Project description:Uterine leiomyosarcoma (LMS) is the worst malignancy among the gynecologic cancers. Uterine leiomyoma (LM) is a benign tumor of myometrial origin and is the most common among women of childbearing age. Because the symptoms of women with LMS such as abnormal vaginal bleeding, palpable pelvic mass, and pelvic pain resemble with those of women with LM, it is difficult to preoperatively distinguish LMS and LM only by ultrasound and pelvic MRI. While histopathological diagnosis after hysterectomy is the current major means to distinguish them postoperatively, unusual histologic variants of LM tend to be misdiagnosed as LMS. Furthermore, the low incidence of LMS has been preventing elucidating its causal mechanisms and developing effective diagnoses and treatments. Therefore, development of molecular diagnosis as an alternative or confirmatory means helps diagnosing LMS more accurately. We adopted omics-based technologies to identify genome-wide features to distinguish LMS from LM, and revealed that copy-number, gene expression, and DNA methylation profiles successfully distinguished between these tumors. LMS was found to possess features typically observed in malignant solid tumors, such as extensive chromosomal abnormalities, overexpression of cell cycle –related genes, and hypomethylation spreading through large genomic regions as well as frequent hypermethylation at polycomb group target gene and cadherin gene loci. We also identified candidate expression and DNA methylation markers, which will help establishing diagnostic tests using conventional quantitative assays. While the identified omics-signatures and certain markers specific to LMS need to be further validated in larger numbers of LM and LMS samples, our results demonstrate the practical feasibility of establishing a postoperative diagnostic test to distinguish LMS from LM with high accuracy, and also suggest the future possibility of developing preoperative and non-invasive diagnostic methods.

Project description:Endometriosis, an estrogen-dependent, progesterone-resistant, inflammatory disorder affects 10% of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Since the uterine lining (endometrium) in women with endometriosis has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n=148 archived endometrial samples from women with endometriosis or without endometriosis (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with endometriosis or no endometriosis involved two binary decisions each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no endometriosis from endometriosis, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified endometriosis with 90-100% accuracy, were cycle phase-specific or independent, and utilized relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism and growth factor signaling in endometrium of women with endometriosis. Similar findings were observed with other disorders versus controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic endometriosis with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate-genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of endometriosis and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue. We analyzed endometrial samples from n=148 women without or with endometriosis and/or other uterine/pelvic pathologies, using whole genome microarrays.

Project description:Endometriosis, an estrogen-dependent, progesterone-resistant, inflammatory disorder affects 10% of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Since the uterine lining (endometrium) in women with endometriosis has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n=148 archived endometrial samples from women with endometriosis or without endometriosis (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with endometriosis or no endometriosis involved two binary decisions each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no endometriosis from endometriosis, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified endometriosis with 90-100% accuracy, were cycle phase-specific or independent, and utilized relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism and growth factor signaling in endometrium of women with endometriosis. Similar findings were observed with other disorders versus controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic endometriosis with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate-genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of endometriosis and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue.

Dataset Information

Genomic, epigenomic, and transcriptomic profiling towards identifying omics-features and specific biomarkers that distinguish uterine leiomyosarcoma and leiomyoma at molecular levels (methylation)

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