Poster Presentation ESA-SRB 2023 in conjunction with ENSA

Somatic KRAS mutations are associated with endometriosis lesion subtypes, recurrence and patient age (#373)

Jacqueline F Donoghue 1 , Meaghan Griffiths 1 , Sylvia Beharis 1 , Brodie Bilston 1 , Leonie Cann 1 , Georgina Prewer 1 , Martin Healey 2 , Peter AW Rogers 1
  1. Obstetrics and Gynaecology Department and Gynaecology Research Centre, University of Melbourne and The Royal Women's Hospital, Parkville, Victoria, Australia
  2. Gynaecology Endometriosis and Pelvic Pain Unit, Royal Women’s Hospital, Parkville, Victoria, Australia

INTRODUCTION: Endometriosis is a common gynaecological disease where endometrial tissue implants in locations ectopic to the uterus. Due to somatic mutations occurring in normal endometrial tissue, the question of what impact these mutations have on endometriosis lesion development remains to be answered.  Further, KRAS mutations induce PGR hypermethylation and decreased epithelial cell expression of progesterone receptors leading to reduced progesterone/progestin therapeutic responsiveness.  The aim of this study was to characterise the expression of two KRAS mutations in eutopic endometrium and endometriosis lesions over time to determine if there is an association between mutation expression, timing of diagnosis, patient age and disease status. 

METHODS: DNA was isolated from FFPE tissue sections using the QIAamp DNA FFPE kit and screened using BioRad ddPCR Mutation Detection Assays for KRASG12C and KRASG12D and normalised to wildtype KRAS.   Immunohistochemistry was used on FFPE sections to visualise progesterone receptor (PR) expression on cytokeratin positive glandular epithelium in lesions and curettes. 

RESULTS:  KRASG12D was significantly increased compared to KRASG12Cin patients with no endometriosis and first-time diagnosed in their 20’s.  KRASG12D was also significantly increased over time compared to KRASG12C in eutopic endometrium and was significantly associated with first time diagnosis in older women.  Increased KRASG12D was also significantly associated with recurrent endometrioma and first-time superficial lesions diagnosis whereas KRASG12C was significantly associated with recurrent Pouch of Douglas lesions.  PR expression in glandular epithelial cells was also significantly reduced in 77% of lesions while 23% of lesions exhibited weak or variable staining.

CONCLUSION:  This is the first study of its kind to demonstrate a link between KRAS mutations, lesion subtypes, patient age, and timing of disease diagnosis and recurrence. This study also demonstrated a reduction/loss of lesion PR expression, supporting the need for further investigations into KRAS mutations as potential therapeutic targets to improve patient outcomes.