Molecular Classification of Endometriosis and Disease Stage Using High-Dimensional Genomic Data

Abstract

Endometriosis (E), 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. Because the uterine lining (endometrium) in women with E 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 E or without E (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 E or no E involved 2 binary decisions, each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no E from E, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified E with 90%-100% accuracy, were cycle phase-specific or independent, and used 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 E. Similar findings were observed with other disorders vs controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic E 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 E and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue.

Stanniocalcin-1 expression in normal human endometrium and dysregulation in endometriosis

“…Menstrual cycle phase was assigned by the day of LH surge and endometrial histology as above. In addition, all samples used for mRNA expression analysis were assigned cycle phase using bioinformatics methods (21). Only samples, where all evaluation criteria were in agreement, were used in the study.…”

Local and systemic factors and implantation: what is the evidence?

“…With the advent of transcriptome microarrays, the signatures of gene expression throughout the menstrual cycle have been well-documented in normal women (120, 121) and in those with gynecological disorders (53, 54, 122, 123). New panels of selected biomarkers are now becoming available with the potential to screen for a receptive and non-receptive endometrium.…”

Research Priorities for Endometriosis: Recommendations From a Global Consortium of Investigators in Endometriosis

“…[127][128][129] Only a few studies have looked at the influence of disease stage 129 or considered other uterine and pelvic abnormalities as confounders. 130 To date, women with more advanced compared to early-stage disease have more difficulty getting pregnant, 131 significantly lower implantation rates (13.7% vs 28.3%, respectively; P < .05) and pregnancy rates (22.6% vs 40.0%, respectively; P < .01), but not fertilization or miscarriage rates, 132 and significantly lower IVF pregnancy rates (13.84% vs 21.12%, respectively; P < .001), 126 underscoring a potential endometrial origin of these differences. Also, patients with advanced disease demonstrate diminished ovarian response and higher cancellation rates in IVF cycles but after surgery show improved implantation, pregnancy, miscarriage, and delivery rates, similar to those of women with tubal factor infertility, 122 suggesting that removal of disease improves endometrial receptivity to embryonic implantation.…”