Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes

Praetorius, T; Леонова, А.Б.; Lac, Vivian; Senz, Janine; Tessier‐Cloutier, Basile; Nazeran, Tayyebeh M.; Köbel, Martin; Grube, Marcel; Kraemer, Bernhard; Yong, Paul J.; Kommoss, Stefan; Anglesio, Michael S.

doi:10.1016/j.fertnstert.2022.05.030

Cited by 17 publications

(15 citation statements)

References 51 publications

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“…macrodissection). However, we recognize that somatic alterations in ARID1A, PIK3CA , and other oncogenes and tumor suppressors have been reported and may coexist with our observed KRAS mutations contributing to clinical phenotypes and heterogeneity [12,15,17,31]. Likewise, we tested only for the most common hot‐spot, KRAS codon 12 variants [21].…”

Section: Discussionmentioning

confidence: 99%

“…A growing literature has also identified somatic cancer‐driver mutations in endometriosis not associated with cancer, across anatomic subtypes and restricted to endometriotic epithelium [ 9 , 10 , 11 , 12 , 13 , 14 ]. Somatic activating KRAS mutations appear to be the most common somatic mutations currently reported in endometriosis, ranging from 19.4 to 46.7% of cases based on previous literature [ 12 , 15 , 16 , 17 ]. Endometriosis can have tumor‐like qualities such as local invasiveness, proliferation, resistance to apoptosis, and spread, which leads to more anatomically severe disease [ 12 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Somatic activating KRAS mutations appear to be the most common somatic mutations currently reported in endometriosis, ranging from 19.4 to 46.7% of cases based on previous literature [ 12 , 15 , 16 , 17 ]. Endometriosis can have tumor‐like qualities such as local invasiveness, proliferation, resistance to apoptosis, and spread, which leads to more anatomically severe disease [ 12 , 16 , 17 , 18 , 19 , 20 ]. Only recently, studies have begun to explore somatic cancer‐driver mutations and endometriosis phenotypes [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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KRAS mutations and endometriosis burden of disease

Orr

Albert

Liu

et al. 2023

The Journal of Pathology CR

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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KRAS mutations and endometriosis burden of disease

Orr

Albert

Liu

et al. 2023

The Journal of Pathology CR

Self Cite

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“…Mutations in KRAS , ARID1A , PIK3CA , and others allow the studying of the clonality of various types of endometriotic lesions [ 19 ]. The redundancy in mutations within the same gene and lesions comforts the oligo-clonal character of the disease: multiple epithelial clones migrate together, especially in deep infiltrating lesions, whereas ovarian endometriomas present the highest potential for oligoclonality.…”

Section: Theories On Endometriosismentioning

confidence: 99%

“…The redundancy in mutations within the same gene and lesions comforts the oligo-clonal character of the disease: multiple epithelial clones migrate together, especially in deep infiltrating lesions, whereas ovarian endometriomas present the highest potential for oligoclonality. These data suggest that ovarian stroma provides perfect conditions for the proliferation of multiple clones, with an increased risk of malignancy [ 19 ].…”

Section: Theories On Endometriosismentioning

confidence: 99%

Endometriosis: Update of Pathophysiology, (Epi) Genetic and Environmental Involvement

2023

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Endometriosis is a chronic disease caused by ectopic endometrial tissue. Endometriotic implants induce inflammation, leading to chronic pain and impaired fertility. Characterized by their dependence on estradiol (via estrogen receptor β (ESRβ)) and their resistance to progesterone, endometriotic implants produce their own source of estradiol through active aromatase. Steroidogenic factor-1 (SF1) is a key transcription factor that promotes aromatase synthesis. The expression of SF1 and ESRβ is enhanced by the demethylation of their promoter in progenitor cells of the female reproductive system. High local concentrations of estrogen are involved in the chronic inflammatory environment favoring the implantation and development of endometriotic implants. Similar local conditions can promote, directly and indirectly, the appearance and development of genital cancer. Recently, certain components of the microbiota have been identified as potentially promoting a high level of estrogen in the blood. Many environmental factors are also suspected of increasing the estrogen concentration, especially prenatal exposure to estrogen-like endocrine disruptors such as DES and bisphenol A. Phthalates are also suspected of promoting endometriosis but throughmeans other than binding to estradiol receptors. The impact of dioxin or tobacco seems to be more controversial.

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Endometriosis caused by retrograde menstruation: now demonstrated by DNA evidence

Bulun¹

2022

Fertility and Sterility

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Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes

Cited by 17 publications

References 51 publications

KRAS mutations and endometriosis burden of disease

KRAS mutations and endometriosis burden of disease

Endometriosis: Update of Pathophysiology, (Epi) Genetic and Environmental Involvement

Endometriosis caused by retrograde menstruation: now demonstrated by DNA evidence

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