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.
Similar content being viewed by others
Data Availability
N/A
References
Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017;8:15539.
Zondervan KT, Rahmioglu N, Morris AP, Nyholt DR, Montgomery GW, Becker CM, et al. Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient. Seminars Reprod Med. 2016;34(4):242–54.
Kobayashi H, Imanaka S, Nakamura H, Tsuji A. Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med Rep. 2014;9(5):1483–505.
Anglesio MS, Bashashati A, Wang YK, Senz J, Ha G, Yang W, et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J Pathol. 2015;236(2):201–9.
Dangel A, Medchill MT, Davis G, Meloni AM, Sandberg AA. Cytogenetic studies in endometriosis tissue. Cancer Genet Cytogenet. 1994;78(2):172–4.
Shin JC, Ross HL, Elias S, Nguyen DD, Mitchell-Leef D, Simpson JL, et al. Detection of chromosomal aneuploidy in endometriosis by multi-color fluorescence in situ hybridization (FISH). Hum Genet. 1997;100(3–4):401–6.
Kosugi Y, Elias S, Malinak LR, Nagata J, Isaka K, Takayama M, et al. Increased heterogeneity of chromosome 17 aneuploidy in endometriosis. Am J Obstet Gynecol. 1999;180(4):792–7.
Bischoff FZ, Heard M, Simpson JL. Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p53 loss in late-stage endometriosis. J Reprod Immunol. 2002;55(1–2):49–64.
Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, Stojkoski A, et al. Detection of DNA copy number changes in human endometriosis by comparative genomic hybridization. Hum Genet. 1999;105(5):444–51.
Veiga-Castelli LC, Silva JC, Meola J, Ferriani RA, Yoshimoto M, Santos SA, et al. Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas. Braz J Med Biol Res. 2010;43(8):799–805.
Guo SW, Wu Y, Strawn E, Basir Z, Wang Y, Halverson G, et al. Genomic alterations in the endometrium may be a proximate cause for endometriosis. Eur J Obstet Gynecol Reprod Biol. 2004;116(1):89–99.
Zhao L, Gu C, Huang K, Han W, Fu M, Meng Y. Endometriosis research using capture microdissection techniques: progress and future applications. Biomed Rep. 2016;5(5):531–40.
Matsuzaki S, Canis M, Mage G. Use of laser capture microdissection in studying hormone-dependent diseases: endometriosis. Methods Mol Biol. 2009;590:295–306.
Zafrakas M, Tarlatzis BC, Streichert T, Pournaropoulos F, Wolfle U, Smeets SJ, et al. Genome-wide microarray gene expression, array-CGH analysis, and telomerase activity in advanced ovarian endometriosis: a high degree of differentiation rather than malignant potential. Int J Mol Med. 2008;21(3):335–44.
Wu Y, Strawn E, Basir Z, Wang Y, Halverson G, Jailwala P, et al. Genomic alterations in ectopic and eutopic endometria of women with endometriosis. Gynecol Obstetric Invest. 2006;62(3):148–59.
Silveira CG, Abrao MS, Dias JA Jr, Coudry RA, Soares FA, Drigo SA, et al. Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. Hum Reprod. 2012;27(11):3187–97.
Saare M, Soritsa D, Vaidla K, Palta P, Remm M, Laan M, et al. No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis. Hum Reprod. 2012;27(6):1857–64.
Medeiros F, Wang X, Araujo AR, Erickson-Johnson MR, Lima JF, Meuter A, et al. HMGA gene rearrangement is a recurrent somatic alteration in polypoid endometriosis. Hum Pathol. 2012;43(8):1243–8.
Jeong K, Lee S, Kim I, Kang JS. Chromosomal aberrations detected by chromogenic in situ hybridization in abdominal wall endometriosis after cesarean section. Int J Gynecol Pathol. 2012;31(4):328–34.
Korner M, Burckhardt E, Mazzucchelli L. Higher frequency of chromosomal aberrations in ovarian endometriosis compared to extragonadal endometriosis: a possible link to endometrioid adenocarcinoma. Mod Pathol. 2006;19(12):1615–23.
Tamura M, Fukaya T, Murakami T, Uehara S, Yajima A. Cytogenetic analysis of cells from endometriotic cysts of the human ovary. Cancer Genet Cytogenet. 1998;102(2):155–7.
Medeiros F, Araujo AR, Erickson-Johnson MR, Kashyap PC, Dal Cin P, Nucci M, et al. HMGA1 and HMGA2 rearrangements in mass-forming endometriosis. Genes Chromosomes Cancer. 2010;49(7):630–4.
Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer. 2007;7(12):899–910.
Vercellini P, Trecca D, Oldani S, Fracchiolla NS, Neri A, Crosignani PG. Analysis of p53 and ras gene mutations in endometriosis. Gynecol Obstet Investig. 1994;38(1):70–1.
Jiang X, Hitchcock A, Bryan EJ, Watson RH, Englefield P, Thomas EJ, et al. Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. Cancer Res. 1996;56(15):3534–9.
Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 2000;60(24):7052–6.
Vestergaard AL, Thorup K, Knudsen UB, Munk T, Rosbach H, Poulsen JB, et al. Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis. Mol Hum Reprod. 2011;17(12):758–61.
Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE, Spandidos DA. Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. Fertil Steril. 2001;75(1):160–5.
Prowse AH, Fakis G, Manek S, Churchman M, Edwards S, Rowan A, et al. Allelic loss studies do not provide evidence for the “endometriosis-as-tumor” theory. Fertil Steril. 2005;83(Suppl 1):1134–43.
Nakayama K, Toki T, Nikaido T, Zhai YL, Konishi I. Genetic alterations in microsatellite marker sites among tumor suppressor genes in endometriosis. Gynecol Obstet Investig. 2001;51(4):240–2.
Wang DB, Ren FY, Ren F. Detecting and investigating the significance of high-frequency LOH chromosome regions for endometriosis-related candidate genes. Gynecol Endocrinol. 2012;28(7):553–8.
Gylfason JT, Dang D, Petursdottir V, Benediktsdottir KR, Geirsson RT, Poindexter A, et al. Quantitative DNA perturbations of p53 in endometriosis: analysis of American and Icelandic cases. Fertil Steril. 2005;84(5):1388–94.
Rai P, Deenadayal M, Shivaji S. Absence of activating somatic mutations of PI3KCA and AKT1 genes in south Indian women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2010;152(1):78–82.
Govatati S, Kodati VL, Deenadayal M, Chakravarty B, Shivaji S, Bhanoori M. Mutations in the PTEN tumor gene and risk of endometriosis: a case-control study. Hum Reprod. 2014;29(2):324–36.
Lv X, Wang D, Ma Y, Long Z. Analysis of the oncogene BRAF mutation and the correlation of the expression of wild-type BRAF and CREB1 in endometriosis. Int J Mol Med. 2018;41(3):1349–56.
Kim MS, Yoo NJ, Hwang H, Kim MR, Lee SH. Absence of KRAS hotspot mutations in endometriosis of Korean patients. Histopathology. 2018;73(2):357–60.
Zou Y, Zhou JY, Guo JB, Wang LQ, Luo Y, Zhang ZY, et al. The presence of KRAS, PPP2R1A and ARID1A mutations in 101 Chinese samples with ovarian endometriosis. Mutat Res. 2018;809:1–5.
Zou Y, Zhou JY, Wang F, Zhang ZY, Liu FY, Luo Y, et al. Analysis of CARD10 and CARD11 somatic mutations in patients with ovarian endometriosis. Oncol Lett. 2018;16(1):491–6.
Guo J, Cao B, Xu X, Wu F, Zhu B. Novel CTCF mutations in Chinese patients with ovarian endometriosis. Mol Med Rep. 2018;18(1):1031–6.
Cao B, Zeng Y, Wu F, Liu J, Shuang Z, Xu X, et al. Novel TRERF1 mutations in Chinese patients with ovarian endometriosis. Mol Med Rep. 2018;17(4):5435–9.
Nakayama K, Toki T, Zhai YL, Lu X, Horiuchi A, Nikaido T, et al. Demonstration of focal p53 expression without genetic alterations in endometriotic lesions. Int J Gynecol Path. 2001;20(3):227–31.
Khalique S, Naidoo K, Attygalle AD, Kriplani D, Daley F, Lowe A, et al. Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers. J Pathol Clin Res. 2018;4(3):154–66.
Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363(16):1532–43.
Samartzis EP, Samartzis N, Noske A, Fedier A, Caduff R, Dedes KJ, et al. Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation? Mod Pathol. 2012;25(6):885–92.
Xiao W, Awadallah A, Xin W. Loss of ARID1A/BAF250a expression in ovarian endometriosis and clear cell carcinoma. Int J Clin Exp Pathol. 2012;5(7):642–50.
Borrelli GM, Abrao MS, Taube ET, Darb-Esfahani S, Kohler C, Chiantera V, et al. (Partial) Loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes. Mol Hum Reprod. 2016;22(5):329–37.
Chene G, Ouellet V, Rahimi K, Barres V, Provencher D, Mes-Masson AM. The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis. Int J Gynaecol Obstet. 2015;130(1):27–30.
Anglesio MS, Yong PJ. Endometriosis-associated ovarian cancers. Clinical Obstet Gynecol. 2017;60(4):711–27.
Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(23):9530–5.
Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noe M, Horlings HM, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017;376(19):1835–48.
Noe M, Ayhan A, Wang TL, Shih IM. Independent development of endometrial epithelium and stroma within the same endometriosis. J Pathol. 2018;245(3):265–9.
Lac V, Huntsman DG. Distinct developmental trajectories of endometriotic epithelium and stroma: implications for the origins of endometriosis. J Pathol. 2018;246(3):257–60.
Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018;24(7):1777–89.
Li L, Chen Q, Fan QB, Wang S, Shi HH, Zhu L, et al. Pathogenetic gene changes of eutopic endometrium in patients with ovarian endometriosis. Chin Med J. 2019;132(9):1107–9.
Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.
Burney RO, Hamilton AE, Aghajanova L, Vo KC, Nezhat CN, Lessey BA, et al. MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis. Mol Hum Reprod. 2009;15(10):625–31.
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9.
Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL. Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer. Cancer Res. 2010;70(15):6225–32.
Lin MC, Burkholder KA, Viswanathan AN, Neuberg D, Mutter GL. Involution of latent endometrial precancers by hormonal and nonhormonal mechanisms. Cancer. 2009;115(10):2111–8.
Yang HP, Meeker A, Guido R, Gunter MJ, Huang GS, Luhn P, et al. PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors. Cancer Causes Control. 2015;26(12):1729–36.
Mutter GL, Monte NM, Neuberg D, Ferenczy A, Eng C. Emergence, involution, and progression to carcinoma of mutant clones in normal endometrial tissues. Cancer Res. 2014;74(10):2796–802.
Lac V, Nazeran TM, Tessier-Cloutier B, Aguirre-Hernandez R, Albert A, Lum A, et al. Oncogenic mutations in histologically normal endometrium: the new normal? J Pathol. 2019;249(2):173–81.
Moore LLD, Coorens T, Sanders M, Ellis P, Maura F, Dawson K, et al. The mutational landscape of normal human endometrial epithelium. Nature. 2020;580(7805):640–6.
Guo SW. Cancer driver mutations in endometriosis: variations on the major theme of fibrogenesis. Reprod Med Biol. 2018;17(4):369–97.
Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA, Zondervan KT, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking harmonisation project: I. surgical phenotype data collection in endometriosis research. Fertil Steril. 2014;102(5):1213–22.
Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, et al. World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril. 2014;102(5):1223–3, 1232.
Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the art and science of endometriosis meeting. Fertil Steril. 2010;93(1):62–7.
Orr NL, Noga H, Williams C, Allaire C, Bedaiwy MA, Lisonkova S, et al. Deep dyspareunia in endometriosis: role of the bladder and pelvic floor. J Sex Med. 2018;15(8):1158–66.
Yong PJ. Deep dyspareunia in endometriosis: a proposed framework based on pain mechanisms and Genito-pelvic pain penetration disorder. Sex Med Rev. 2017;5(4):495–507.
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethics Approval
N/A for review article.
Consent to Participate
N/A
Consent for Publication
N/A
Ethical Consents
N/A for review article.
Code Availability
N/A
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yong, P.J., Talhouk, A. & Anglesio, M.S. Somatic Genomic Events in Endometriosis: Review of the Literature and Approach to Phenotyping. Reprod. Sci. 28, 2743–2757 (2021). https://doi.org/10.1007/s43032-020-00451-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43032-020-00451-9