Iatrogenic endometriosis harbors somatic cancer-driver mutations

Lac, Vivian; Praetorius, T; Verhoef, Lisanne; Aguirre-Hernández, Rosalía; Nazeran, TM; Tessier‐Cloutier, Basile; Orr, Natasha L; Noga, Heather; Khattra, Jaswinder; Köebel, Martin; Horlings, HM; Kommoss, Friedrich; Brucker, SY; Pasternak, J; Yong, P.; Dg, Huntsman; Kommoss, Stefan; Anglesio,; Krämer, B.

doi:10.1055/s-0038-1671405

Cited by 10 publications

(29 citation statements)

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“…The latter observation is likely due to distinct KRAS mutation rates in endometrial cancer subtypes that, themselves, have distinct age distributions . Since patients in our study underwent hysterectomies, D&Cs, or endometrial biopsies for benign uterine‐related pathologies or related concerns, it is plausible that KRAS mutations may play a role in these pathologies – potentially similar to a recent report of KRAS mutations in arteriovenous malformations of the brain or as we have previously observed in endometriosis . It is also possible that early activation of KRAS induces senescence in endometrial cells, thereby inhibiting progression towards malignant transformation.…”

Section: Discussionsupporting

confidence: 72%

“…All specimens were sequenced using FIND IT™ version 3.4 (Contextual Genomics Inc., Vancouver, BC, Canada), a proprietary hypersensitive cancer hotspot assay that covers over 120 hotspots and 17 exons spanning 33 genes (see supplementary material, Table S3) . Using the same protocol detailed in our previous study , DNA samples were barcoded and libraries were constructed using 75 ng of total DNA input. Libraries were run on the MiSeq system (Illumina Inc., San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Loss of PTEN immunoreactivity was used as a surrogate for PTEN loss‐of‐function mutations. Following the protocol outlined in our previous study , specimens were stained using a Ventana Discovery Ultra (Ventana Medical Systems, Tucson, AZ, USA) immunostainer using a 1:25 dilution of rabbit monoclonal antibody, 138G6 (Cell Signaling Technology, Danvers, MA, USA). Similarly, loss of nuclear ARID1A immunoreactivity was used as a surrogate for ARID1A loss‐of‐function mutations .…”

Section: Methodsmentioning

confidence: 99%

“…Following the protocol outlined in our previous study , specimens were stained using a Ventana Discovery Ultra (Ventana Medical Systems, Tucson, AZ, USA) immunostainer using a 1:25 dilution of rabbit monoclonal antibody, 138G6 (Cell Signaling Technology, Danvers, MA, USA). Similarly, loss of nuclear ARID1A immunoreactivity was used as a surrogate for ARID1A loss‐of‐function mutations . Specimens were stained on the Dako Omnis (Agilent Technologies, Santa Clara, CA, USA) automated immunostainer using a 1:2000 dilution of ARID1A rabbit monoclonal antibody EPR13501 (ab182560; Abcam, Cambridge, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…It is plausible that somatic driver mutations may preexist in the eutopic endometrium even in the absence of malignancy or endometrial hyperplasia, especially considering the dynamic nature of the endometrium as it undergoes many cycles of regeneration and tissue breakdown throughout a woman's reproductive years . Our own observations of recurrent somatic driver mutations in the glandular, endometrial‐like epithelial cells of deep infiltrating endometriosis and iatrogenic endometriosis , forms which rarely progress to malignancy, also pose the question of when driver mutations may have accumulated. Moreover, a series of previous studies have described ‘latent precancers’ (alterations in otherwise normal tissue with unknown contribution to long‐term cancer risk) in the form of PTEN‐null and PAX2‐null glands within histologically normal endometrium .…”

Section: Introductionmentioning

confidence: 95%

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Oncogenic mutations in histologically normal endometrium: the new normal?

Lac¹,

Nazeran

Tessier‐Cloutier

et al. 2019

The Journal of Pathology

118

105

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The advent of next generation sequencing has vastly improved the resolution of mutation detection, thereby both increasing the resolution of the analysis of cancer tissues and shining light on the existence of somatic driver mutations in normal tissues, even in the absence of cancer. Studies have described somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in other tissues, such as the eutopic endometrium in particular, due to the highly regenerative nature of the endometrium and the recent observation of recurrent somatic driver mutations in deep infiltrating and iatrogenic endometriosis (tissues believed to be derived from the eutopic endometrium) by our group and others. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty‐five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin‐fixed, paraffin‐embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver‐like events in over 50% of normal endometrial samples analyzed, including hotspot mutations in KRAS, PIK3CA, and FGFR2 as well as PTEN‐loss by IHC. Analysis of anterior and posterior samplings collected from women who underwent hysterectomies was consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 [95% CI: 1.00–1.10], p = 0.035). These findings have implications on our understanding of aging and so‐called ‘normal tissues’, thereby necessitating caution in the utilization of mutation‐based early detection tools for endometrial or other cancers. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 3 more Smart Citations

Oncogenic mutations in histologically normal endometrium: the new normal?

Lac¹,

Nazeran

Tessier‐Cloutier

et al. 2019

The Journal of Pathology

118

105

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Oncogenic BRAF and KRAS mutations in endosalpingiosis

Chui

Shih

2019

The Journal of Pathology

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Endosalpingiosis, a microscopic lesion composed of ectopic Fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian serous borderline tumour or low-grade serous carcinoma, but its pathogenic significance remains unclear. Using laser-capture microdissection and droplet digital PCR, we investigated whether endosalpingiosis harbours the driver mutations in BRAF and KRAS that characterise ovarian low-grade serous neoplasms. Somatic mutations were detected in 14 (33%) of 43 endosalpingiotic lesions analysed. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumour, mutations were identified in endosalpingiotic lesions from 11 (52%) women, with most cases (10/11, 91%) demonstrating identical mutations in both tumour and endosalpingiosis. In contrast, of 13 cases of endosalpingiosis not associated with an ovarian tumour, only one harboured a KRAS mutation. The proliferative activity as assessed by Ki-67 immunohistochemistry was lower in endosalpingiosis than in low-grade serous tumours, and endosalpingiosis with either a BRAF or KRAS mutation had a significantly lower Ki-67 index than those without. Ectopic expression of KRAS G12V in Fallopian tube epithelial cells led to ERK phosphorylation, p21 induction, growth arrest and cellular senescence. In conclusion, we demonstrate that endosalpingiosis represents an interesting example of cancer driver mutations in deceptively normal-appearing cells, which may be prone to neoplastic transformation upon bypass of endogenous oncosuppressive mechanisms.

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Extra‐pelvic endometriosis: A review

Hirata

Koga

Osuga

2020

Reprod Medicine & Biology

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Endometriosis is defined as a condition in which endometrium-like tissues are present in organs other than the uterus. It has been reported that 5%-10% of women of reproductive age have endometriosis. 1-3 It is an estrogen-dependent inflammatory disease, which causes pelvic pain and infertility. Endometriosis usually involves the ovaries, ligaments, and peritoneal surfaces, and less commonly occurs in the intestine, bladder, abdominal wall, thoracic cavity, and other organs. The etiology of endometriosis has remained mostly unknown, despite much literature and some predominant theories. The most widely accepted theory for the pathogenesis of endometriosis is retrograde menstruation through the fallopian tubes into the pelvic cavity. 4 Once endometrial cells adhere to peritoneal surfaces, they can grow and invade onto peritoneal structures, under the influence

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Iatrogenic endometriosis harbors somatic cancer-driver mutations

Cited by 10 publications

References 0 publications

Oncogenic mutations in histologically normal endometrium: the new normal?

Oncogenic mutations in histologically normal endometrium: the new normal?

Oncogenic BRAF and KRAS mutations in endosalpingiosis

Extra‐pelvic endometriosis: A review

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