited in 2000-2002, 2006-2008 and 2010-2014 included in the present analysis.MethodsReproductive history was ascertained through an interviewer-administered questionnaire at the baseline visit. Blood pressure was measured by a trained study physician following a standard protocol at the baseline visit. Vital status was ascertained at the biennial follow-up of study participants through June 2017. Linear and logistic regression models estimated the relationship between parity and gravidity with blood pressure and hypertension, respectively. Cox proportional hazards models estimated the relationship with all-cause mortality only among women aged >45 years.ResultsDiastolic blood pressure was lowest in women with parity one (reference) and elevated in nulliparous women (adjusted % change=3.12; 95% CI 1.93 to 4.33) and women with parity >2 (adjusted % change=1.71; 95% CI 1.12 to 2.31). The associations with nulliparity were stronger for women aged >45 years. Similar association patterns were observed with hypertension. Further, in nulliparous women aged >45 years, 265 deaths (6.6%) were ascertained during the follow-up period (median follow-up time=8 years), and we observed suggestive elevated risks of all-cause mortality (adjusted HR 3.83; 95% CI 0.74 to 19.78). The relationships between reproductive history, blood pressure, hypertension and mortality were similar when modelling reproductive history as gravidity rather than parity.ConclusionsFor women in rural Bangladesh, nulliparity and nulligravidity appear to be associated with higher blood pressure and subsequent elevated risk of mortality.
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Project description:Angiolipoleiomyoma is a very rare lesion of the uterus. To the best of our knowledge, only 20 cases have been described in the literature. It is an insufficiently defined entity, which is not included in the WHO classification. This lesion may be therefore underdiagnosed and underestimated. We describe here a case of a 58-yr-old woman who underwent routine gynecological examination. Ultrasonography revealed a heterogeneous myometrial mass, while magnetic resonance imaging showed a voluminous corporeal and fundic myometrial mass protruding into the uterine cavity. A total hysterectomy was performed. The macroscopic examination revealed an intramural solitary round mass with a heterogeneous cut-surface. Microscopically, the lesion consisted of an admixture of smooth muscle, adipose tissue, and blood vessels. Desmin was positive, while HMB45 was negative in the tumor. Molecular tests were performed and revealed, for the first time to our knowledge, a case of an angiolipoleiomyoma harboring KRAS and KIT mutations.
| S-EPMC9586823 | biostudies-literature
Project description:Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.
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Project description:To characterize the genomic features of endometriosis, we performed whole-exome sequencing for ovarian endometriotic epithelium samples obtained from subjects without concurrent gynecological cancers. Additionally, we analyzed histologically normal uterine endometrial epithelium samples obtained from subjects with benign gynecologic diseases. All the epithelium samples were isolated by laser microdissection from frozen sections.
| EGAS00001003095 | EGA
Project description:IntroductionCardiovascular disease is the leading cause of death among women worldwide, and hypertension is one of the most prevalent and modifiable risk factors. Parity and gravidity, independent of pregnancy complications, have each been associated with hypertension, although results are conflicting. Therefore, we propose to estimate the association between parity and gravidity with hypertension and blood pressure in a systematic review of the literature.Methods and analysisA systematic review will be conducted to estimate the association between parity and gravidity and hypertension and blood pressure. Electronic databases (Excerpta Medica Database, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature Plus and Web of Science) will be searched from inception to January 2025. Two investigators will independently screen identified abstracts and select observational cohort studies, case-control studies and randomised controlled trials examining parity or gravidity and hypertension or blood pressure. Extracted data will include study and population characteristics, comorbidities, parity, gravidity, incidence of hypertension and changes in blood pressure, study quality and risk of bias. If there are sufficient data, they will be summarised using random effects meta-analysis to estimate the pooled risk ratio or odds ratio of hypertension. Stratified and subgroup analyses will be used to explore potential sources of heterogeneity.Prospero registration numberCRD42024560535.
| S-EPMC11800290 | biostudies-literature
Project description:Recent studies have elucidated the role of several pro-inflammatory factors as mediators of inflammatory processes in the bovine endometrium. Only few studies, however, have analyzed samples collected from different regions of the uterus of the same animal. In this study, we tested the hypothesis that on a molecular level, clinical endometritis is characterized by inflammatory responses spread over the entire endometrium. Furthermore, we assume that subclinical endometritis is described by an inflammation of local regions of the uterus. Therefore, the objective of this study was to assess the mRNA expression of uterus-associated pro-inflammatory factors at five pre-defined endometrial sites, i.e., corpus uteri, left horn base, left horn tip, right horn base, and right horn tip, in cows with clinical and subclinical endometritis and in healthy controls. We analyzed the mRNA expression of interleukin 1 alpha, interleukin 1 beta, C-X-C motif chemokine ligand 8, prostaglandin-endoperoxide synthase 2, protein tyrosine phosphatase receptor type C, carcinoembryonic antigen related cell adhesion molecule 1, and mucin 4 and 16. Based on vaginoscopy and endometrial cytology (≥ 5% polymorphonuclear neutrophils) between 28 to 34 days in milk, 18 Simmental cows were categorized in clinical endometritis group (n = 7), subclinical endometritis group (n = 4), and healthy group (n = 7). In general, the analyses revealed a great variation of mRNA expression between sites and animals. Differences were found between different uterine health statuses, but the variation between the sampling sites within the groups was not significant (P > 0.05). This indicates that inflammatory processes at the end of the postpartum period can be regarded as multi-focal or spread throughout the uterus independent from the uterine health status.
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Project description:BackgroundContamination of the uterine lumen with bacteria is ubiquitous in cattle after parturition. Some animals develop endometritis and have reduced fertility but others have no uterine disease and readily conceive. The present study tested the hypothesis that postpartum cattle that develop persistent endometritis and infertility are unable to limit the inflammatory response to uterine bacterial infection.MethodsEndometrial biopsies were collected several times during the postpartum period from animals that were subsequently infertile with persistent endometritis (n = 4) or had no clinical disease and conceived to first insemination (n = 4). Quantitative PCR was used to determine the expression of candidate genes in the endometrial biopsies, including the Toll-like receptor (TLR 1 to 10) family of innate immune receptors, inflammatory mediators and their cognate receptors. Selected proteins were examined by immunohistochemistry.ResultsThe expression of genes encoding pro-inflammatory mediators such as interleukins (IL1A, IL1B and IL6), and nitric oxide synthase 2 (NOS2) were higher during the first week post partum than subsequently. During the first week post partum, there was higher gene expression in infertile than fertile animals of TLR4, the receptor for bacterial lipopolysaccharide, and the pro-inflammatory cytokines IL1A and IL1B, and their receptor IL1R2. The expression of genes encoding other Toll-like receptors, transforming growth factor beta receptor 1 (TGFBR1) or prostaglandin E2 receptors (PTGER2 and PTGER4) did not differ significantly between the animal groups. Gene expression did not differ significantly between infertile and fertile animals after the first week postpartum. However, there were higher ratios of IL1A or IL1B mRNA to the anti-inflammatory cytokine IL10, during the first week post partum in the infertile than fertile animals, and the protein products of these genes were mainly localised to the epithelium of the endometrium.ConclusionCattle may maintain fertility by limiting the inflammatory response to postpartum bacterial infection in the endometrium during the first week after parturition.
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Project description:Transcriptomic approaches are increasingly used in reproductive medicine to identify candidate endometrial biomarkers. However, it is known that endometrial progression in the molecular biology of the menstrual cycle is a main factor that could affect the discovery of disorder-related genes. Therefore, the aim of this study was to systematically review current practices for considering the menstrual cycle effect and to demonstrate its bias in the identification of potential biomarkers. From the 35 studies meeting the criteria, 31.43% did not register the menstrual cycle phase. We analysed the menstrual cycle effect in 11 papers (including 12 studies) from Gene Expression Omnibus: three evaluating endometriosis, two evaluating recurrent implantation failure, one evaluating recurrent pregnancy loss, one evaluating uterine fibroids and five control studies, which collected endometrial samples throughout menstrual cycle. An average of 44.2% more genes were identified after removing menstrual cycle bias using linear models. This effect was observed even if studies were balanced in the proportion of samples collected at different endometrial stages or only in the mid-secretory phase. Our bias correction method increased the statistical power by retrieving more candidate genes than per-phase independent analyses. Thanks to this practice, we discovered 544 novel candidate genes for eutopic endometriosis, 158 genes for ectopic ovarian endometriosis and 27 genes for recurrent implantation failure. In conclusion, we demonstrate that menstrual cycle progression masks molecular biomarkers, provides new guidelines to unmask them and proposes a new classification that distinguishes between biomarkers of disorder or/and menstrual cycle progression.
| S-EPMC8063681 | biostudies-literature