Abstract:
BACKGROUND:Endometrial cancer is the most common gynecologic malignancy, and its incidence and associated mortality are increasing. Despite the immediate need to detect these cancers at an earlier stage, there is no effective screening methodology or protocol for endometrial cancer. The comprehensive, genomics-based analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) revealed many of the molecular defects that define this cancer. Based on these cancer genome results, and in a prospective study, we hypothesized that the use of ultra-deep, targeted gene sequencing could detect somatic mutations in uterine lavage fluid obtained from women undergoing hysteroscopy as a means of molecular screening and diagnosis. METHODS AND FINDINGS:Uterine lavage and paired blood samples were collected and analyzed from 107 consecutive patients who were undergoing hysteroscopy and curettage for diagnostic evaluation from this single-institution study. The lavage fluid was separated into cellular and acellular fractions by centrifugation. Cellular and cell-free DNA (cfDNA) were isolated from each lavage. Two targeted next-generation sequencing (NGS) gene panels, one composed of 56 genes and the other of 12 genes, were used for ultra-deep sequencing. To rule out potential NGS-based errors, orthogonal mutation validation was performed using digital PCR and Sanger sequencing. Seven patients were diagnosed with endometrial cancer based on classic histopathologic analysis. Six of these patients had stage IA cancer, and one of these cancers was only detectable as a microscopic focus within a polyp. All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions. In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples. Mutations originally only detected in lavage fluid fractions were later confirmed to be present in tumor but at allele fractions significantly less than 1%. Of the remaining 95 patients diagnosed with benign or non-cancer pathology, 44 had no significant cancer mutations detected. Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%-30.4%), cancer-associated mutations. Participants with detected driver and potential driver mutations were significantly older (mean age mutated = 57.96, 95% confidence interval [CI]: 3.30-∞, mean age no mutations = 50.35; p-value = 0.002; Benjamini-Hochberg [BH] adjusted p-value = 0.015) and more likely to be post-menopausal (p-value = 0.004; BH-adjusted p-value = 0.015) than those without these mutations. No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status. Long-term follow-up was not presently available in this prospective study for those women without histopathologic evidence of cancer. CONCLUSIONS:Using ultra-deep NGS, we identified somatic mutations in DNA extracted both from cell pellets and a never previously reported cfDNA fraction from the uterine lavage. Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy. In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis. Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer. Given that a uterine lavage can be easily and quickly performed even outside of the operating room and in a physician's office-based setting, our findings suggest the future possibility of this approach for screening women for the earliest stages of endometrial cancer. However, our findings suggest that further insight into development of cancer or its interruption are needed before translation to the clinic.
journal_name
PLoS Medjournal_title
PLoS medicineauthors
Nair N,Camacho-Vanegas O,Rykunov D,Dashkoff M,Camacho SC,Schumacher CA,Irish JC,Harkins TT,Freeman E,Garcia I,Pereira E,Kendall S,Belfer R,Kalir T,Sebra R,Reva B,Dottino P,Martignetti JAdoi
10.1371/journal.pmed.1002206subject
Has Abstractpub_date
2016-12-27 00:00:00pages
e1002206issue
12eissn
1549-1277issn
1549-1676pii
PMEDICINE-D-16-02326journal_volume
13pub_type
杂志文章相关文献
PLOS MEDICINE文献大全abstract:BACKGROUND:trans-fatty acids (TFAs) are a well-known risk factor of ischemic heart disease (IHD). In Australia, the highest TFA intake is concentrated to the most socioeconomically disadvantaged groups. Elimination of industrial TFA (iTFA) from the Australian food supply could result in reduced IHD mortality and morbid...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003407
更新日期:2020-11-02 00:00:00
abstract:BACKGROUND:The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Poli...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001907
更新日期:2015-11-24 00:00:00
abstract:BACKGROUND:Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002099
更新日期:2016-08-23 00:00:00
abstract::Leo Sher and colleagues discuss recent research on interventions to prevent secondary suicide and discuss the additional research that is needed. ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1000271
更新日期:2010-06-01 00:00:00
abstract:BACKGROUND:In South Africa, within-country migration is common. Mobility affects many of the factors in the pathway for entry to or retention in care among people living with HIV. We characterized the patterns of migration (i.e., change in residency) among peripartum women from rural South Africa and their association ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003085
更新日期:2020-03-31 00:00:00
abstract::Harald Schmidt and Anne Barnhill highlight the need to ensure equity in the proposed Sustainable Development Goals. ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001872
更新日期:2015-09-08 00:00:00
abstract:BACKGROUND:There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline an...
journal_title:PLoS medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1371/journal.pmed.0050076
更新日期:2008-04-01 00:00:00
abstract::In an Editorial accompanying PLOS Medicine's Special Issue on Diabetes Prevention, Guest Editors Nicholas Wareham and William Herman discuss some of the challenges for researchers and policy makers in developing effective and equitable solutions to the worldwide problem of type 2 diabetes. ...
journal_title:PLoS medicine
pub_type: 社论
doi:10.1371/journal.pmed.1002097
更新日期:2016-07-26 00:00:00
abstract:BACKGROUND:Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. METHODS AND FINDINGS:Following a review of published epidemiological evidence of the association between o...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析
doi:10.1371/journal.pmed.1002739
更新日期:2019-01-31 00:00:00
abstract:BACKGROUND:Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. METHODS AND FINDINGS:Using data from UK Biobank on 306,654 individual...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003498
更新日期:2021-01-14 00:00:00
abstract:BACKGROUND:Schistosomiasis--infection with helminth parasites in the genus Schistosoma, including S. mansoni--is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 milli...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0040206
更新日期:2007-06-01 00:00:00
abstract:BACKGROUND:This paper examines the efforts of consultants affiliated with Philip Morris (PM), the world's leading transnational tobacco corporation, to influence scientific research and training in Thailand via the Chulabhorn Research Institute (CRI). A leading Southeast Asian institute for environmental health science...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0050238
更新日期:2008-12-23 00:00:00
abstract::Voluntary medical male circumcision (VMMC) is capable of reducing the risk of sexual transmission of HIV from females to males by approximately 60%. In 2007, the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended making VMMC part of a comprehensive HIV prevention package in countries with a ge...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001641
更新日期:2014-05-06 00:00:00
abstract:BACKGROUND:HIV self-testing (HIVST) may play a role in addressing gaps in HIV testing coverage and as an entry point for HIV prevention services. We conducted a cluster randomized trial of 2 HIVST distribution mechanisms compared to the standard of care among female sex workers (FSWs) in Zambia. METHODS AND FINDINGS:T...
journal_title:PLoS medicine
pub_type: 杂志文章,随机对照试验
doi:10.1371/journal.pmed.1002442
更新日期:2017-11-21 00:00:00
abstract:BACKGROUND:Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among p...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0040167
更新日期:2007-05-01 00:00:00
abstract:BACKGROUND:It remains unclear when standard systematic reviews and meta-analyses that rely on published aggregate data (AD) can provide robust clinical conclusions. We aimed to compare the results from a large cohort of systematic reviews and meta-analyses based on individual participant data (IPD) with meta-analyses o...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003019
更新日期:2020-01-31 00:00:00
abstract:BACKGROUND:Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity. METHODS AND FINDINGS:One-sample Mendelian randomisation (MR) analyses were conducted on up to ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002641
更新日期:2018-08-28 00:00:00
abstract::Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers...
journal_title:PLoS medicine
pub_type: 共识发展会议,指南,杂志文章
doi:10.1371/journal.pmed.1000100
更新日期:2009-07-21 00:00:00
abstract:BACKGROUND:Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would b...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001628
更新日期:2014-04-15 00:00:00
abstract:BACKGROUND:Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depress...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析
doi:10.1371/journal.pmed.0050045
更新日期:2008-02-01 00:00:00
abstract:BACKGROUND:Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. METHODS AND FINDINGS:We conducted a population-based c...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001633
更新日期:2014-04-22 00:00:00
abstract:BACKGROUND:Temporary labor migration is an increasingly important mode of migration that generates substantial remittance flows, but raises important concerns for migrant well-being. The migration and health literature has seen a growing call for longitudinal, binational surveys that compare migrants to relevant non-mi...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003081
更新日期:2020-03-31 00:00:00
abstract:BACKGROUND:A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002781
更新日期:2019-04-16 00:00:00
abstract::This month in PLOS Medicine we launched a Special Issue on New Tools and Strategies for Tuberculosis Diagnosis, Care, and Elimination. In this issue's Editorial, the Guest Editors Claudia Denkinger, Richard Chaisson, and Mark Hatherill highlight some of the research that will publish and how these studies focusing on ...
journal_title:PLoS medicine
pub_type: 社论
doi:10.1371/journal.pmed.1002795
更新日期:2019-04-30 00:00:00
abstract:BACKGROUND:Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, an...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0050032
更新日期:2008-02-01 00:00:00
abstract:BACKGROUND:The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral t...
journal_title:PLoS medicine
pub_type: 临床试验,杂志文章
doi:10.1371/journal.pmed.1001067
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND:The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the...
journal_title:PLoS medicine
pub_type: 杂志文章,评审
doi:10.1371/journal.pmed.1001489
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the uti...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析
doi:10.1371/journal.pmed.1002992
更新日期:2019-12-13 00:00:00
abstract:BACKGROUND:Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeut...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0030493
更新日期:2006-12-01 00:00:00
abstract:BACKGROUND:Spurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco "harm reduction," leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001450
更新日期:2013-01-01 00:00:00