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The current staging system for endometriosis: does it help?

Abstract

A multicenter collaboration for data collection and statistical analysis may be necessary to establish and validate a classification system based on empirically derived scores for specific pathologic observations. The endometriosis pain instrument may be a tool for some of those variables with regard to pelvic pain. A similar strategy for uniform collection of data for analysis of important factors also is necessary for infertility. The challenge of creating a satisfactory classification of endometriosis remains. The ability of the current classification schemes to predict pregnancy outcome or aid in the management of pelvic pain is recognized to be inadequate. Further revisions of the current classification scheme are anticipated as the understanding of how endometriosis contributes to infertility and pelvic pain evolves. In any revision of the classification system, use of empirically derived weights and breakpoints to define disease stages based on outcome data in larger clinical trials should be attempted. It is also possible that additional factors, such as CA-125 level or lesion characteristics, may be shown to play an important role in prognosis. If so, these must be accounted for in the classification scheme. Careful and consistent use of the recommendations of the American Society for Reproductive Medicine classification of endometriosis subcommittee should allow for collection of data for use in further revisions. It is possible that a classification scheme that is designed to predict outcome with respect to pregnancy may be totally inadequate in assessing patients who have endometriosis and pelvic pain. Factors found to be important in the assessment of pelvic pain may be different from those involved with the pathophysiology of endometriosis and infertility. The AFS form suggested for use in the management of endometriosis in the presence of pelvic pain allows for recording of variables such as depth of invasion, histology, and documenting adjunct investigations and preoperative physical findings. Such prospective data collection and review in large centers may provide a large clinical base from which to derive empirical point scores and breakpoints in a classification scheme.

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BibTeXRIS

Carla P Roberts, John A Rock. 2003. The current staging system for endometriosis: does it help?. https://doi.org/10.1016/s0889-8545(02)00056-6

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Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife&#xae; combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

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