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J Pathol. 2019 Jun 12. doi: 10.1002/path.5314. [Epub ahead of print]

Oncogenic mutations in histologically normal endometrium: the new normal?

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Department of Molecular Oncology, BC Cancer Research Centre, Room 3-218, 675 West 10th Ave, Vancouver, BC V5Z 1L3, Canada.
Department of Anatomical Pathology, Vancouver General Hospital, 899 W 12th Ave, Vancouver, BC V5Z 1M9, Canada.
Department of Pathology and Laboratory Medicine, Rm. G227 - 2211 Wesbrook Mall, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Contextual Genomics, 2389 Health Sciences Mall #204, Vancouver, BC V6T 1Z3, Canada.
Women's Health Research Institute, 4500 Oak St, Vancouver, BC V6H 2N9, Canada.
Department of Women's Health, Tuebingen University Hospital, Calwerstrasse 7, 72076 Tuebingen, Germany.
Department of Pathology and Laboratory Medicine, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada.
Department of Obstetrics and Gynaecology, University of British Columbia, Suite 930, 1125 Howe Street, Vancouver, BC V6Z 2K8, Canada.
BC Women's Centre for Pelvic Pain & Endometriosis, BC Women's Hospital and Health Centre, Women' Health Centre, F2 - 4500 Oak St., Vancouver, BC V6H 3N1, Canada.


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. This article is protected by copyright. All rights reserved.


aging; digital PCR; endometrium; normal tissue; somatic mutations


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