Molecular alterations in eutopic endometrium of women with endometriosis and implications in its diagnostic

Júlia Vallvé-Juanico
In: TDX (Tesis Doctorals en Xarxa) · 2018 · W3034991819
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This study explored molecular alterations in eutopic endometrium for endometriosis diagnosis, finding a classifier with initial high sensitivity and specificity that failed clinical validation, and identified LGR5 macrophages potentially linked to disease aggressiveness and reproductive outcomes.

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This thesis investigated molecular alterations in eutopic endometrium to develop a less invasive diagnostic approach for endometriosis, using RNA-high sequencing and a biomarker discovery/classification strategy with formalin-fixed paraffin-embedded samples from different endometriosis types and controls. The discovery model could not distinguish between endometriosis types, although it showed high sensitivity and specificity for diagnosing endometriosis overall, but when validated with increased sample numbers only 60% of endometriosis patients were correctly diagnosed, leading to the explicit conclusion that the validated model cannot be translated to clinical practice. Separately, LGR5 was studied in eutopic endometrium and cells expressing LGR5 showed a macrophage-like phenotype; however, no significant differences were found between healthy and diseased women, so LGR5 was not supported as a diagnostic biomarker. Relevance to endometriosis: the entire thesis focuses on endometriosis biomarker discovery and specifically evaluates LGR5 in eutopic endometrium and macrophage-like phenotypes, including findings related to deep infiltrating endometriosis and infertility.

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Abstract

La endometriosi és una malaltia benigna que afecta a un 10-15% de les dones en edat reproductiva I els seus símptomes principals són dolor i infertilitat. El seu diagnòstic pot ser retardat fins a 6,7 anys de mitjana, i el diagnòstic principal és per laparoscòpia. L'objectiu principal d'aquesta tesi era trobar una nova eina diagnòstica menys invasiva que la cirurgia. Per aconseguir-ho, es van dur a terme dos objectius; trobar nous biomarcadors per la malaltia a l'endometri eutòpic i estudiar el marcador Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) com a possible biomarcador per a l'endometriosi. Per al primer objectiu, es va fer un estudi de Discovery de biomarcadors a partir de RNA-High-Sequencing i es va desenvolupar un classificador utilitzant el leave one out cross validation model de Partial Least Squares (PLS) a partir de mostres fixades i incloses en parafina de tots els tipus d'endometriosi i controls. No vam ser capaços de discernir entre tipus d'endometriosi però es va trobar una elevada sensitivitat i especificitat per a diagnosticar la malaltia en global. No obstant, al validar el model amb un increment del nombre de mostres, només el 60% de les pacients amb endometriosi van poder ser diagnosticades com a endometriosi. En conclusió, el model validat no es pot traslladar a la pràctica clínica. En el segon objectiu, vam estudiar LGR5 a l'endometri eutòpic amb RNA-High-Sequencing i vam descobrir que aquestes cèl·lules tenen un fenotip de macròfags. No vam observar diferències significants entre dones sanes i malaltes, per tant, LGR5 no és un bon biomarcador per a la malaltia. No obstant, vam trobar que l'endometriosi profunda, el tipus més agressiu de la malaltia, sobre-expressava gens únics relacionats amb infertilitat. Així doncs, concloem que LGR5 podria estar relacionat amb l'agressivitat de la malaltia així com en els resultats reproductius. Sabent que les cèl·lules LGR5 positives tenien un fenotip de macròfag, vam estudiar els macròfags a l'endometri eutòpic de dones amb la malaltia i vam trobar que presenten un fenotip més pro-inflamatori que les de l'endometri sa, el que podria influir en la fisiopatologia de la malaltia i en els resultats reproductius en aquestes dones.
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Abstract

La endometriosi és una malaltia benigna que afecta a un 10-15% de les dones en edat reproductiva I els seus símptomes principals són dolor i infertilitat. El seu diagnòstic pot ser retardat fins a 6,7 anys de mitjana, i el diagnòstic principal és per laparoscòpia. L’objectiu principal d’aquesta tesi era trobar una nova eina diagnòstica menys invasiva que la cirurgia. Per aconseguir-ho, es van dur a terme dos objectius; trobar nous biomarcadors per la malaltia a l’endometri eutòpic i estudiar el marcador Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) com a possible biomarcador per a l’endometriosi. Per al primer objectiu, es va fer un estudi de Discovery de biomarcadors a partir de RNA-High-Sequencing i es va desenvolupar un classificador utilitzant el leave one out cross validation model de Partial Least Squares (PLS) a partir de mostres fixades i incloses en parafina de tots els tipus d’endometriosi i controls. No vam ser capaços de discernir entre tipus d’endometriosi però es va trobar una elevada sensitivitat i especificitat per a diagnosticar la malaltia en global. No obstant, al validar el model amb un increment del nombre de mostres, només el 60% de les pacients amb endometriosi van poder ser diagnosticades com a endometriosi. En conclusió, el model validat no es pot traslladar a la pràctica clínica. En el segon objectiu, vam estudiar LGR5 a l’endometri eutòpic amb RNA-High-Sequencing i vam descobrir que aquestes cèl·lules tenen un fenotip de macròfags. No vam observar diferències significants entre dones sanes i malaltes, per tant, LGR5 no és un bon biomarcador per a la malaltia. No obstant, vam trobar que l’endometriosi profunda, el tipus més agressiu de la malaltia, sobre-expressava gens únics relacionats amb infertilitat. Així doncs, concloem que LGR5 podria estar relacionat amb l’agressivitat de la malaltia així com en els resultats reproductius. Sabent que les cèl·lules LGR5 positives tenien un fenotip de macròfag, vam estudiar els macròfags a l’endometri eutòpic de dones amb la malaltia i vam trobar que presenten un fenotip més pro-inflamatori que les de l’endometri sa, el que podria influir en la fisiopatologia de la malaltia i en els resultats reproductius en aquestes dones. Endometriosis is a benign disease that affects 10-15% of reproductive age women and the main symptoms are pain and infertility. Its diagnostic can be delayed for 6.7 years in average, and the final diagnostic is by laparoscopy. The main objective of this thesis was to find a new and less invasive diagnostic approach for the disease than surgery. For this purpose, two objectives were performed; to find new biomarkers for the disease in eutopic endometrium and to study Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) as a putative biomarker for endometriosis. For the first objective, a discover study of biomarkers was done by RNA-High-Sequencing and a classifier was developed by using Partial Least Squares (PLS) leave one out cross validation model using formalin-fixed paraffin embedded samples from all types of endometriosis and controls. We were not able to distinguish between types of disease but there was a high sensitivity and specificity to diagnose the disease in global. However, when we validated the model by increasing the sample size, only the 60% of patients could be diagnosed as endometriosis. In conclusion, the validated model cannot be translated to the clinics. In the second objective, we studied LGR5 in eutopic endometrium by RNA-High-Sequencing and we discovered that these cells have a macrophage-like phenotype. We did not observe significant differences between healthy and diseased women and thus, LGR5 is not a good biomarker for the disease. However, we found that deep infiltrating endometriosis (DIE), the most aggressive type of the disease, overexpressed unique genes related to infertility. Hence, we concluded that LGR5 could be related to the aggressiveness of the disease as well as in reproductive outcomes. Knowing that LGR5 positive cells phenotype was macrophage-like, we studied macrophages in eutopic endometrium of diseased women and we found that they present a more pro-inflammatory phenotype than healthy endometrium which could also influence to the pathophysiology of the disease and to the reproductive outcomes in this women.

Keywords

Endometriosis; Diagnòstic; Diagnóstico; Diagnosis; Biòpsia endometrial; Biopsia endometrial; Endometrial biopsy Subjects 618 - Gynaecology. Obstetrics

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endometriosis

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