Pathogenesis of EAOC: Comparison
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Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. In the systematic review and meta-analysis, the summary relative risk of EAOC was estimated as 1.93 compared to women with no endometriosis.

  • endometriosis
  • endometrioma
  • endometriosis-associated ovarian cancer

1. Background

Clear-cell and endometrioid carcinomas are the most intensely and reproducibly associated malignancies with endometriosis. Coexistence with endometriosis is observed in 21–51% of patients with clear-cell carcinoma and 23–43% with endometrioid carcinoma [1][2]. While endometriosis is also associated with low-grade serous ovarian carcinoma, this linkage needs to be more defined. In the last few years, genuine efforts have been invested in exploring the pathogenesis of EAOC occurrence and whether there is a causal relationship. Numerous theories of endometriosis occurrence, development, and expansion are still cited and discussed. Succinctly, they include retrograde menstruation, coelomic metaplasia, circulatory or lymphatic spread, genetic predisposition, and self-abnormalities in the humoral and cell-mediated immune systems. Their relation to the development of EAOC is still under investigation. Genetic, inflammatory (including free-iron-induced oxidative stress), immunological, and hormonal factors have been implicated in the malignant transformation of endometriosis [3]. However, the pathogenesis of EAOC is still an unresolved enigma and has been a matter of active investigation and debate over the last few years. Several recent reviews, systematic reviews, and meta-analyses targeting this topic did not reach definite conclusions [3][4][5][6]. A recent systematic review has addressed the topic of cancer-associated mutations (CAMs) in endometriosis patients, shedding some light on the pathogenesis and pathophysiology of the disease. However, it must still achieve a clear picture or definitive conclusion [7]. Furthermore, CAMs do not necessarily lead to malignant transformation, as it requires gaining and accumulating the precise type in a specific combination of CAMs to complete the malignant transformation. An innovative dual paradigm has been developed to gain insight into and explore the composite molecular genetic pathways implicated in the pathogenesis of primary ovarian epithelial carcinomas and to elate these pathways with histopathological classification [8][9]. This dual model suggests two distinct types of ovarian epithelial carcinoma with different molecular profiles, type I and type II. Type I presents at an early stage with low-grade features, including clear-cell, endometrioid, and low-grade serous carcinomas. Type I frequently arises through a defined sequence, either from endometriosis or borderline serous tumors. Type II carcinoma is a much more frequent disease and usually presents at advanced stages. Type II are typically high-grade serous carcinomas, arising in most cases from the fimbriated end of the fallopian tubes, as foci of small in-situ tubal intraepithelial carcinoma [10], with silent progression, peritoneal seeding, and fast spread. Indeed, the molecular profiles of these two types seem to be different and correlate well with the distinct nature of type I and type II carcinomas. Recent molecular studies in type I ovarian carcinomas identified somatic mutations in ARID1A, KRAS, PTEN, PIK3CA, MLH1, and B catenin [11][12]. In addition, TP53, BCL2, and POLE mutations have also been described [13][14]. In contrast, most type II tumors are characterized mainly by TP53 mutations. In fact, according to the Cancer Genome Atlas dataset, the TP53 mutations are present in almost 96% of high-grade serous ovarian carcinomas [15]. Nevertheless, TP53 mutation, otherwise pathognomonic for high-grade serous ovarian carcinoma, is found in 30% of endometriosis associated with clear cell carcinoma. Benign endometriosis has not been associated with TP53 mutation, nor has it been found in endometriosis coexisting with endometrioid carcinoma [16]. To further explore the pathogenesis of malignant transformation of endometriosis to EAOC, a recent study evaluated the genomic-wide functions involved with data-driven analysis based on the functionomes of endometriosis, clear-cell ovarian carcinoma, and endometrioid ovarian carcinoma [17]. This was achieved by studying the microarray gene expression datasets of these three illnesses, from the National Center for Biotechnology Information Gene Expression Omnibus, with the quantified molecular functions defined by 1454 Gene Ontology term gene sets. Theis study demonstrated that deregulated metabolism, cell cycle control, cell–cell signaling, hormone activity, inflammatory response, immune response, and oxidoreductase activity are vital components of EAOC pathogenesis. Furthermore, several studies have suggested that atypical endometriosis, characterized by cytological and architectural atypia, hyperplasia, large nuclei, and increased nuclear–cytoplasmic ratio, may be a direct precursor of EAOC [18]. A recent systematic review of molecular biomarkers of atypical endometriosis, summarizing 39 eligible studies, has found a high heterogeneity among the reports [19]. Nevertheless, certain constancy was detected for altered expression in phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, ARID1a, estrogen and progesterone receptors, and transcriptional, nuclear, and growth factors in such cases. The authors concluded that since these biomarkers involve expensive molecular analysis and none has solid evidence, there is no justification for their regular application in the clinical setting.

2. Evidence for Causality in EAOC

Currently, advanced human genetics seems to be the best tool to explore complex and heterogeneous disease causality in modern medicine. Genetics provides a robust scientific platform for establishing a relationship between a cause and an effect—in this case, endometriosis and EAOC—however, causality in genetics is probabilistic and rarely a deterministic certainty. The causal relationship between a genetic variant and a phenotype is provisional and based on the conditions and the environment, such as the genetic backgrounds in which the causal variants and the phenotype operate. These fundamental aspects seem to apply to the composite pathogenesis of EAOC. Genetic studies published to explore common genetic grounds between endometriosis and ovarian cancer have employed three different strategies. The first inspect common alleles associated with different histotypes of epithelial ovarian cancer, pooling data from multiple genome-wide genotyping projects or utilizing the Mendelian randomization methodology to look for germline genetic variants as proxies for causal effects of risk factors [20][21]. The second assesses the association between endometriosis and ovarian cancer as a distinct disease [22][23], while the third explores the link between endometriosis and specific histotypes of ovarian cancer [24][25]. Each strategy adds value and is complementary to the others. However, since ovarian epithelial cancer is a heterogeneous disease with diverse pathogenesis and pathways, the third strategy seems more appropriate and straightforward for exploring EAOC causality. One large study explored shared genetic etiologies between two endometriosis databases genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10,065 cases and 21,663 controls). Evidence was found for shared genetic risks between endometriosis and all ovarian cancer histotypes, except for the mucinous type. Clear-cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18–0.84) [24]. Just recently, a strong genetic relationship between endometriosis and epithelial ovarian cancers was reported employing state-of-the-art methods, including genetic correlation, Mendelian randomization, bivariate genome-wide association studies, colocalization, and functional genomic analyses [25]. The data explored included 14,949 cases/190,715 controls for endometriosis and 25,509 cases/40,941 controls for ovarian epithelial carcinoma. A significant genetic correlation (rg) was found between endometriosis and clear-cell carcinoma (rg = 0.71) and endometrioid carcinoma (rg = 0.48), verified by Mendelian randomization analysis. Furthermore, a bivariate meta-analysis identified 28 loci associated with endometriosis and ovarian epithelial cancer, including 19 with evidence for a shared underlying association signal. Collectively, previous epidemiological observations have shown an association between endometriosis and EAOC, specifically with clear-cell and endometrioid carcinomas. Several studies have been conducted to understand the underlying mechanisms of this malignant transformation, suggesting multi-factorial pathways. Employing state-of-the-art genetic methods has provided evidence of genetic correlation and a strong potential causal relationship between endometriosis and EAOC. Future fine-mapping and histotype-specific functional analyses may substantiate EAOC causality. Furthermore, these novel advancements may pave the way for targeted ovarian epithelial cancer screening and facilitate potential preventive pharmacological interventions.

References

  1. Jimbo, H.; Yoshikawa, H.; Onda, T.; Yasugi, T.; Sakamoto, A.; Taketani, Y. Prevalence of ovarian endometriosis in epithelial ovarian cancer. Int. J. Gynecol. Obstet. 1997, 59, 245–250.
  2. Stamp, J.P.; Gilks, C.B.; Wesseling, M.; Eshragh, S.; Ceballos, K.; Anglesio, M.S.; Kwon, J.S.; Tone, A.; Huntsman, D.G.; Carey, M.S. BAF250a Expression in Atypical Endometriosis and Endometriosis-Associated Ovarian Cancer. Int. J. Gynecol. Cancer 2016, 26, 825–832.
  3. Tanha, K.; Mottaghi, A.; Nojomi, M.; Moradi, M.; Rajabzadeh, R.; Lotfi, S.; Janani, L. Investigation on factors associated with ovarian cancer: An umbrella review of systematic review and meta-analyses. J. Ovarian Res. 2021, 14, 153.
  4. Wentzensen, N.; Poole, E.M.; Trabert, B.; White, E.; Arslan, A.A.; Patel, A.V.; Setiawan, V.W.; Visvanathan, K.; Weiderpass, E.; Adami, H.-O.; et al. Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis from the Ovarian Cancer Cohort Consortium. J. Clin. Oncol. 2016, 34, 2888–2898.
  5. Thomsen, L.H.; Schnack, T.H.; Buchardi, K.; Hummelshoj, L.; Missmer, S.A.; Forman, A.; Blaakaer, J. Risk factors of epithelial ovarian carcinomas among women with endometriosis: A systematic review. Acta Obstet. Gynecol. Scand. 2016, 96, 761–778.
  6. Bulun, S.E.; Wan, Y.; Matei, D. Epithelial Mutations in Endometriosis: Link to Ovarian Cancer. Endocrinology 2019, 160, 626–638.
  7. Guo, S.-W. Cancer-associated mutations in endometriosis: Shedding light on the pathogenesis and pathophysiology. Hum. Reprod. Update 2020, 26, 423–449.
  8. Nezhat, F.R.; Apostol, R.; Nezhat, C.; Pejovic, T. New insights in the pathophysiology of ovarian cancer and implications for screening and prevention. Am. J. Obstet. Gynecol. 2015, 213, 262–267.
  9. Kurman, R.J.; Shih, I.M. The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. Am. J. Pathol. 2016, 186, 733–747.
  10. Przybycin, C.G.; Kurman, R.J.; Ronnett, B.M.; Shih, I.M.; Vang, R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am. J. Surg. Pathol. 2010, 34, 1407–1416.
  11. Takeda, T.; Banno, K.; Okawa, R.; Yanokura, M.; Iijima, M.; Irie-Kunitomi, H.; Nakamura, K.; Iida, M.; Adachi, M.; Umene, K.; et al. ARID1A gene mutation in ovarian and endometrial cancers. Oncol. Rep. 2015, 35, 607–613.
  12. Zou, Y.; Zhou, J.-Y.; Guo, J.-B.; Wang, L.-Q.; Luo, Y.; Zhang, Z.-Y.; Liu, F.-Y.; Tan, J.; Wang, F.; Huang, O.-P. The presence of KRAS, PPP2R1A and ARID1A mutations in 101 Chinese samples with ovarian endometriosis. Mutat. Res. Mol. Mech. Mutagen. 2018, 809, 1–5.
  13. Nezhat, F.; Cohen, C.; Rahaman, J.; Gretz, H.; Cole, P.; Kalir, T. Comparative immunohistochemical studies of bcl-2 and p53 proteins in benign and malignant ovarian endometriotic cysts. Cancer 2002, 94, 2935–2940.
  14. Ishikawa, M.; Nakayama, K.; Nakamura, K.; Ono, R.; Sanuki, K.; Yamashita, H.; Ishibashi, T.; Minamoto, T.; Iida, K.; Razia, S.; et al. Affinity-purified DNA-based mutation profiles of endometriosis-related ovarian neoplasms in Japanese patients. Oncotarget 2018, 9, 14754–14763.
  15. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615.
  16. Kajiyama, H.; Suzuki, S.; Yoshihara, M.; Tamauchi, S.; Yoshikawa, N.; Niimi, K.; Shibata, K.; Kikkawa, F. Endometriosis and cancer. Free Radic. Biol. Med. 2019, 133, 186–192.
  17. Chang, C.-M.; Yang, Y.-P.; Chuang, J.-H.; Chuang, C.-M.; Lin, T.-W.; Wang, P.-H.; Yu, M.-H.; Chang, C.-C. Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis. Int. J. Mol. Sci. 2017, 18, 2345.
  18. LaGrenade, A.; Silverberg, S.G. Ovarian tumors associated with atypical endometriosis. Hum. Pathol. 1988, 19, 1080–1084.
  19. Bartiromo, L.; Schimberni, M.; Villanacci, R.; Mangili, G.; Ferrari, S.; Ottolina, J.; Salmeri, N.; Dolci, C.; Tandoi, I.; Candiani, M. A Systematic Review of Atypical Endometriosis-Associated Biomarkers. Int. J. Mol. Sci. 2022, 23, 4425.
  20. Phelan, C.M.; Kuchenbaecker, K.B.; Tyrer, J.P.; Kar, S.P.; Lawrenson, K.; Winham, S.J.; Dennis, J.; Pirie, A.; Riggan, M.J.; Chornokur, G.; et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat. Genet. 2017, 49, 680–691.
  21. Yarmolinsky, J.; Relton, C.L.; Lophatananon, A.; Muir, K.; Menon, U.; Gentry-Maharaj, A.; Walther, A.; Zheng, J.; Fasching, P.; Zheng, W.; et al. Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis. PLoS Med. 2019, 16, e1002893.
  22. Lee, A.W.; Templeman, C.; Stram, D.A.; Beesley, J.; Tyrer, J.; Berchuck, A.; Pharoah, P.P.; Chenevix-Trench, G.; Pearce, C.L.; Ness, R.B.; et al. Evidence of a genetic link between endometriosis and ovarian cancer. Fertil. Steril. 2015, 105, 35–43.e10.
  23. Burghaus, S.; Fasching, P.A.; Häberle, L.; Rübner, M.; Büchner, K.; Blum, S.; Engel, A.; Ekici, A.B.; Hartmann, A.; Hein, A.; et al. Genetic risk factors for ovarian cancer and their role for endometriosis risk. Gynecol. Oncol. 2017, 145, 142–147.
  24. Lu, Y.; Cuellar-Partida, G.; Painter, J.N.; Nyholt, D.R.; Morris, A.P.; Fasching, P.A.; Hein, A.; Burghaus, S.; Beckmann, M.W.; Lambrechts, D.; et al. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. Hum. Mol. Genet. 2015, 24, 5955–5964.
  25. Mortlock, S.; Corona, R.I.; Kho, P.F.; Pharoah, P.; Seo, J.-H.; Freedman, M.L.; Gayther, S.A.; Siedhoff, M.T.; Rogers, P.A.; Leuchter, R.; et al. A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes. Cell Rep. Med. 2022, 3, 100542.
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