{"paper_id":"1334a1ae-8c00-4703-8274-f1cff49051b1","body_text":"Int J Cancer Manag. 2022 July; 15(7):e120754.\nPublished online 2022 August 29.\ndoi: 10.5812/ijcm-120754.\nResearch Article\nKRAS Mutation in Endometriosis-Associated Ovarian Borderline and\nMalignant Epithelial Tumors\nSoheila Sarmadi\n 1, *, Narges Izadi-Mood 1, Marzieh Fakhari 2, Reza Shahsiah 2, Rosa Miri 2 and Maniya\nMozafari 3\n1Department of Pathology , Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran\n2Department of Pathology , Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran\n3Department of Pathology , Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran\n*Corresponding author: Department of Pathology , Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran. Email: ssarmadi@gmail.com\nReceived 2021 October 31; Revised 2022 August 01; Accepted 2022 August 09.\nAbstract\nBackground: Endometriosis is a common disease among women with the capacity to transform into ovarian neoplasms. KRAS\nmutation is a keystone in tumor-genesis of many malignant neoplasms.\nObjectives: In the current study , we investigated KRAS mutations in endometriosis-associated ovarian borderline and malignant\nepithelial tumors.\nMethods: The specimens of 42 consecutive patients undergoing a surgical procedure whose final diagnosis comprised\nendometriosis-associated borderline and malignant epithelial ovarian tumors including 12 borderline epithelial tumors and 30\novarian epithelial carcinomas were histopathologically reviewed. All cases were evaluated regarding the type of tumor, differenti-\nation and simultaneous presence of endometriosis or atypical endometriosis. DNA extraction from the selected paraffin block was\ndone and mutation of codons 12 and 13 was assessed.\nResults: Due to the quality of genomic DNA for PCR study was not acceptable in 6 out of 42 cases, among remaining 36 cases, KRAS\nmutation was observed in 6 cases including 2 cases with mutations in 2nd base of 12th codon (G →T), 3 cases with substitution of\nG→A in the 2nd base of 12th codon, and one with substitution of G→T in the 1st base of 12th codon.\nConclusions: We evaluated the KRAS mutation in the spectrum of ovarian epithelial tumors associated with endometriosis for treat-\nment approaches including targeted therapies. Our results suggested a possible link between KRAS mutation and endometriosis-\nassociated ovarian borderline and malignant tumors but there was no convincing evidence to prove a definite linkage.\nKeywords: Carcinoma, Ovary, Mutation, Endometriosis\n1. Background\nEndometriosis is a common chronic and painful gy-\nnecological disease characterized by the presence of en-\ndometrial tissue out of the uterus. The prevalence of en-\ndometriosis is not easy to estimate due to some asymp-\ntomatic patients (1). Endometriosis leading some symp-\ntoms such as dysmenorrhea, infertility , pelvic pain, and re-\nduction in quality of life. There are various hypotheses for\nendometriosis such as retrograde menstruation, stem cell\ntheory , and coelomic metaplasia (2). Endometriosis which\nis regarded as a benign and common condition has the can\ntransform and increase the risk of ovarian epithelial tu-\nmors, particularly of endometrioid type and clear cell car-\ncinoma; however, the pathogenesis is remained to be elu-\ncidated (3, 4). Most ovarian endometrioid carcinomas are\nassociated with endometriosis in the ovary . A transition\nof atypical endometriosis between endometriotic foci and\nthe invasive tumor is evidence that endometriosis may be\na culprit in the pathogenesis of epithelial tumors (5). Ovar-\nian endometriosis may share some features with neoplas-\ntic conditions such as monoclonality and loss of heterozy-\ngosity (6-8). In addition, the presence of endometriosis in\ndistant areas far from the site of origin is a reminiscence of\nmetastatic behavior of malignancies (9, 10). Many investi-\ngators have attempted to determine special molecular al-\nterations in the genome that may lead to the transforma-\ntion of endometriosis into malignancy . Finding these alter-\nations is helpful to determine whether or not endometrio-\nsis is a causative matter in tumorigenesis (11). Due to sim-\nilarities between endometrioid carcinoma of the uterus\nand ovary , these two entities may share a common patho-\ngenesis. KRAS mutation has been reported to be the most\nfrequent genetic aberration in uterine endometrioid ade-\nCopyright © 2022, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License\n(http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly\ncited.\n\nSarmadi S et al.\nnocarcinoma (11).\n2. Objectives\nIn this study , we evaluated the mutation of KRAS in a\nspectrum of ovarian epithelial tumors associated with en-\ndometriosis.\n3. Methods\n3.1. Sample Collections\nIn this cross-sectional study all the patients by a fi-\nnal pathology report with the diagnosis of endometriosis-\nassociated borderline and malignant epithelial ovarian tu-\nmors undergoing oophorectomy with or without hysterec-\ntomy referring to Yas and Imam Khomeini hospital, Tehran\nUniversity of Medical Sciences, Tehran, Iran during years\n2005 until 2015 were evaluated. In this study , only paraf-\nfin blocks from archive files and patients’ medical records\nwere used. There was no harm to patients’ privacy or\nhealth in our research. The study has been approved by\nthe committee of ethics of Tehran University of Medical Sci-\nences.\nAll histological slides were collected and reviewed re-\ngarding tumor type; degree of differentiation; and pres-\nence of squamous metaplasia (in endometrioid carci-\nnoma), evident endometriosis in available slides, and atyp-\nical endometriosis; finally the best paraffin block accord-\ning to the best slide was designated for polymerase chain\nreaction (PCR). Then selected paraffin blocks of the pa-\ntients were gathered and two sections, each measuring five\nmicrometers and one Hematoxylin and Eosin (H&E) slide,\nas trailing slide were prepared. In order to avoid contami-\nnation, we used one blade for each patient’s paraffin block.\nFor atypical endometriosis diagnosis using LaGrenada\nand Silverberg criteria, as follow:\nAll foci of endometriosis were examined histopatho-\nlogically and large nuclei, pale pleomorphic hyperchro-\nmasia, nuclear crowding, stratification and tufting, and\neosinophilic cytoplasm were recorded. Diagnosis of atyp-\nical endometriosis was made in cases with at least three\nmentioned histomorphological features (12).\n3.2. Genomic DNA Extraction and Sequencing\nGenomic DNA was extracted using Roche High\nPure PCR Template Preparation kit (Roche Diagnostics\nGmbH, Mannheim, Germany) according to the instruc-\ntion of the manufacturer. Subsequently , 30 to 60 ng\nof formalin-fixed tumor DNA was amplified in a 20 mi-\ncroliter reaction containing 10 microliters of TaKaRa\nEx Taq 2 master mix (Shiga, Japan) and 5 picomole/liter\nof forward and reverse primers, (forward primer 5’-\nGGTGAGTTTGTATTAAAAGGTACTGG-3’ and reverse primer\n5’-GGTCCTGCACCAGTAATATGC-3’). PCR cycling was started\nwith initial denaturation (0.5 min at 94°C), continued\nby 40 cycles of denaturation (10 s at 95°C), and anneal-\ning/extension (30 s at 60°C). In the last step, a final\nextension (10 min at 72°C) was added. All the samples were\nkept at 4°C until they were sent for sequencing Macrogen\n(Seoul, Korea) for direct Sanger sequencing using reverse\nprimer. The sequencing result was analyzed using Chroma\nsoftware version 2.6. The target sequence was used as\nan amplification control. Moreover, those samples that\nshowed a mutation in either codon 12 or codon 13 were\nre-amplified and re-sequenced using forward primer for\nconfirmation.\n3.3. Statistical Analysis\nFinally , in this descriptive study , all the gathered data\nentered Microsoft Excel software. Results of qualitative\nvariables were reported as frequency , and percent and\nresults of quantitative variables were calculated and re-\nported as mean and standard deviation.\n4. Results\nWe identified a total number of 42 patients with\nendometriosis-associated borderline and malignant ep-\nithelial ovarian tumors including 12 patients with border-\nline epithelial tumor and 30 patients with ovarian epithe-\nlial carcinoma.\nThe mean age ± SD was 43 ± 11.3 years (range, 22 -\n67), definite pathological diagnosis, and frequency of each\ntype of epithelial tumor and association with endometrio-\nsis are shown in Tables 1 and 2, respectively . The mean di-\nameter of the tumor was 11.9 ± 6 cm (range, 4 - 30 cm).\nThe mean number of paraffin blocks per case was 16.2± 7.1\n(range, 6 - 36). One paraffin block was prepared for each\ncentimeter of tumor except in four cases (including two\nendometrioid carcinomas, one clear cell carcinoma on one\nside and seromucinous borderline tumor, and one muci-\nnous borderline tumor on the other side.)\n4.1. Genomic DNA Evaluation\nDue to inappropriate fixation technique and DNA de-\nstruction, the quality of genomic DNA for PCR study was\nnot acceptable in 6 out of 42 (14.3%) cases. Among the re-\nmaining 36 cases, KRAS mutation was observed in 6 (16.7%)\ncases. In two cases mutations in the 2nd base of the 12th\ncodon were (G→T) detected, which histological diagnosis\nof tumor type was seromucinous borderline tumor and\nclear cell carcinoma. In three cases substitution of G→A in\n2 Int J Cancer Manag. 2022; 15(7):e120754.\n\nSarmadi S et al.\nTable 1. Frequency of Epithelial Ovarian Tumors with and Without Endometriosis\nFinal Histological Diagnosis Number of Cases\nClear cell carcinoma 11\nEndometrioid carcinoma 18\nNon-invasive papillary tumor arising from\nendometrioid cyst\n1\nBilateral serous borderline and mucinous\nborderline tumor\n1\nEndometrioid borderline tumor 1\nSeromucinous borderline tumor 3\nMucinous borderline tumor 4\nSerous borderline tumor 3\nTotal 42\nthe 2nd base of the 12th codon was seen. Histological diag-\nnosis tumor types in these three cases were endometrioid\ncarcinoma, serous borderline tumor, and bilateral seromu-\ncinous borderline tumor. In one case with histological di-\nagnosis of clear cell carcinoma on one side and seromuci-\nnous borderline tumor, on the other side, substitution of\nG→T in the 1st base of the 12th codon was seen. The charac-\nteristics of tumors with KRAS mutations are shown in de-\ntail in Table 3.\n5. Discussion\nMutations in the KRAS gene occur in approximately\n20% of all human tumors. The occurrence of irreversible\nalteration of the 12th codon of KRAS gene has been found\nto be early during the development of lung adenocarci-\nnoma (13). Among gynecological pathologies, KRAS mu-\ntations were identified in endometrial hyperplasia with a\nsimilar prevalence to that found detected in endometrial\ncarcinoma, therefore, it is postulated that KRAS may play a\nrole in the early step of carcinogenesis (14-16).\nSimilarly , numerous studies have evaluated the asso-\nciation of ovarian epithelial tumors with KRAS mutations\n(13). Higher rate of KRAS mutation has been found in\nserous borderline tumors (27 - 36%) than in high-grade\nserous carcinoma (0 - 12%). Other studies showed that low-\ngrade and high-grade serous carcinomas have different\npathogenesis. The hypothesis of adenoma-carcinoma se-\nquence with KRAS or BRAF mutation has been suggested\nfor low-grade serous carcinomas which means progression\nfrom typical to micropapillary borderline tumors to low-\ngrade serous carcinoma (3, 4, 13-16). In our study , KRAS mu-\ntation was also detected in low-grade epithelial ovarian tu-\nmors FIGO stage I.\nThe association of endometriosis with ovarian ep-\nithelial tumors is well-established in the literature and\nsince Sampson first described this association in 1925,\nmany subsequent studies including molecular studies\nwere performed to discover the molecular pathway of\nendometriosis-associated tumor genesis (17). Among\nall ovarian epithelial tumors, clear cell carcinoma, en-\ndometrioid carcinoma, and seromucinous borderline tu-\nmor to a lesser extent, are associated with endometriosis\n(18). In some of the mentioned tumors, there is a contin-\nuum of the sequential morphological spectrum from en-\ndometriotic focus to tumor. In the current study , among\n36 epithelial tumors of different categories, KRAS muta-\ntion was found in 6 patients includingendometrioid car-\ncinoma, clear cell carcinoma, and seromucinous border-\nline tumor, while the association of KRAS mutation and tu-\nmor type was not statistically significant in our study but\nthis mutation occurred in three tumor types which are re-\nported to be highly associated with endometriosis.\nKRAS mutation has been reported to occur in approx-\nimately 10% of endometrial carcinomas, although the in-\ncidence of this mutation in various studies ranged from\n0% up to 36% (19-21). These significant variations in the\nreported frequency of KRAS mutation in endometriosis-\nassociated ovarian tumors can be due to the small sample\nsize and different histologic grades of the tumors (22-24).\nStwart et al. evaluated the molecular alterations in KRAS\ngene in endometrioid adenocarcinoma (FIGO grade 1 and\n2) including 42 patients with endometriosis-associated en-\ndometrioid adenocarcinoma and 29 patients with inde-\npendent endometrioid adenocarcinoma. KRAS mutation\nwas detected in 29% of the former while it was identified in\n3% of the latter. The study suggested KRAS mutations can\nplay a role in the pathogenesis of the former tumors (21).\nIn the present study , 18 out of a total of 42 cases were di-\nagnosed as endometrioid carcinoma with endometriosis.\nNine cases were well-differentiated and eleven cases had\naccompanying squamous metaplasia. KRAS mutation was\nfound in 2 (11%) cases of well-differentiated endometrioid\ncarcinoma. In both of the mentioned cases, KRAS mutation\nwas detected in the 2nd base of 12th codon G →A. One of\nthem had also atypical endometriosis. Both of them had\nsquamous metaplasia.\nAlthough the pathogenesis of endometriosis has not\nbeen fully elucidated, one of the current theories is ret-\nrograde transtubal spread, implantation and subsequent\nproliferation of endometrial tissue within ovaries and\nother peritoneal sites. Thus, endometriosis originates\nfrom eutopic endometrium. The similar spectrum of ge-\nnetic alteration in endometriosis-associated carcinomas\nand their uterine counterparts may support this theory\nof the origination of endometriosis (25). The presence\nof the same codon-KRAS mutation in two cases of en-\ndometriosis associated well-differentiated endometrioid\nInt J Cancer Manag. 2022; 15(7):e120754. 3\n\nSarmadi S et al.\nTable 2. Detailed Categorization of Epithelial Ovarian Tumors with and Without Endometriosis\nTumor Diagnosis Endometriosis Presence of Atypical Endometriosis\nEndometrioid carcinoma 12 2\nBilateral endometrioid carcinoma 1 1\nunilateral endometrioid carcinoma and endometrioid borderline tumor 1 -\nEndometrioid carcinoma in one side and serous borderline tumor in the other side 1 -\nUnilateral endometrioid and serous carcinoma 1 -\nUnilateral endometrioid and clear cell carcinoma 3 -\nClear cell carcinoma 7 3\nBilateral clear cell carcinoma 1 -\nClear cell carcinoma in one side and seromucinous borderline tumor , in the other side 1 1\nClear cell carcinoma in one side and endometrioid borderline tumor in the other side 1 1\nBilateral serous borderline tumor 1 -\nMucinous borderline tumor 4 -\nSeromucinous borderline tumor 3 1\nEndometrioid borderline tumor 1 -\nSerous borderline tumor 2 2\nBilateral serous borderline and mucinous borderline tumor 1 -\nNon-invasive papillary tumor arising from endometriotic cyst 1 1\nTotal 42 12\nTable 3. Frequency of Squamous Metaplasia, Degree of Differentiation and Tumor Stage in Patients with KRAS Mutation\nTumor Type Age Endometriosis Atypical\nEndometriosis\nSquamous\nMetaplasia\nDegree of\nDifferentiation\nFIGO Stage KRAS Mutation\nEndometrioid\ncarcinoma\n58 Yes Yes Yes Well differentiated IA 2nd base of 12th\ncodon G>A\nEndometrioid\ncarcinoma and\nserous borderline\ntumor\n38 Yes No Yes Well differentiated IC2 2nd base of 12th\ncodon G>A\nClear cell\ncarcinoma and\nseromucinous\nborderline tumor\n46 Yes Yes IA 1st base of 12th\ncodon G>T\nClear cell\ncarcinoma\n43 Yes No IC2 2nd base of 12th\ncodon G>T\nSeromucinous\nborderline tumor\n25 Yes No IA 2nd base of 12th\ncodon G>T\nBilateral\nseromucinous\nborderline tumor\n45 Yes Yes IB 2nd base of 12th\ncodon G>A\ncarcinoma, FIGO stage 1 with squamous metaplasia sup-\nports the hypothesis that endometriosis-associated well-\ndifferentiated endomerioid carcinoma progress through\ncertain molecular pathways which may have implications\nfor future treatment approaches including targeted thera-\npies of patients.\nIn a study by Otsuka et al. KRAS mutation was evaluated\nin 37 patients with clear cell carcinoma and mutation of\nKRAS was found in six cases. Three out of six specimens con-\ntained adjacent typical or atypical endometriosis. Molec-\nular studies using direct sequencing of the 12th codon in\ntumoral cells and adjacent atypical endometriotic areas\nwere performed separately . KRAS mutation was detected\nin tumoral areas but it was negative in adjacent foci of\nendometriosis. This observation postulated that ovarian\nclear cell carcinoma may arise from KRAS mutation in the\n4 Int J Cancer Manag. 2022; 15(7):e120754.\n\nSarmadi S et al.\nendometriotic part (26). In the present study , KRAS mu-\ntation was identified in only 2 out of 11(18%) cases of ovar-\nian clear cell carcinomas. Detected mutations were in the\n1st base of the 12th codon G →T the 2nd base of the 12th\ncodon G→T. Cuatrecasas et al. reported that the frequency\nof codon 12/13 KRAS gene mutations was 31.3% (5/16) in clear\ncell carcinomas and 36.4% (12/33) in endometrioid carcino-\nmas, and Okuda et al. found KRAS codon 12/13 mutations\nin 16.2% of clear cell carcinomas and 3.7% of endometrioid\ncarcinomas (22, 27, 28). In the present study , we detected\nKRAS codon 12/13 mutations in 18% of clear cell carcino-\nmas and 11% of endometrioid carcinomas with frequencies\ncloser to Okuda study . One possible explanation for dis-\ncrepancies between various studies is that the prevalence\nof KRAS mutations differs according to an ethnic group or\ngeographic region.\nIn 1993, Mok et al. performed a study to detect KRAS\nmutations in endometriosis-independent epithelial ovar-\nian neoplasms. KRAS mutation was found in 21 out of 44\nincluding 19 mucinous and 25 serous borderline tumor\ncases of this study . All of the cases had mutations in the\n12th codon except one mucinous borderline tumor with\nthe 13th codon mutation. In Mok series, KRAS mutation was\nseen in 12 out of 19 mucinous borderline tumors, includ-\ning 9 tumors with mutation of 2nd base of 12 codon G→T,\n2 cases of 2nd base of 12th codon G→A, and one case with\n2nd base G→A substitution (24).\nIn our study , KRAS mutation of the 2nd base of 12th\ncodon G→T and 2nd base of 12th codon G →A was also\nfound in two cases of seromucinous borderline tumor, and\nbilateral seromucinous borderline tumor, respectively .\nThese findings are in concurred with Mok series; also, in\nour study , all the cases with KRAS mutation were catego-\nrized as stage I. KRAS mutation is common in mucinous\novarian tumors and in seromucinous borderline tumors.\nThis genetic alteration has been identified in histologically\nbenign epithelium adjacent to borderline serous or mu-\ncinous elements suggesting that these mutations occur\nearly during neoplastic development (24, 26).\nOne of the advantages of the current study is the pres-\nence of several mixed ovarian epithelial tumors and de-\ntailed sequencing of the 12th and 13th KRAS codon; how-\never, there were some limitations regarding method of se-\nquencing. Sanger sequencing was the method used to de-\ntect mutations of KRAS gene. This method is unable to de-\ntect mutations that are present in less than 20% of tumor\ncells (29, 30). For detecting more mutated cells, new gener-\nation sequencing is helpful. In addition, in our study muta-\ntion of KRAS is assessed in the 12th and 13th codons. Other\ncodons such as 59th, 61st, and 146th may also have muta-\ntions that we did not evaluate in this study .\nIn conclusion, this is the first study , which evaluated\nthe association between endometriosis-associated mixed\novarian epithelial tumors and KRAS mutation. Our results\ndid not provide convincing evidence to prove a definite\nlinkage. However, only a few cases were included in this\nreport, and therefore further research will be needed to de-\nfine the role of KRAS in the development of endometriosis-\nassociated ovarian epithelial tumors.\nFootnotes\nAuthors’ Contribution: The authors contributed exten-\nsively to the work presented in this paper. Dr. Soheila Sar-\nmadi and Marzieh Fakhari helped in gathering data. Dr\nManiya Mozafari prepared and edited the article. Dr Reza\nShahsiah, Dr Narges Izadi-Mood and Dr. Rosa Miri helped\nin reviewing pathological reports and molecular studies.\nConflict of Interests: There are no conflict of interests.\nData Reproducibility: The data presented in this study\nare openly available in one of the repositories or will be\navailable on request from the corresponding author by\nthis journal representative at any time during submission\nor after publication. Otherwise, all consequences of possi-\nble withdrawal or future retraction will be with the corre-\nsponding author.\nFunding/Support: This study was supported in part by\ngrant 94-02-30-29436 from Tehran University of Medical\nSciences as thesis of Dr. Marzieh Fakhari (Dr. Soheila Sar-\nmadi).\nInformed Consent: No human subject was directly in-\nvolved in this study . We used only archived paraffin blocks\nand medical records.\nReferences\n1. 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