Somatic Genomic Events in Endometriosis: Review of the Literature and Approach to Phenotyping

Abstract

In this review, we provide a survey and appraisal of research into somatic genomic events in endometriosis. Methodologies have evolved from conventional cytogenetics to next-generation sequencing, with findings ranging from chromosome imbalances to recurrent somatic cancer driver mutations. Somatic cancer driver mutations have been described in a range of endometriosis lesions, dominated by recurrent mutations in KRAS and PIK3CA as well as loss of PTEN and BAF250a (ARID1A). These somatic events appear to be largely restricted to the endometriosis glandular epithelium. Somatic mutations, particularly PTEN loss, have also been observed in eutopic (uterine) endometrium, although at lower mutant allele frequencies compared with ectopic lesions. Systematic studies of the potential clinical phenotype of these somatic genomic events have yet to be performed. Thus, we propose a framework to investigate the potential clinical phenotype associated with somatic genomic events in endometriosis. Technical requirements include pathology review of histological endometriosis, microdissection for tissue enrichment, orthogonal validation of whole genome/exome sequencing, and a germline sample for confirmation of somatic origin. Clinical requirements include annotation of surgical findings; patient demographics; cross-sectional and prospective data on pain and fertility; consideration of sampling multiple lesions in each patient, mutant allele frequency, and somatic events in the eutopic endometrium; and confirmation of any associations with mechanistic studies. Given the multifactorial nature of endometriosis-associated symptoms, it is likely that somatic events have small (or at most, moderate) effect sizes, and thus careful consideration will have to be given to future study design.

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Funding

The authors hold salary awards: PJY is supported by a Health Professional Investigator Award from the Michael Smith Foundation for Health Research (MSFHR), AT is supported by a Scholar Award from MSFHR, and MSA is supported by a Scholar Award from MSFHR and the Janet D. Cottrelle Foundation Scholars Program from the BC Cancer Foundation.

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PJY and MSA had the idea for the review article; PJY performed the literature search and analysis; and PJY, AT, and MSA drafted and critically revised the work.

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Correspondence to Paul J. Yong.

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Yong, P.J., Talhouk, A. & Anglesio, M.S. Somatic Genomic Events in Endometriosis: Review of the Literature and Approach to Phenotyping. Reprod. Sci. (2021). https://doi.org/10.1007/s43032-020-00451-9

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Keywords

  • Endometriosis
  • Somatic mutations
  • Cytogenetics
  • Next generation sequencing
  • KRAS