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Abstract
Endometriosis is a chronic and destructive developmental gynecologic condition that affects approximately 10% percent of females worldwide, and is one of the most frequent causes of extreme pelvic pain. The endometrium-like tissue, glands, and stroma outside the uterine cavity are often affected by endometriosis. It is estrogen-dependent and frequently affects the ovaries, fallopian tubes, and pelvic peritoneum. Symptoms such as chronic pelvic pain, infertility, dyspareunia, as well as digestive and urinary symptoms often accompany endometriosis. The overall condition shares characteristics with ovarian carcinoma such as enhanced vascular activation of the endothelial growth factor, local invasion, lymph angiogenesis, neoangiogenic, mechanism tolerance to apoptosis, and genome instability. Genetic studies have shown that endometriotic lesions contain gene mutations related directly to malignancies, particularly the ARID1A, p53, KRAS, and PTEN genes. However, women with endometriosis have a lower risk of ovarian cancer than the general population, where endometriosis was seen in only 1.3%, and did not diagnose ovarian cancer progression among them. We need to look into the connection between endometriosis and uterine carcinomas, as well as the common lesions and correlations in the uterine microenvironment, which may play a role in mutations and malignant exchanges. Although endometriosis is a risk factor of ovarian cancer, malignant cells from the uterus can migrate to the ovary and cause endometriosis-related ovarian cancer. The purpose of this article is to examine current data on genetic phenomena and molecular changes for endometriosis associated with ovarian cancer, focusing primarily on the proliferation of uterine and precise cell biomarkers.
- Endometriosis
- Ovarian carcinoma
- Genetic polymorphism
- Malignant transformation
- Biomarkers
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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1 Introduction
Endometriosis is a painful long-term gynecological disorder that affects about 10% (190 million)of adolescent and reproductive-aged women globally.1 Women with endometriosis are mostly severely affected between 25 and 35 years of age, when accumulation of endometrium tissue occurs between the cervical canal and the fallopian tubes inside the uterus. Although endometrioses usually begins as a benign rupture, it shares significant characteristics with piercing cancer. Like malignancy, endometriosis can attack and spread extensively.2Significant symptoms associated with endometriosis are infertility, crippling pelvic pain, dyspareunia, dysuria, and dysmenorrhea.3 Also, women with endometriosis often experience aberrant immune reactions and hormonal imbalances.4,5 Although the rudimentary etiology of endometriosis is inconclusive, an epigenetic connection is likely. Complications of endometriosis include bleeding and the proliferation of adhesion bands that link the cervical and midline organs. In addition, there is also an undeniable fertility problem in association to ovaries or fallopian tubes. Furthermore, extreme vulnerability of failed labor or frantic fertilization of an offspring, rupturing cysts causing severe pain, obstructed or distorted digestive tract, and specific types of malignancy with a severe risk of uterine cancer are common.6
Laparoscopy is the backbone in diagnosing endometriosis as it provides visual evidence of endometrial lesions and helps to stage the diseases.7 Four stages of endometriosis are conventionally based upon the location and expanses of aberrantuterine tissue. In Stage1 (minimal) some superficial implants are seen, while in Stage 2 (mild) more implants are involved. Stage 3 (moderate) involves small amounts of endometrium tissue in the ovaries with deep implants and some grafts. Finally, Stage 4(severe) involves multiple deep implants, and large areas of endometrium in both ovaries with multiple dense grafts.8 Pathogenesis, molecular changes, advanced cancer series, ovarian cancer, and mucosal cancer formation often occur in a varying order.9
In addition to the known risk factors of endometriosis-related cancer as shown in Fig. 1. Genetics certainly play a crucial role in both the probability and pathogenesis of uterine cancer.10,11 Familial endometriosis is estimated to be 50%, and identification of involved gene variants is essential for establishing personalized treatments. However, as with many complicated human diseases, discovering causative genetic factors remain a significant challenge. Disease systematic studies evaluating the mechanisms and factors in endometriosis associated ovarian cancer (EAOC) are have provided some understanding. Women with EAOC are generally younger, have an earlier stage of development, and also have a worse oncologic outcome than women with non-EAOC, suggesting that EAOC's biologic activity varies from non-endometriosis-associated endometriosis ovarian cancer.12Clear cell carcinoma and endometriosis carcinoma are the most frequent pathologic forms, according to a detailed investigation of the EAOC, followed by serous carcinoma and mucinous carcinoma.13This study aims to review the existing research on genetic and molecular changes in endometriosis-related ovarian cancer, with a particular emphasis on uterine and precise cell biomarkers.
Risk factors involved in endometrial carcinoma.
The incidence of endometrial cancer increased by 0.69% worldwide between 1990 and 2019, and mortality increased significantly in more than 40% of countries (highest in low-middle-income countries). The most pronounced increase of EAOC was in the United Kingdom (>1%), followed by Brazil (0.8-1%), and the USA (0.6-0.8%). However, some developed countries (Canada and Sweden) increased by less than 0.2%. Asian and African countries actually had a decrease in prevalence rate (<1%).Gu and colleagues reported that endometrial-related ovarian cancer significantly increased in developed countries (Fig. 2).14
Worldwide rate of incidence of endometrial-associated ovarian cancer.
According to epidemiological and molecular results, endometriosis has malignancy potencies that contribute to ovarian cancers. Some pathological trials have shown that 5–10% of women with ovarian endometriosis have ovarian cancer with clear cell and endometrial cancers mostly linked with endometriosis. Furthermore, experiments have shown that ovarian cancers and adjacent endometriotic lesions share genetic mutations, implying a malignant genetic transition spectrum. The prevalence of endometriosis was seen in 39.2% of clear cell ovarian cancer cases and 21.2% of endometrioid ovarian cancer cases compared to 3.3% and 3% of severe and mucinous subtypes, respectively.15
2 Genetics of endometriosis-associated ovarian cancer
2.1 Overview
In 1925, Sampson first noted a relationship between endometriosis and ovarian cancer and his recommendations are still being used to identify endometriosis-inducing cancer cells. Borgfeldt et al. also argued that initially benign endometriosis could progress to malignant ovarian carcinoma. The natural history, pathological presentation, sex hormone activity, and inflammatory micro-environments are important steps in a pathway for tumor-related endometriosis.16 Anglesio and Young revealed a direct association between an abnormal endometrioid and ovarian cancer in 1988.17 Researchers have shown that women with endometriosis are at greater risk of developing ovarian cancer. The speculation that endometriosis may offer access to these malignancies was first proposed, on the perception of endometriosis occurring with some nearby ovarian carcinoma. This concept was subsequently extended by demonstrating that cytological atypical ovarian endometriosis was the immediate antecedent, as this atypical endometriosis seemed coterminous with clear cell and endometrioid carcinomas.18 The recent extensive Genome Wide Association Study (GWAS) study demonstrated an association of endometriosis with various carcinomas {i.e. endometrioid cancer (OR = 2.33), ovarian carcinoma (OR = 3.44), breast cancer (OR = 1.04) and thyroid cancer (OR = 1.39)}.19 Early endometriosis, atypical endometriosis, limiting tumors, and fully malignant growth are all stages of tumor carcinoma associated with endometriosis. It has been documented that mutation in Phosphate and tensin Homolog gene(PTEN), KRAS, ARID1A, and P53 lead to tumorigenesis.20 These genes and their mutations involved in this are discussed in the following sections, and are listed in Table 1.
Genes involved in endometriosis associated ovarian cancer.
2.2 Phosphate and tensin homolog gene (PTEN)
PTEN is the tumor-regulating gene located on chromosome 10 (10q23.3) that was discovered in 1997. Mutations of this gene have been linked to glioma, uterine endometrial carcinoma, and endometrioid ovarian carcinoma (Fig. 3). The phosphorylation-resistant phosphate is a secondary phosphatidylinositol-3-kinase phosphorylation messenger (PI3K). PTEN inhibits PI3K activity and affects serine/threonine kinase to act as its downstream target. Phosphorylated a serine/threonine protein kinase (Akt) monitors the action of several proteins downstream, including proapoptotic factor that helps cell survival through apoptosis suppression. A protein-mediated phosphate inhibits cell death by promoting cell proliferation and by interfering with B kinase and phosphatidylinositol-3, 4, 5-triphosphate activity. Interestingly, PTEN mutations are linked to early-stage endometrial carcinomas rather than late-stage or metastatic carcinomas. Atypical and endometrial hyperplasia has also been linked to PTEN mutations. According to these findings, the PTEN gene is inactivated early in the development of uterine endometrial carcinoma.21 Because endometrioid ovarian cancers are derived from endometrial cells, they are endometrial rather than ovarian, suggesting a developmental connection between the two tumor forms. Loss of heterozygosity (LOH) at 10q23 and mutations in all nine exons of PTEN were screened in endometrioid, serous, mucinous, and clear cell carcinomas.22 PTEN inactivation occurs early in the growth of endometrial hyperplasia in both endometrial and ovarian cancers.23 Cancer has been linked to decreased PTEN expression and increased PI3K/Akt function.24 Over-expression of PTEN in endometrial epithelial cells eliminates cell proliferation as apoptosis, and G1 cell cycle detention is increased.25 Raffone and colleagues reported that the loss of PTEN gene expression in endometrial hyperplasia was significantly linked with endometrial cancer.26
Association of PTEN polymorphism in the formation of tumor cells in endometrial ovarian cancer.
2.3 Kirsten’s rat sarcoma gene (KRAS)
The oncogene homology of the KRAS virus was one of the first genes identified to mutate into human cancers, including colorectal, lung, and pancreatic. The KRAS is a proto-oncogene controls cellular processes related to signal transduction and is located on chromosome 12 (12p12.1). The dysregulation of mitogen-activated protein kinases (MAPK) and phosphoinositide-3 kinase/v-Akt murine thymoma viral oncogene PI3K/AKT pathways directly correlates with this. KRAS is a 21 kDa transcriptional protein binding MAPK and PI3K/AKT pathway to the membrane receptors activated. A mutant KRAS facilitates MAPK or PI3K/AKT downregulation, contributing to massive cellular proliferation and carcinogenesis. These mutations are characterized by a repeated change in guanine to adenine, most often occurring in codon 12.27 In several human cancers, mutations of KRAS (a central oncogene in the EGFR signaling cascade) are an early oncogenic event. These gene variants have been attributed to various diseases in ovarian mucinous carcinomas, and the gene is necessary for the rehabilitation of cancer patients. The oncogene's frequent mutations have prompted efforts to produce a drug that treats tumors with KRAS mutations. According to recent research, KRAS mutations appear to be an accurate biomarker of resistance to therapies dependent on epidermal growth factor receptors.28 KRAS mutation promote overexpression of angiotensin II, endothelin-1, platelet derived growth Factor(PDGF), epidermal growth factor(EGF), and thrombin.29 Estrogen stabilizes PKC-Δ by inhibiting ubiquitylation-based proteasome degradation. PKC-Δ binds to KRAS by ER-α36 to estrogen and then stops KRAS from degrading. The stable KRAS promotes tumor growth through the signaling cascade of extra cellular signal regulated kinase(ERK) and PI3 kinase (Fig. 4).30Recent findings show that the expression of the KRAS p.G12V mutant allele and KRAS wild-type allele was significantly associated with the endometriosis-associated ovarian carcinoma.31
KRAS estrogen stabilization in tumor genesis endometrial.
2.4 AT-rich interaction domain 1A gene (ARID1A)
The ARID1A gene is located on chromosome1 (1p36.11), a region that is often deleted in tumors. It has been hypothesized that tumor-suppressing genes of the 1p36 region may be present lost with such deletions.32 These mutations were found in 46% of ovarian clear cell cancers, 30% of endometrioid cancers, and 1% other cancers. They also found that BRG1-associated factor 250a(BAF250a) proteinuria is associated with ovarian and endometrial carcinoma subtypes, as well as ARID1A mutations. Uterine clear cell carcinomas are common women with persistent abnormal endometrial lesions. It was found that they may be individually present in tumors in the same mutations.33 An ARID1A mutation was found in 17 clones from atypical endometriosis, but not in 52 clones from a distant endometrial lesion, BAF250a was lost in female internal reproductive clear cell neoplastic disease and pathology, ; but maintained in endometriosis lesions. The steroid hormone receptor was expressed in transmissible endometriosis, but not in clear cell cancer. Ovarian cancer exhibited HNF-1 but not the neighboring atypical or remote endometriosis. Therefore, a distinct mucosal membrane can be distinguished from the distal mucosa, which is only strengthened by the absence of interpretation correlated with the subsistence of ARID1A mutation. Rearrangements in ARID1A have been found in breast and lung cancer cell lines, as well as an absence of BAF250a in cervical and breast-carcinoma cell lines.34 According to new findings, protein 1A (ARID1A), which contains the interactive AT-rich domain that acts as a tumor suppressor gene, is often inhibited in endometrial and clear cell ovarian cancers.35 Superficial carcinomas can lead to neoplasms, but low malignancy potential and endometriotic lesions with several benign focuses are clonally associated in patients with cancer-associated mutilations. Endometriosis mutations are a sign that tumors associated with endometriosis can evolve. The results of patients in endometriosis-related tumors are contrasted with the existence or lack of expression of BAF250a.36
The occurrence of mutations in ARID1A is closely linked to a BAF250a protein deficiency. Loss of expression of BAF250a was seen in anARID1Amutation in both clear cell ovarian and endometrial carcinoma. Loss of heterozygosity, based on the occurrence and the resulting loss of expression of BAF250a, often occurs in ovary clear cell carcinomas. Somatic mutations of ARID1A as well as BAF250a expression deficiencies seem to have a wild allele. Therefore, genetic polymorphism in ARID1A and damage of BAF250a protein expression are especially present in endometriosis-associated ovarian carcinomas that do not feature chromosomal instability.37 Defects in the protein of this gene that change the accessibility (besides the PI3 kinase pathway and WNT mutations); of chromatin transcription factors (CTF) such as ARID1A can lead to the definition of ovarian cell carcinomas and endometrial carcinoma is shown in Fig. 5.38
ARID1A associated ovarian and endometrial carcinomas.
2.5 Tumor protein gene (P53/TP53)
The p53 gene, located on the short arm of chromosome 17, codes for a nuclear protein that ordinarily prevents uncontrolled cell proliferation. It is a tumor suppressor gene that controls cell division adversely. Because of the enhanced longevity of the mutant version of the protein, it accumulates in cells, and is routinely detected by immunohistochemical staining. In ovarian epithelial carcinoma, p53 overexpression or mutation has been identified as a molecular genetic modification.39 The gene p53 encodes a 53-kDa nuclear phosphoprotein that acts on target genes that trigger the repair of DNA, cell cycle arrest, apoptosis, or metabolic modifications in response to different cell stresses. The growth and proliferation of multiple tumors has been linked to frequent allelic loss at the 17p13.1 locus and p53 variants. Within the coding region of the p53 gene, two significant polymorphisms modify the amino-acid sequence codons 47 and 72 in exon 4 are the sites of these mutations.40 There is no significant association between in this gene codon and endometriosis in Pakistani women even though there is aexistence of TP53 gene codon 72 arg/pro genetic alteration.41
Epithelial ovarian carcinoma is divided into Type I and Type II based on clinical, histological, and biological research in about 90% of ovarian hematological malignancies. High-grade serous carcinoma is a primary histological subtype of class II ovarian endothelial carcinoma. Endometrial cancer based on histopathological and molecular observations is categorized as Type-I and Type-II. Type I endometrial cancer primarily consists of estrogen-dependent endometrial cancer, which appears in premenopausal women, and is consistent with a favorable prognosis with atypical endometrial hyperplasia. Genetically, endometrial carcinoma type-I is associated with carcinogenesis of the endometrium. Endometrial Type II cancer occurs in postmenopausal women, andis associated with weak prognostics. The disease arises directly from the atrophic endometrium. P53 deficiency is closely associated with the TP53 mutation in endometrial cancer. TP53 mutations were closely linked to low endometrial carcinoma survival, although they were not substantially associated endometrial carcinomas. The mutation of TP53 contributes to an accumulation of nuclear p53 proteins that have been identified as over-expressed in immunohistochemistry.42
The multi-phase cascade involves oncogene activation and inactivation of the tumor suppressor genes that cause endometriosis to produce ovarian cancer. P53 (primarily a transcriptional factor) is triggered by many signals, including DNA damage, hypoxia, expression of oncogenes, and osmotic strain. DNA damage causes p53 to trigger p21 expression. P21 is a cyclin-dependent kinase (CDK) inhibitor, which suppresses complex CDK-cyclin and hinders the cell cycle in stage G1. As a result, DNA can berepaired in G1before replication in S1. Although the cell can correct DNA damage, p53 induces apoptosis, like P53 apoptosis effector related to PMP22(PERP), BCL 2 Associated X(BAX), and p53 upregulated modulator of apoptosis(PUMA) by activating apoptosis signals. The absence of p53 function permits a pathological proliferation of the cell. In several malignant tumors, p53 dysfunction was found. In malignant tumors, p53 dysfunction is primarily caused by p53 protein inactivation by binding proteins and mutations in TP53 shown in Fig. 6. 43
Role of P53 in the formation of tumor cells.
3 Oxidative stress and endometriosis
Oxidative stress (OS) markers and antioxidant status have been assessed in endometriosis patients. The menstrual system may be affected by erythrocytes, as well as apoptotic and indigestible endometrial cells. These substances can produce mononuclear phagocytes. The interaction of apolipoproteins in activated macrophages with peroxides causes the OS and lipid peroxide formation and other by-products. It increases the metabolic rate response in the pelvis, resulting in the activation of cytokines, cell growth, and anti-inflammatory mediators. The activation of xanthine oxidase, are active oxygen species (ROS) generating enzyme, is essential in women even without endometriosis during menopause. Although patients with pelvic pain had greater concentrations of ectopic and eutopicendometriosis xanthine oxidase during the processes, cyclic mutations of the enzyme were seen in women who did not have the condition. Scaping and disabling excess free radicals are enzymatic and non-enzymatic antioxidants that help prevent damage to cells. Several antioxidant pathways influence the consumption of non-enzymatic antioxidants, such as manganese, zinc, beta carotenes, selenium, and iron. Peritoneal liquid containing ROS-generating iron, macrophages, and toxins such as polychlorinated biphenyls, leading to increased tissue and adhesion, direct cytotoxic activity, and increased compromised rates of cellular disease, will disturb the balance of ROS with antioxidants, as shown in Fig. 7.44
Role of oxidative stress in cellular and extra cellular environment.
The mRNA is rendered cyclically in the uterine lining with the endometrial glands of nitric oxide synthesis (NOS). Patients with endometriosis havesignificant increased the levels of nitric oxide and NOSand patients ovarian, endometrial lining of adenomyosis also have NOS expression during menstruation. Endometrial development affects embryo implantation. Synchronization between the endometrial receptivity and embryo development can make it difficult for the embryo to implant. Oxidative stress may also induce asynchrony. Endometriosis patients have significantly different uterine hyperperistalsis and dispersalist than controls, often resulting in sperm transfer problems and low fertility.45 After a retrograde menstruation, Samson's theory shows that desquamated menstrual cells and apoptotic endometrial tissue are transmitted to the peritoneal cell. Chronic inflammation can be induced by this process, with pro-inflammatory cytokines that attract and activate immune cells (including granulocytes and macrophages). These cells emit a lot of ROS and endometriosis. Disease aggressiveness can cause oxidative stress in endometriosis patients. This research would attempt to compare the association between the amounts of OS biomarkers measured in endometriosis patients.46
Iron is needed for oxygen distribution and several enzymatic reactions. The iron-related compounds (heme, ferritin, red blood cells, and free iron) are developed excessively during menstrual bleeding and vesicoureteral reflux in the peritoneal cavity. Patients with endometriosis have elevated amounts of iron, ferritin, transferrin, and hemoglobin in their peritoneal fluid overpeople without endometriosis.47 Via iron-induced persistent oxidative stress, endometriotic cysts (resulting in increased concentrations of free iron) promote carcinogenesis. Due to an imbalance with reactive oxygen species and antioxidant barriers, the pathophysiology of atypical endometriosis and resultant endometriosis associated ovarian cancer (EAOC) in the peritoneum can be associated with increased oxidative stress. The degradation of the peritoneal mesothelium caused by iron-related compounds can be responsible for the adhesion of ectopic endometrial and tumor cells.48 Furthermore, in the plasma of women with endometriosis, superoxide dismutase (which activates the dismutation of superoxide into hydrogen peroxide and oxygen)plays a crucial role asan antioxidant, and can become down-regulated, indicating diminished antioxidant ability.49
Iron-mediated and heme oxidative stress triggers a process, contributing to systemic inflammation and persistent bleeding. Oxidative stress causes changes at the level of the DNA.50 Their formation is a necessary condition for the modulation of different biochemical functions, and these free species are provided by an integrated antioxidants defense mechanism. Down-regulation of the estrogen's receptor (ER) is detected during malignant endometriosis transformation.51 Loss of estrogen activity, heterozygosity loss, and mutation of other genes cause the transition between ovarian neoplasms similar to endometriosis (Fig. 8).52
Progression of endometriosis associated ovarian cancer.
4 Biomarkers in endometriosis-associated ovarian cancer
The use of biomarkers been proposed for ovarian screening, and future biomarker tests may identify which patients with endometriosis are firmly at risk for ovarian cancer. Stage 1 ovarian cancer is diagnosed with some strong early risk factors in about 25 percent of cases. The most often assessed tumor marker of epithelial ovarian cancer is the CA-125 glycoprotein.53 For ovarian cancer screening, many biomarkers have been investigated. Ovarian carcinogen was observed by the overexpression of human epididymitis (HE4) (especially in endometriosis and serous tumors), but not in endometriosis or other benign gynecological conditions.54 Because p53 is mutated in specific cancers, autoantibodies to the mutant forms are an appealing biomarker.In a recent report, serum p53 autoantibodies(p53-AAb) was studied as a prognostic biomarker of ovarian cancer. Bojesan and co-workers studied the p53 expression among cancer patients (60 women participants) and found that 41.7% of antibodies present in 30 with non-serous ovarian cancer and 30 patients with benign disease.55
The researchers concluded that p53AAb's poor specificity in early disease and nonspecific activation in multiple p53overexpressing cancers hinders its therapeutic use as a biomarker for early detection of ovarian cancer.56 However, according to a review, 17 ꞵ-hydroxysteroid dehydrogenases 2, IL1R2, caldesmon protein (encoded by the CALD1 gene), and neural markers such as a neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal peptide (VIP), and protein gene product 9.5, have the potential to reliably diagnose endometriosis.57,58 Some biomarkers used in the screening of endometrial carcinogenesis have been illustrated in Table 2.59
Biomarkers related to endometriosis and ovarian carcinogenesis.
Endometriosis biomarkers derived from the preclinical stage of diagnosis to discover new biomarkers.60 Glycoproteins, adhesion factors, proteins, and hormones linked to angiogenesis or immunology are the most common endometriosis biomarkers. Glycosylation creates tumor-associated glycoproteins that are consistently secreted or expelled along with a cell membrane into the bloodstream and can also serve as tumor markers. Excessive expression of glycoproteins containing various glycans, changes in nucleotide sugar donors, and changes in the expression of glycosyltransferase and glycosidase enzymes all contribute to increased tumor cell glycosylation.61 In addition, inflammatory markers have been linked to endometriosis pathogenesis. The following were investigated as possible endometriosis biomarkers INF γ, IL-8, IL-6, IL-1; tumor necrosis factor-α (TNF-α), monocyte chemical attractant protein 1 (MCP-1) and interferon-γ 62. T cell dysfunction has been linked to endometriosis. As a result, helper T cells improve the cytokine IL-4 function, which is increased in injuries and facilitates the proliferation of endometriotic cells.63 Endometriotic cells proliferate and migrate more efficiently, as IL-17 activates COX-2 expression and IL-8. MCP-1 are involved in monocyte recruitment to damage and inflammatory sites. The effect of MCP-1 in peritoneal fluid and serum is high, particularly in the early stages of endometriosis.64
5 Conclusion
Endometriosis often causes extreme pelvic pain, and affects 10% to 15% of sexually active women worldwide. As a result, the clinician's primary duty is to be familiar with the different atypical symptoms and imaging modalities used to diagnose endometriosis. The importance of this information cannot be overstated. It can be treated with the proper medical treatment, but patients should be mindful that severe complications (including infertility)can occur. Retrograde menstruation, coelomic metaplasia, vascular invasion, and immune system deficiency account for the disease's mysterious pathophysiology. Endometriosis-associated ovarian cancer differs from other subcutaneous ovarian cancers in that it mostly affects younger women. Future research aims to provide a minor surgical procedure for both malignant and benign gynecological diseases, preventing postoperative infection. The current review gives new insights into pathways for advancing endometriosis carcinoma. Treatment choices should be individualized utilizing clinical characteristics, patient status, and family history. Future studies should concentrate on the early identification of malignant endometriosis, and how individual patients may benefit from specialized therapy. A genetic association study has the huge application to find a crucial relationship between the disease and specific genetic polymorphism. Endometriosis has been linked to various genetic loci identified through genetic linkage analysis. Ovarian cancer etiology is confounded by genetics: women with a first-degree relative with the disease have a risk that is more than twice as large. Endometriosis-associated cancer is now being studied for early genetic changes that contribute to their onset.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors thank the Chettinad Academy of Research Education (CARE) for the constant support and encouragement.
Appendix
Authors’ contributions
IBK has written the contents of this manuscript.
VM edited the figures and tables.
RV designed the study, revised and approved the final manuscript.
All authors have read and approved the manuscript.