KRAS mutations and endometriosis burden of disease

Natasha L Orr; Arianne Albert; Yang Doris Liu; Amy Lum; JooYoon Hong; Catalina L Ionescu; Janine Senz; Tayyebeh M Nazeran; Anna F Lee; Heather Noga; Kate Lawrenson; Catherine Allaire; Christina Williams; Mohamed A Bedaiwy; Michael S Anglesio; Paul J Yong

doi:10.1002/cjp2.317

KRAS mutations and endometriosis burden of disease

Orr NL, Albert A, Liu YD, Lum A, Hong J, Ionescu CL, Senz J, Nazeran TM, Lee AF, Noga H, Lawrenson K, Allaire C, Williams C, Bedaiwy MA, Anglesio MS, Yong PJ

Published July 2023 The journal of pathology. Clinical research

DOI 10.1002/cjp2.317 PMID 36977195 PMC PMC10240146

RRM Academy Synopsis

KRAS mutations were found more often in higher-stage endometriosis

In a group of 122 people having endometriosis surgery, those with more severe disease were far more likely to carry a KRAS gene mutation in the tissue. About 3 in 10 at Stage I had the mutation, versus roughly 6 in 10 at Stage II through IV. Pain levels after surgery were similar with or without the mutation.

Study at a glance, cohort study of 122 people: KRAS mutations were more common in higher-stage endometriosis. Source: Orr NL et al., 2023, PMID 36977195.

Key Findings

Mutation prevalence was 35.1% (13/37) with superficial endometriosis only, 57.9% (11/19) with deep infiltrating endometriosis or endometrioma only, and 60.6% (40/66) with mixed subtypes (p = 0.04).
By stage, mutation prevalence was 27.6% (8/29) in Stage I, 65.0% (13/20) in Stage II, 63.0% (17/27) in Stage III and 58.1% (25/43) in Stage IV (p = 0.02).
Grouped, Stage II to IV against Stage I gave a relative risk of 1.40 (95% CI = 1.12–1.75); deep, endometrioma and mixed subtypes against superficial only gave 1.36 (95% CI: 1.06–1.74).
People with KRAS mutation had a higher risk of needing ureterolysis, a dissection of the ureter, at surgery (relative risk 1.47).
Re-operation occurred in 17.2% (11/64) of people with a mutation and 10.3% (6/58) of those without (relative risk 1.66, 95% CI 0.66–4.21).

Interpretation

This cohort study followed 122 people having endometriosis surgery at one tertiary referral center. The authors found that KRAS codon 12 mutations were linked with anatomically severe endometriosis. A person counted as mutation-positive if any sampled lesion carried one. In the 51 people with only one sample, the relative risks were similar to the full group. The authors note the cohort was mostly Caucasian, treated at one referral center, and only codon 12 was tested. The findings support larger studies of this mutation across more diverse populations.

RRM Context

Restorative reproductive medicine looks for the underlying cause of endometriosis. This paper adds a molecular finding from tissue removed at surgery. Overall, pain scores fell after surgery for painful periods, deep pain during sex, pain with bowel movements and chronic pelvic pain. The change did not differ by KRAS status. The authors note that endometriosis pain has many causes and correlates only marginally with anatomic severity. Re-operation over 5 to 9 years was 13.9% (17/122) at this high-volume center, which the authors suggest may reflect surgeon experience.

Our editorial summary of this paper, not the article's abstract.

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.

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Topics

Endometriosis

Pathophysiology Genetics

Endometriosis › Pathophysiology › Genetics

Natasha L Orr, Arianne Albert, Yang Doris Liu, Amy Lum, JooYoon Hong, Catalina L Ionescu, Janine Senz, Tayyebeh M Nazeran, Anna F Lee, Heather Noga, Kate Lawrenson, Catherine Allaire, Christina Williams, Mohamed A Bedaiwy, Michael S Anglesio, Paul J Yong

N Orr, A Albert, Y Liu, A Lum, J Hong, C Ionescu, J Senz, T Nazeran, A Lee, H Noga, Catherine Lawrenson, Katherine Lawrenson, Kathryn Lawrenson, K Lawrenson, Cathy Allaire, Kate Allaire, C Allaire, C Williams, M Bedaiwy, Mike Anglesio, M Anglesio, P Yong

PMID 36977195 36977195 DOI 10.1002/cjp2.317 10.1002/cjp2.317 Orr et al. 2023, Orr 2023

KRAS mutations and endometriosis burden of disease

KRAS mutations were found more often in higher-stage endometriosis

Key Findings

Interpretation

RRM Context

Abstract

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Topics

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