Elevated urine histone 4 levels in women with ovarian endometriosis revealed by discovery and parallel reaction monitoring proteomics

Endometriosis is a common gynecologic disorder and due to a lack of non-invasive detection methods, it can take up to 12 years before an affected woman obtains a diagnosis and receives appropriate treatment. Therefore, the identification of a specific biomarker that can be detected quickly and non-invasively is urgently needed. In this study, the urine proteome, a potentially rich source of biomarkers, is examined in patients with or without endometriosis in an attempt to identify novel protein biomarkers that can be used to diagnose endometriosis. This study is the first to combine tandem mass tags and parallel reaction monitoring approaches to aid in identifying and validating urine biomarkers for endometriosis. The findings presented herein support previous conclusions that endometriosis is a chronic inflammatory disease. Additionally, Histone 4 was identified as a potential biomarker and/or therapeutic target for endometriosis. At a cutoff of 14.2, the area under the curve for H4 was 0.848, with a sensitivity of 70% and specificity of 80%. Moreover, to our knowledge, this is the first study to observe an elevated histone level in body fluids obtained from endometriosis patients. While this study provides a good foundation, further studies are required to further validate the results presented. Significance Endometriosis is a common gynecologic disorder and due to a lack of non-invasive detection methods, it can take up to 12 years before an affected woman obtains a diagnosis and receives appropriate treatment. Therefore, the identification of a specific biomarker that can be detected quickly and non-invasively is urgently needed. We believe our results have an important impact on detection and treatment of endometriosis. Firstly, this study is the first to combine tandem mass tags and parallel reaction monitoring approaches to aid in identifying and validating urine biomarkers for endometriosis, which has established the methodology required for subsequent studies. Secondly, this is also the first study to observe an elevated histone level in body fluids obtained from endometriosis patients. Compared with other urine biomarkers reported in literature, histone 4 has a potential to serve as a biomarker of endometriosis and a therapeutic target. Thirdly, our study supports previous conclusions that endometriosis is a chronic inflammatory disease. These findings can warrant further investigation of the pathophysiology of endometriosis.