KRAS mutations and endometriosis burden of disease

Abstract

The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.

Association between KRAS and PIK3CA Mutations and Progesterone Resistance in Endometriotic Epithelial Cell Line

“…It is reported that KRAS mutation is associated with greater anatomic disease burden and surgical complexity. Their results showed KRAS mutation is not associated with pain, but efficacy of progestin on pain is not assessed [70]. To the best of our knowledge, the mechanisms underlying KRAS mutation-associated progesterone resistance in PGE2 synthesis or pain in endometriotic epithelial cells are unknown.…”

Genetic Links between Endometriosis and Endometriosis-Associated Ovarian Cancer—A Narrative Review (Endometriosis-Associated Cancer)

“…PIK3CA and KRAS mutations have been demonstrated to be clonally expanded in endometriosis [ 53 ]. KRAS codon 12-activating mutations have been shown to be associated with the proliferation, local invasion, and metastatic spread of endometriosis and large disease burden resulting in advanced-stage disease with increased surgical complexity [ 54 ]. The RAS/RAF/MEK (MAPK, mitogen-activated protein kinase) signaling pathway may therefore be a relevant target to reduce the invasiveness, spread, or burden of endometriosis.…”

Standardized protocol for quantification of nerve bundle density as a biomarker for endometriosis

“…Linked clinical data from the patient were available from a prospective registry as described previously (H16-00264; Clinicaltrials.gov NCT02911090), ( 13 ) which included standardized surgeon-reported data at the time of surgery. This cohort has been described previously ( 14 ). For each tissue block from each patient included in the study, a tissue slide was cut for H&E and histological endometriosis was confirmed.…”