An overview of endometrial cancer risk factors
DOI:
https://doi.org/10.12775/JEHS.2024.76.56569Keywords
Endometrial cancer, risk factors, obesity,, polycystic ovarian syndromeAbstract
In developed countries, endometrial cancer is the most common form of invasive gynecological cancer. Endometrial cancer is rare in less developed countries where there are fewer common risk factors, but the specific mortality rate is higher. The histological types of endometrial cancers show significant differences in prognosis. The first type of lesions is usually responsive to hormones, at a low stage, and has an excellent outlook, while the second type consists of high-grade tumors that are prone to recurrence, even at an early stage. The majority of endometrial cancers are influenced by hormones, with estrogen playing a role in promoting cancer through its interaction with estrogen receptor α (ER). Obesity is one of the most significant and common risk factors for endometrial cancer. Women who are obese have a three times higher risk of developing endometrial cancer. Many nonobese women can develop PCOS despite obesity being a risk factor, and many obese women may not show signs of PCOS. PCOS involves more than just a decrease in progesterone; progesterone levels may not always be lowered, and other hormone levels can also be impacted. Women affected by infertility may be more at risk for endometrial cancer, particularly if affected by ovulatory disorders. The expression of G-protein coupled estrogen receptor 1 (GPER-1) explains the estrogen-agonistic effect of tamoxifen in endometrial cancers. Tamoxifen and other "antiestrogens" act as pure agonists for GPER-1, a membrane-bound estrogen receptor. Besides genetic predisposition syndromes such as Lynch syndrome and Cowden syndrome, the development of endometrial cancer is associated with risk factors related to estrogen signaling as the main contributing factor. It's important to create prevention strategies by understanding the key risk factors and how they are involved in the formation of tumors.
References
[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians 2021;71:209–49. https://doi.org/10.3322/caac.21660.
[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018;68:394–424. https://doi.org/10.3322/caac.21492.
[3] Dunneram Y, Greenwood DC, Cade JE. Diet, menopause and the risk of ovarian, endometrial and breast cancer. Proc Nutr Soc 2019;78:438–48. https://doi.org/10.1017/S0029665118002884.
[4] Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941–53. https://doi.org/10.1002/ijc.31937.
[5] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38. https://doi.org/10.1056/NEJMoa021423.
[6] Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K, et al. Body Fatness and Cancer--Viewpoint of the IARC Working Group. N Engl J Med 2016;375:794–8. https://doi.org/10.1056/NEJMsr1606602.
[7] Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. https://doi.org/10.1158/0008-5472.CAN-14-0155.
[8] Raglan O, Kalliala I, Markozannes G, Cividini S, Gunter MJ, Nautiyal J, et al. Risk factors for endometrial cancer: An umbrella review of the literature. International Journal of Cancer 2019;145:1719–30. https://doi.org/10.1002/ijc.31961.
[9] Braun MM, Overbeek-Wager EA, Grumbo RJ. Diagnosis and Management of Endometrial Cancer. Am Fam Physician 2016;93:468–74.
[10] Lu KH, Broaddus RR. Endometrial Cancer. New England Journal of Medicine 2020;383:2053–64. https://doi.org/10.1056/NEJMra1514010.
[11] Amant F, Moerman P, Neven P, Timmerman D, Limbergen EV, Vergote I. Endometrial cancer. The Lancet 2005;366:491–505. https://doi.org/10.1016/S0140-6736(05)67063-8.
[12] Passarello K, Kurian S, Villanueva V. Endometrial Cancer: An Overview of Pathophysiology, Management, and Care. Seminars in Oncology Nursing 2019;35:157–65. https://doi.org/10.1016/j.soncn.2019.02.002.
[13] Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 2002;11:1531–43.
[14] Arend RC, Jones BA, Martinez A, Goodfellow P. Endometrial cancer: Molecular markers and management of advanced stage disease. Gynecol Oncol 2018;150:569–80. https://doi.org/10.1016/j.ygyno.2018.05.015.
[15] Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, Koenig KL, Shore RE, Kim MY, et al. Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer 2001;84:975–81. https://doi.org/10.1054/bjoc.2001.1704.
[16] Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer 2015;15:484–98. https://doi.org/10.1038/nrc3967.
[17] Hopkins BD, Goncalves MD, Cantley LC. Obesity and Cancer Mechanisms: Cancer Metabolism. J Clin Oncol 2016;34:4277–83. https://doi.org/10.1200/JCO.2016.67.9712.
[18] Luo J, Chlebowski RT, Hendryx M, Rohan T, Wactawski-Wende J, Thomson CA, et al. Intentional Weight Loss and Endometrial Cancer Risk. J Clin Oncol 2017;35:1189–93. https://doi.org/10.1200/JCO.2016.70.5822.
[19] Hutt S, Tailor A, Ellis P, Michael A, Butler-Manuel S, Chatterjee J. The role of biomarkers in endometrial cancer and hyperplasia: a literature review. Acta Oncol 2019;58:342–52. https://doi.org/10.1080/0284186X.2018.1540886.
[20] Cerretelli G, Ager A, Arends MJ, Frayling IM. Molecular pathology of Lynch syndrome. J Pathol 2020;250:518–31. https://doi.org/10.1002/path.5422.
[21] WARTHIN AS. HEREDITY WITH REFERENCE TO CARCINOMA: AS SHOWN BY THE STUDY OF THE CASES EXAMINED IN THE PATHOLOGICAL LABORATORY OF THE UNIVERSITY OF MICHIGAN, 1895-1913. Archives of Internal Medicine 1913;XII:546–55. https://doi.org/10.1001/archinte.1913.00070050063006.
[22] Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 2018;67:1306–16. https://doi.org/10.1136/gutjnl-2017-314057.
[23] Shai A, Segev Y, Narod SA. Genetics of endometrial cancer. Fam Cancer 2014;13:499–505. https://doi.org/10.1007/s10689-014-9722-7.
[24] Joehlin-Price AS, Perrino CM, Stephens J, Backes FJ, Goodfellow PJ, Cohn DE, et al. Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables. Gynecol Oncol 2014;133:43–7. https://doi.org/10.1016/j.ygyno.2014.01.017.
[25] Dominguez-Valentin M, Sampson JR, Seppälä TT, Broeke SW ten, Plazzer J-P, Nakken S, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genetics in Medicine 2020;22:15–25. https://doi.org/10.1038/s41436-019-0596-9.
[26] Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009;76:1–18. https://doi.org/10.1111/j.1399-0004.2009.01230.x.
[27] Mester J, Eng C. Cowden syndrome: Recognizing and managing a not-so-rare hereditary cancer syndrome. Journal of Surgical Oncology 2015;111:125–30. https://doi.org/10.1002/jso.23735.
[28] Mutter GL, Lin M-C, Fitzgerald JT, Kum JB, Baak JPA, Lees JA, et al. Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers. JNCI: Journal of the National Cancer Institute 2000;92:924–30. https://doi.org/10.1093/jnci/92.11.924.
[29] Djordjevic B, Barkoh BA, Luthra R, Broaddus RR. Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas. Modern Pathology 2013;26:1401–12. https://doi.org/10.1038/modpathol.2013.67.
[30] Dörk T, Hillemanns P, Tempfer C, Breu J, Fleisch MC. Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management. Cancers 2020;12:2407. https://doi.org/10.3390/cancers12092407.
[31] Vasen HFA, Ghorbanoghli Z, Bourdeaut F, Cabaret O, Caron O, Duval A, et al. Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). Journal of Medical Genetics 2014;51:283–93. https://doi.org/10.1136/jmedgenet-2013-102238.
[32] Palles C, Cazier J-B, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013;45:136–44. https://doi.org/10.1038/ng.2503.
[33] Elsayed FA, Kets CM, Ruano D, van den Akker B, Mensenkamp AR, Schrumpf M, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet 2015;23:1080–4. https://doi.org/10.1038/ejhg.2014.242.
[34] Rohlin A, Zagoras T, Nilsson S, Lundstam U, Wahlström J, Hultén L, et al. A mutation in POLE predisposing to a multi-tumour phenotype. International Journal of Oncology 2014;45:77–81. https://doi.org/10.3892/ijo.2014.2410.
[35] Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genetics in Medicine 2016;18:325–32. https://doi.org/10.1038/gim.2015.75.
[36] Siraj AK, Parvathareddy SK, Bu R, Iqbal K, Siraj S, Masoodi T, et al. Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region. Cancer Cell International 2019;19:334. https://doi.org/10.1186/s12935-019-1058-9.
[37] I T. An update on the molecular pathology of the intestinal polyposis syndromes. Diagnostic Histopathology 2015;21:147–51.
[38] Win AK, Dowty JG, Cleary SP, Kim H, Buchanan DD, Young JP, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 2014;146:1208-1211.e1-5. https://doi.org/10.1053/j.gastro.2014.01.022.
[39] Vogt S, Jones N, Christian D, Engel C, Nielsen M, Kaufmann A, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009;137:1976-1985.e1-10. https://doi.org/10.1053/j.gastro.2009.08.052.
[40] Win AK, Reece JC, Dowty JG, Buchanan DD, Clendenning M, Rosty C, et al. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer 2016;139:1557–63. https://doi.org/10.1002/ijc.30197.
[41] Weren RDA, Ligtenberg MJL, Kets CM, de Voer RM, Verwiel ETP, Spruijt L, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet 2015;47:668–71. https://doi.org/10.1038/ng.3287.
[42] Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, et al. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. Cancer Cell 2019;35:256-266.e5. https://doi.org/10.1016/j.ccell.2018.12.011.
[43] Thompson D, Easton DF, the Breast Cancer Linkage Consortium. Cancer Incidence in BRCA1 Mutation Carriers. JNCI: Journal of the National Cancer Institute 2002;94:1358–65. https://doi.org/10.1093/jnci/94.18.1358.
[44] Spurdle AB, Bowman MA, Shamsani J, Kirk J. Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing. Mod Pathol 2017;30:1048–68. https://doi.org/10.1038/modpathol.2017.20.
[45] Shu CA, Pike MC, Jotwani AR, Friebel TM, Soslow RA, Levine DA, et al. Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations. JAMA Oncol 2016;2:1434–40. https://doi.org/10.1001/jamaoncol.2016.1820.
[46] Ali AT. Reproductive Factors and the Risk of Endometrial Cancer. International Journal of Gynecologic Cancer 2014;24. https://doi.org/10.1097/IGC.0000000000000075.
[47] Venn A, Watson L, Bruinsma F, Giles G, Healy D. Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet 1999;354:1586–90. https://doi.org/10.1016/S0140-6736(99)05203-4.
[48] Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, et al. Cancer incidence in a cohort of infertile women. Am J Epidemiol 1998;147:1038–42. https://doi.org/10.1093/oxfordjournals.aje.a009397.
[49] Ignatov A, Ortmann O. Endocrine Risk Factors of Endometrial Cancer: Polycystic Ovary Syndrome, Oral Contraceptives, Infertility, Tamoxifen. Cancers (Basel) 2020;12:1766. https://doi.org/10.3390/cancers12071766.
[50] Cetin I, Cozzi V, Antonazzo P. Infertility as a cancer risk factor - a review. Placenta 2008;29 Suppl B:169–77. https://doi.org/10.1016/j.placenta.2008.08.007.
[51] Pleasant V, Pearlman MD. Does tamoxifen use increase the risk of endometrial cancer in premenopausal patients? OBG Manag 2023;35:17–21. https://doi.org/10.12788/obgm.0297.
[52] Emons G, Mustea A, Tempfer C. Tamoxifen and Endometrial Cancer: A Janus-Headed Drug. Cancers (Basel) 2020;12:2535. https://doi.org/10.3390/cancers12092535.
[53] Jordan VC. The 38th David A. Karnofsky lecture: the paradoxical actions of estrogen in breast cancer--survival or death? J Clin Oncol 2008;26:3073–82. https://doi.org/10.1200/JCO.2008.17.5190.
[54] Burke C. Endometrial cancer and tamoxifen. Clin J Oncol Nurs 2005;9:247–9. https://doi.org/10.1188/05.CJON.247-249.
[55] Fleming CA, Heneghan HM, O’Brien D, McCartan DP, McDermott EW, Prichard RS. Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. British Journal of Surgery 2018;105:1098–106. https://doi.org/10.1002/bjs.10899.
[56] Garuti G, Grossi F, Centinaio G, Sita G, Nalli G, Luerti M. Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer. European Journal of Obstetrics and Gynecology and Reproductive Biology 2007;132:101–6. https://doi.org/10.1016/j.ejogrb.2006.04.001.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Piotr Żychoń , Eryk Prajwos , Kamil Janawa, Michał Tomaszek , Małgorzata Domagała, Klaudia Cękalska, Wiktoria Stenka
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 94
Number of citations: 0
