{"paper_id":"7732d898-88cd-4a44-baf5-03799bdbbda0","body_text":"Common Dysregulated Genes in Endometriosis\nand Malignancies\nG e n e sc o m u n sd e s r e g u l a d o se me n d o m e t r i o s eed o e n ç a s\nmalignas\nDaniel Blasioli Dentillo 1 Juliana Meola 1 Rui Alberto Ferriani 2 Julio César Rosa-e-Silva 3\n1 Department of Gynecology and Obstetrics, Faculdade de Medicina\nde Ribeirão Preto, Universidade de São Paulo – USP, Ribeirão Preto,\nSP, Brasil\n2 Human Reproduction Sector, Department of Gynecology and\nObstetrics, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão\nPreto, SP, Brasil\n3 Gynecology Surgery Sector, Department of Gynecology and\nObstetrics, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão\nPreto, SP, Brasil\nRev Bras Ginecol Obstet 2016;38:253 –262.\nAddress for correspondence Daniel Blasioli Dentillo, PhD,\nDepartamento de Ginecologia e Obstetrícia, Hospital das Clínicas da\nFMRP-USP, Avenida Bandeirantes, 3900, 8° andar, Monte Alegre,\nRibeirão Preto, SP, Brasil 14049-900 (e-mail: danieldentillo@usp.br).\nKeywords\n► cancer\n► endometriosis\n► gene expression\nAbstract Several authors have investigated the malignant transformation of endometriosis,\nwhich supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but\nthere are few data about the pathways and molecular events related to this phenome-\nnon. This review provides current data about deregulated genes that may function as\nkey factors in the malignant transition of endometriotic lesions. In order to do so, we\nfirst searched for studies that have screen ed differential gene expression between\nendometriotic tissues and normal endometrial tissue of women without endometri-\nosis, and found only two articles with 139 deregulated genes. Further, using the\nPubMed database, we crossed the symbol of each gene with the terms related to\nmalignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444\nwere studies about gene expres sion associated with speci fict y p e so ft u m o r .T h i s\nrevealed that more than 68% of the analyzed genes are also deregulated in cancer. We\nhave also found genes functioning as tumor suppressors and an oncogene. In this\nstudy, we present a list of 95 informative genes in order to understand the genetic\ncomponents that may be responsible for endometriosis ’ malignant transformation.\nHowever, future studies should be conducted to con firm these findings.\nResumo Vários autores têm estudado transformações malignas em endometriose que supor-\ntam a hipótese de um estado pré-neoplásico das lesões endometrióticas; contudo,\nexistem poucos dados sobre as vias e eventos moleculares relacionados a este\nfenômeno. Esta revisão fornece dados atuais sobre genes desregulados que possam\nfuncionar como fatores-chave para a transição maligna das lesões endometrióticas.\nAssim, inicialmente, estudos de expressão gênica diferencial em larga escala\nreceived\nNovember 19, 2015\naccepted\nJanuary 7, 2016\nDOI http://dx.doi.org/\n10.1055/s-0036-1583293.\nISSN 0100-7203.\nCopyright © 2016 by Thieme Publicações\nLtda, Inc., Rio de Janeiro, Brazil\nTHIEME\nReview Article 253\n\n\nIntroduction\nEndometriosis is a chronic gynecological disorder that af-\nfects nearly 10% of women in reproductive age worldwide.1 It\nis characterized by the existence of endometrial tissue\noutside the uterus, mainly ovary and pelvic peritoneum,\nand is related to pelvic pain and infertility symptoms in\ngreat part of the patients.\n2,3 Although endometriosis is\nconsidered a benign disease, it shares some biological char-\nacteristics with cancer, like cell invasion, expansion of new\nblood vessels, unrestrained growth, resistance to apoptosis,\npotential to metastasize and occurrence of chronic\ninflammation.\n4,5\nSeveral investigations have focused on the malignant\ntransformation of ectopic endometrial tissue, supporting\nthe hypothesis of its pre-neoplastic state, predominantly in\nthe ovary.\n6–18 Studies have revealed that endometriotic\nlesions in endometriosis-associated ovarian cancer (and\ntumor) may go through multistep transition stages, from\ntypical to atypical endometriosis, and then to carcino-\nma.19,20 It has also been documented that the two major\ncancer histotypes related to the malignization of ovarian\nendometriosis are endometrioid and clear cell carcinomas, 21\nand serous and mucinous carcinomas are encountered less\nfrequently.22,23 Even though rare, the occurrence of the\nmalignant transformation of endometriosis in other organs\nsuch as the colon and the rectum is reported, 24,25 including\ncases like endometriosis-associated abdominal wall cancer,\nwhich shows aggressiveness and poor prognosis. 21\nRegarding the frequency, some authors have estimated\nthe overall risk of 1% for the development of neoplasms\nfrom endometriotic tissue, but this percentage is supposed\nto be higher, since there are few studies of cancer arising\nfrom endometriosis available.\n14,22 Besides, a great limita-\ntion to calculate the real risk of endometriosis ’ progression\nto malignancy is associated with the rigorous histopatho-\nlogical criteria used to characterize this transition: proof of\nendometriotic foci close to the tumor; the carcinoma must\narise from endometriosis, and not invade it from other\nsources; presence of tissue resembling endometrial stroma\nsurrounding characteristic glands; and morphological dem-\nonstration of continuity between benign and malignant\ntissues within endometriosis.\n26,27 Rarely all these stringent\nfeatures are ful filled, leading to the underestimation of the\nmalignant conversion of endometriotic tissue. 28 Moreover,\nanother aggravating condition is that cancerous tissue\nprobably destroys endometriotic foci, removing the histo-\nlogical evidence of endometriosis ’ transformation to\ncancer.\n28,29\nCurrently, molecular events that would clarify endome-\ntriosis transformation into cancer are being researched. It is\nbelieved that epigenetic processes and somatic genetic\nchanges in endometriotic implants could initiate tumorigen-\nesis.\n5,30–32 Gogusev et al 33,34 showed that ectopic endome-\ntrium in peritoneal implants and ovarian endometrioma\nhave gain and loss of certain chromosomal regions that\nharbor genes representative of those involved in malignan-\ncies, such as oncogenes and tumor suppressors. However, the\nreal frequency of these alterations and which genes really\ncontribute to the benign –malign phenomenon in endome-\ntriosis remain unknown.\n28\nThe aim of this review is to identify in the literature\nderegulated genes in endometriotic lesions that may be\ninvolved with cancer pathways, explain malign transition\nfrom endometriosis, and bring new insights about the origin\nand development of endometriosis itself.\nMethods\nWe performed two rounds of searches based on the survey of\ndata available in PubMed (from 1985 to 2015) from articles\npublished in English only.\nIn the first round, we used the terms gene expression and\nendometriosis . The inclusion criteria were studies that have\nscreened global differential gene expression (individual\nstudies of a single gene expression were not included) and\nthose that have compared endometriotic tissues and normal\nendometrial tissues of women without endometriosis. We\ndid not consider the comparison between ectopic and eu-\ntopic endometria of women with endometriosis since these\ntissues share biochemical and functional changes that are\nnot detected in the endometria of women without endome-\ntriosis.\n35 We excluded from our search works in which: a) the\nabsence and presence of endometriosis were not con firmed\ncomparando tecido endometriótico e endométrio normal de mulheres sem endo-\nmetriose foram procurados, e apenas dois a rtigos com 139 genes desregulados foram\nobtidos. Posteriormente, usando o banco de dados do PubMed, foram cruzados os\nsímbolos de cada gene com termos relacionados à malignidade, como câncer e tumor,e\n9.619 artigos foram obtidos, dos quais 444 eram estudos sobre expressão de genes\nassociados a tipos especí ficos de tumor. Isto revela que mais de 68% dos genes\nanalisados eram também desregulados em câncer. Também foram encontrados genes\nque funcionam como supressor tumoral e um oncogene. Este estudo apresenta uma\nlista de 95 genes informativos para compreender os componentes genéticos que\npossam ser responsáveis por transformações malignas na endometriose. Contudo,\nestudos futuros são necessários para con firmar estes achados.\nPalavras-chave\n► câncer\n► endometriose\n► expressão gênica\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al.254\n\n\nby laparoscopy; and b) the patients had undergone hormonal\ntherapy prior to the sample collection.\nIn the second round, we crossed the symbol of each\nselected gene from the papers obtained in the first search\nwith the terms: cancer, tumor, endometrioid carcinoma , clear\ncell carcinoma , serous carcinoma , mucinous carcinoma , onco-\ngene, and tumor suppressor gene . We just considered cancers\nand tumors in female organs, and genes with altered expres-\nsion in both endometriosis and cancer. Genetic polymor-\nphisms were not considered.\nResults\nIn the first search, we excluded 843 articles because we found\njust 2 studies that satis fied the established criteria. 36,37\nHonda et al36 defined the profile of gene expression by serial\nanalysis of gene expression (SAGE) using ovarian lesions as\nsamples, and showed 34 deregulated genes. In another work\npublished by our group,\n37 we utilized samples of peritoneal\nlesions and ovarian endometriotic tissues and de fined 105\nderegulated genes using rapid subtraction hybridization\n(RaSH). ITGB1, which encodes the integrin β-1 subunit, is\nthe unique gene shared by both analyzed articles. In the two\ninvestigations, the control group of women and the endo-\nmetriosis patients were at the proliferative phase of the\nmenstrual cycle.\nIn the second search, we obtained 9,619 articles that\nresulted from the match of each gene symbol with the\nspecific terms. Among these articles, 444 of them were\nstudies about gene expression associated with different\ntypes of tumor (\n►Table 1 ). We found that more than 68%\nof the genes deregulated in endometriosis were also deregu-\nlated in cancer.\nThe list of genes with deregulated expression in the major\ncancer histotypes related to the malignization of endometri-\nosis is the following: clear cell carcinoma ( LDHA, RHOC, ILK,\nHLA-DRA, MMP2, ACTN4); endometrioid carcinoma ( ILK,\nHLA-DRA, MMP2, MMP7, ANAXA2 ); serous carcinoma\n(CRABP2, RHOC, SPARC, SP1, ILK, MMP2, MMP7, HLA-DRA,\nACTN4, IGF2, ANAXA2 ); and mucinous carcinoma ( SP1, ILK,\nHLA-DRA). We have also found in the literature ENO1, TXNIP\nand SPARC acting as tumor suppressor genes and ID2 acting\nas an oncogene.\nDiscussion\nThe investigations about the development of cancer from\nendometriosis initiated with Sampson (1925). 26 Since then,\nsome publications and case reports have documented\ncancerous tissues forming within endometriotic\nlesions.\n24,38–44\nThe majority of works that have tried to comprehend the\nmalignant progression of endometriosis refers to the ovary,\nwhich is responsible for 80% of cases. 45 It is estimated that\novarian cancer develops in 1 to 5% of cases of ovarian\nendometriosis (10 to 20% endometrioid carcinoma and less\nthan 5% clear cell carcinoma histotypes).\n4,22,46 Nevertheless,\nif we take into account histological transition from benign to\nmalign endometriosis, according to the description of Samp-\nson26 and Scott,27 its prevalence is estimated as 0.9%. Appar-\nently, in patients with endometriosis the ovaries are more\nsusceptible to malignization. 47,48 Findings from ultrasound\nassessment of carcinomas forming in endometrioid cysts\npoint to some characteristics that are indicative of malignant\ntransformation in the ovaries,\n49 where a continuum of typi-\ncal and atypical endometriosis with transition to an inva-\nsiveness condition was already found.\n50 Indeed, the\ncalculated risk of women developing ovarian cancer is two\ntimes higher compared with the general population, and\nafter a follow-up period of over 10 years, this risk may\nincrease 4.2-fold.\n4,17 Although the ovary is the most affected\norgan by endometriosis-originated tumors, reports have\nrecently showed that endometriosis is a risk factor for the\ndevelopment of endometrial cancer.\n48,51\nEven if infrequently, there have been reports of extra-\novarian sites affected by malignant transition from endo-\nmetriotic implants. The organs most usually affected are the\nrectovaginal septum, the vagina, the urinary bladder and the\ncolorectum (the last corresponding to 5%), but alterations in\nthe pelvic ligaments, the umbilicus, the abdominal wall, the\ncervix, and the uterine tubes were also reported. However,\nno risk of ectopic endometrium conversion to cancer in these\nlocations has been calculated.\n21,22,52,53\nThe predicted incidence for ovarian and extraovarian\nmalignization in endometriosis is an underestimate. Some\nof the reasons for this are: dif ficulty to ful fill Sampson’sa n d\nScott’s criteria; excision of endometriotic foci is generally\ncomplete, and atypical unidenti fied lesions may be absent\nafter surgery; the emerging cancerous cells can obliterate\nendometriotic lesions, removing the signs of a clear transi-\ntion of a benign to a malignant condition; some endometri-\notic tissues are never treated surgically: they are only\npartially resected, preventing extensive sampling perfor-\nmance; and the number of investigations about the transi-\ntion between endometriosis and cancer is insuf ficient until\nnow.\n14,22,28,47,54\nEven so, the cancerous potential of endometriosis should\nbe carefully analyzed, for malignancy is often not recognized\nuntil a precise pathologic examination of the extirpated\nspecimen.\n54 Besides, in some cases malignancy can occur\nin residual remnant derived from an inadequate total endo-\nmetriotic foci removal surgery.\n55 In this way, most speci fi-\ncally for ovarian endometriosis, it is essential to run a\ndetailed inspection and an effective surgical intervention,\nas epithelial ovarian cancer is the main cause of death among\nthe female genital tract malignancies.\n54 In patients with\nrecurrent endometriosis, more incisive observation should\nbe directed to a continued sampling of recurrences, once\nmalignant transformation can take place.\n56\nEndometriosis ’ Malignant Transformation\nfrom the Molecular Point of View\nThe malignization of endometriosis is considered according\ntwo main hypotheses. The first is that endometriotic lesions\ncan directly go through cancerous transformation, maybe\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al. 255\n\n\nTable 1 Differentially expressed genes in endometriosis (endometr iotic lesions in comparison with endometrial tissue of women\nnot affected by endometriosis) that have deregulated expression in cancer\nSymbol Locus Type of cancer or tumor\nGene (Honda el at 36)\nRPS9 19q13.4 /C3 pancreatic, breast, brain\nACTN4 19q13.2 /C3 breast, brain, bladder, oral, pancreas, ovary, liver, renal, esophageal,\ncolorectal, lung, leukemia\nIGF2 11p15 /C3 a d r e n a l ,c o l o r e c t a l ,b r a i n ,p a n c r e a s ,m e l a n o m a ,p e r i p h e r a la n dc e n t r a l\nnervous systems, rhabdomyosarcoma, esophageal, renal, gastric, uterine\n(cervix, endometrium and myometrium), liver, breast, ovary, head and\nneck, meninges, bone, lung, bladder, laryngeal, synovial, leukemia\nCHI3L1 1q32.1 brain, uterus (cervix and endo metrium), lung, breast, pancreas, gastric,\nlymphoma, renal, head and neck, melanoma, liver, colorectal, multiple\nmyeloma, leukemia\nCEBPB 20q13.1 /C3 brain, gastric, bone, leukemia, lung, lymphoma, uterine cervix\nITGB1 10p11.2 /C3 brain, gastric, rectal, oral, liver, lung, kidney, esophageal, leukemia\nEFEMP2 11q13.1 /C3 endometrium\nAXL 19q13.2 /C3 oral, bladder, breast, melanoma, thyroid, leukemia, liver, pancreas, ovary,\nesophageal, brain, renal, lung, gastric, bone, synovial, colorectal, uterus\n(endometrium, myometrium)\nDYNLRB1 20q11.22 liver\nPTBP1 19p13.3 /C3 brain, multiple myeloma\nJUND 19p13.11 breast, liposarcoma, oral, pancreas, brain, lung, lymphoma, colon, liver,\nmelanoma, ovary\nPGK1 Xq21.1 liver, gastric, lung, pancreas, colon, renal\nSHC1 1q21.3 gastrointestinal, leukemia, breast, colon\nNNMT 11q23.2\n/C3 bladder, renal, brain, oral, lung, liver, pancreas, colorectal, thyroid\nSMARCC2 12q13.2 /C3 lung\nACTG1 17q25.3 /C3 bone, liver\nPPIE 1p32 /C3 brain, lung\nMRLC2 18p11.31 /C3 ovary\nHINT1 5q23.3 gastric, liver, colon\nRPS14 5q33.1 leukemia\nPAPSS2 10q23.2-q23.3 esophageal, gastric\nB3GNT5 3q28\n/C3 brain\nANXA2 15q22.2 pancreas, endometrium, liver, colon, breast, brain, multiple myeloma,\nlung, bone, leukemia\nGAPDH 12p13.31 ovarian, breast, brain, colorectal, lung, liver, thyroid, pancreas, renal,\nuterine cervix\nNUCB2 11p15.1 /C3 breast, gastric\nCAMLG 5q23 /C3 breast\nGene (Dentillo et al 37)\nCRABP2 1q23.1 brain, head and neck, lung, oropharyngeal, renal, ovary, retina\nTH1L 20q13 /C3 breast, colorectal\nATP5A1 18q21 /C3 colon, leukemia\nUBE1 Xp11.23 gastric, lymphoma, leukemia, multiple myeloma, lung\nTRIM28 19q13.4 /C3 breast, colorectal, gastric\nSOX17 8q11.23 liver, leukemia, breast, gastrointestinal, colorectal, gastric\nENO1 1p36.2\n/C3 gastric, thyroid, breast, lung, melanoma, brain, liver, colon, oral\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al.256\n\n\nTable 1 (Continued )\nSymbol Locus Type of cancer or tumor\nXRCC5 2q35 /C3 liver, lung, uterine cervical, melanoma, multiple myeloma, breast\nPCBP1 2p13.3 pancreas, liver\nID2 2p25 /C3 multiple myeloma, lung, lymphoma, liver, leukemia, breast, brain\nRNPS1 16p13.3 /C3 ovary\nLMO4 1p22.3 /C3 breast, pancreas, oral\nSMARCE1 17q21.2 /C3 breast\nPABPC1 8q22.3 /C3 esophageal, bladder\nPCBP2 12q13.13 oral\nFOSB 19q13.32 pancreas, colorectal, liver, breast, melanoma, endometrium, ovary\nIMPDH2 3p21.31 bone, colorectal, melanoma\nSRSF3 6p21\n/C3 ovary, lymphoma\nSP1 12q13.13 breast, ovary, gastric, leukemia, pancreas, lung, melanoma, colorectal,\nendometrium, liver\nHNRPA1 12q13.13 colorectal, leukemia\nP4HB 17q25 /C3 endometrium\nPGK1 Xq13.3 gastric, pancreas, lung, colon\nPPIB 15q22.31 colorectal\nLDHA 11p15.1\n/C3 retina, colorectal, uterine cervix\nPSAP 10q22.1 breast, bladder\nACSL5 10q25.2 /C3 brain\nTCP1 6q25.3 colorectal\nLCMT1 16p12.1 /C3 brain\nTXNIP 1q21.1 head and neck, liver, gastrointestinal, breast, melanoma\nACTG1 17q25\n/C3 bone\nTP53I3 2p23.3 bladder\nRTN4 2p16.1 brain, liver\nHSPB1 7q11.23\n/C3 head and neck, uterine cervix, leukemia, breast, ovary, liver, retina,\ngastric, brain, melanoma, pancreas, colorectal, esophageal, laryngeal\nDDAH2 6p21.3 /C3 ovary, breast\nNR2F2 15q26 /C3 lung, breast, lymphoma, salivary gland\nEIF4G2 11p15 /C3 brain, bladder\nTPT1 13q14 /C3 colon\nIFITM3 11p15.5 /C3 colon, rectal\nSERPINB6 6p25 /C3 colorectal\nRHOC 1p13.2 lung, tongue, uterine cervix, head and neck, breast, pancreatic, mela-\nnoma, liver, renal, esophageal, gastric, colon, ovary, bladder\nTRAF3 1p34.2 /C3 pancreas\nGNB2L1 5q35.3 breast, lung, colon, oral, head and neck\nGNAS 20q13.3\n/C3 ovary\nSPARC 5q33.1 lymphoma, brain, gastric, bladder, pancreas, lung, liver, ovary, melanoma,\nendometrium, colorectal\nSTC1 8p21.2 colorectal, breast, ovary\nECM1 1q21\n/C3 breast, thyroid, esophageal, gastric, colorectal\nID1 20q11 /C3 thyroid, lung, head and neck, ovary, gastric, breast, multiple myeloma\nCALM2 2p21 /C3 lymphoma\n(Continued )\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al. 257\n\n\nafter acquiring genetic alterations; in the second, it is specu-\nlated that endometriosis and cancer have common molecular\nmechanisms or share similar predisposing in fluences (such\nas genetic and immune deregulations, environmental fac -\ntors) that originate both diseases. 5,22,45 In any case, the\ngenetic component is important, as it implies modi fications\nin cellular metabolism, which can lead to the malign state.\nMoreover, there are molecular genetics evidences that en-\ndometriosis is a precursor of ovarian carcinoma, even though\nall the genes and pathways implicated in this transition are\nyet unidentified.\n57 Then, understanding the related process-\nes between endometriosis and cancer at a molecular level\nmight clarify if the malignant condition can be a consequence\nof endometriosis or just a parallel phenomenon.\nThe importance of this knowledge is directly related to the\nearly diagnostics of malignancies in endometriosis patients\nas well as their prognosis, as it is reported that the risk of\ncancer may become greater in patients with a long history of\nendometriosis.\n48,51,53,58 Furthermore, recognizing endo-\nmetriotic lesions turning malignant would require different\ntherapeutic management to treat adequately the two disor-\nders concomitantly. 59 In reality, comprehending the malig-\nnant transformation of endometriosis would require a long-\nterm survey of untreated cases, which is unfeasible for\nobvious reasons.\n28 Due to that, finding other approaches\nthat allow a reliable characterization of the endometriosis\nmalignization occurrence would be desirable. Thereby, mo-\nlecular information can be a good tool. Previous works have\nshown that molecules like the in flammatory cytokine Il-1,\ngrowth factors and TNF- α are expressed in endometriosis,\ncreating a condition comparable to the one found in malig-\nnancies.\n4,17,60 Another work has detected overexpression of\np53 in atypical endometriosis and cancer associated with\nendometriosis by immunohistochemistry. The authors con-\ncluded that the molecule may be used to identify endome-\ntriosis with premalignant potential.\n50\nAdditionally, genetic background obtained by observa-\ntions of endometriosis patients with familial cancer history\nsuggests the role of genes favoring the onset of cancer. 61\nStudies have also provided data which show that genomic\ninstability in endometriosis may lead to mechanisms similar\nto those that cause carcinogenesis. 45,57 Using polymorphic\nTable 1 (Continued )\nSymbol Locus Type of cancer or tumor\nEEF2 19p13.3 /C3 gastrointestinal, head and neck, lung\nHBB 11p15.5 /C3 breast\nACTB 7p22 /C3 gastrointestinal, liver, lymphoma\nHSD3B2 1p12 /C3 adrenal, endometrium\nCFL1 11q13 /C3 breast, lung, colon, esophageal, leukemia, lymphoma\nCUL3 2q36.2 breast\nNGFRAP1 Xq22.2 ovary\nITGB1 10p11.2\n/C3 ovary, brain, gastric, rectal, oral, liver, lung, kidney, esophageal, leukemia\nCD81 11p15.5 /C3 brain, liver, multiple myeloma, lymphoma, leukemia\nILK 11p15.4 bladder, colorectal, brain, lung, breast, ovary, head and neck, gastric,\npancreas, thyroid\nH T R A 1 1 0 q 2 6 . 1 3 l i v e r ,o v a r y ,e n d o m e t r i u m ,l u n g ,m e l a n o m a\nSAT1 Xp22.1 /C3 bladder\nLGI1 10q24 /C3 brain, colorectal\nTMSB10 2p11.2 /C3 pancreas\nGSN 9q33 /C3 breast, leukemia\nPEBP1 12q24.23 pancreas, ovary, gastric, colorectal, liver, breast, melanoma, lymphoma,\nbladder\nATP2A2 12q24.11 colon, lung, oral, colorectal\nTAGLN 11q23.2\n/C3 colorectal, lung, bladder, esophageal, gastric\nHLA-DRA 6p21.32 liver, brain, breast, lung, ovary, lymphoma, melanoma, colon, leukemia\nMMP2 16q12.2 /C3 m e l a n o m a ,b r a i n ,o v a r y ,e n d o m e t r i u m ,l i v e r ,b l a d d e r ,g a s t r i c ,l u n g ,o r a l ,\nrenal, head and neck, breast, colorectal, thyroid\nMMP7 11q22.2 colorectal, breast, bladder, ovary, oral, pancreas, renal, lymphoma, lung,\nthyroid, endometrium, gastric, esophageal, colon\nSource: Data provided by the National Center for Biotechnology Information (NCBI) website.\nNote: /C3Indicates the loci (referring to breakpoints, loss or gain of the speci fic chromosomal region) that have been reported to be associated with\nevery kind of cancer.\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al.258\n\n\nmicrosatellite markers from the 22 autosomal human chro-\nmosomes, Prowse et al offer indications that endometriotic\nlesions carry genetic changes that can originate cells with\nreplicative advantages, equivalent to what happens in neo-\nplasms.\n57 Another study from 2011 exposed common up and\ndown-deregulated genes in both endometriosis and ovarian\ncancer.17 All of these findings put together denote a consis-\ntent link between endometriosis and cancer. Despite that,\nthe precise groups of genes and molecules that may contrib-\nute to endometriosis ’ malignant transformation are not\ncompletely elucidated.\n62\nA range of studies has evidenced clearly that the endome-\ntrial tissue of women with endometriosis expresses a differ-\nent repertoire of genes in relation to both ectopic\nendometrium and the endometrium of women not affected\nby the disease.\n2,36,63–65 The paired comparison between\neutopic endometrium versus endometriotic lesions has re-\nvealed an altered expression of some genes, such as CTGF,\nTP53 and MYC, which were already described as having a\nderegulating expression in cancer pathways as well.\n2,66–69\nHowever, the association of differentially expressed genes in\na normal endometrium (without anatomical, histological\nand physiological alterations) and in endometriotic im-\nplants, evidencing their participation on cancerous process-\nes, has not been displayed until now.\nThe result of our search shows a list of genes that exhibit\ndifferent expression in endometriotic lesions and in the\nendometria of women without endometriosis. Of the total\n139 gene sequences analyzed, we found that 95 (68.11%) also\nhad altered expression in diverse types of cancer; moreover,\na greater part of the genetic loci where the analyzed genes\nare has any relation to cancer (\n►Table 1 ). We think that these\ngenes may participate in molecular pathways that generate\ncancer-like behavior in endometriosis, and are also related to\nendometriosis pathogenesis. Furthermore, these genes\nmight also contribute to the malignization of endometriotic\nimplants, as they play a role in carcinogenesis and could be\nused to explain the premalignant potential of endometriosis.\nOne example is ITGB1, which is involved in cell adhesion,\nparticipates in the metastasis process and contributes to the\nmalignant enhancement in ovarian cancer cells.\n70–72\nObviously, for the description of a real involvement of\nthese genes (presented in our work) with cancer one must do\na direct comparison of cancerous and endometrial ectopic\ntissues. Moreover, for accurate results the use of suitable\nmethodologies is essential, like real-time PCR, which cur-\nrently is the “gold standard” confirmative technique for gene\nexpression investigation. However, the list of genes pre-\nsented here can trigger some insights regarding the path-\nways or group of genes that should be include in studies\nrelated to endometriosis ’ malignization.\nWe have also found genes deregulated in endometriosis\nand in the most frequent histotype of cancers, as well as\ngenes that can function as tumor suppressors and oncogenes.\nThese data expose the roles of some genes in cancerous\nprocesses in endometriosis, reinforcing its malignant trans-\nformation potential. Moreover, in our study some investigat-\ned genes play roles related to cancer onset and development,\nsuch as cell invasion, metastasis enhancement (RHOC in\nmelanoma and GNB2L1 in breast carcinoma), angiogenesis\n(PEPB1) and anti-apoptosis behavior ( HSPB1 in several can-\ncers, in which it was also referenced as a therapeutic tar-\nget).\n73–76 Other genes are associated with more aggressive\ntumor behavior and poor clinical prognosis ( ID1 in breast,\ncervical and endometrial carcinomas, and ILK in a large\nnumber of malignancies). 77–81\nThe relationship of endometriosis and cancer in different\ntypes of organs does not imply that these tissues are in fact\nstricken directly by endometriosis. This statement aims to\npoint to the frequency with which the genetic expression of\neach gene is deregulated in a variety of cancer types. At the\nsame time, several authors have detected that having endo-\nmetriosis itself may increase the risk of developing lympho-\nma, melanoma and breast cancer, which are not associated\nwith pelvic or abdominal organs.\n22,82 However, this is based\njust on empiric observations and there is no available\nexplanation about what mechanisms cause those elevated\nrisks in women affected by endometriosis. Perhaps a tissue\ncould have more susceptibility to malignant transformation\nor correlate better with certain organs depending on the\nbiological microenvironment where endometriotic lesions\nimplant themselves.\n45\nConclusion\nEndometriosis and cancer are complex, and heterogeneous\ndisorders and malignization of endometrial ectopic im-\nplants must be considered particularly, as they might\nhave more complicated provenance than each of the dis-\neases individually.\n45,83–85 Both entities can have their own\nproper pathogenesis associated with a particular gene or\nm u l t i p l eg e n e t i cl o c ia n dp a t h w a y s ,a sw e l la sb ea f f e c t e d\nby a variety of environmental factors. Identifying genomic\nprofiles that overlap in endometriosis and cancer in dis-\ntinct situations (such as stage and location) may provide\nclues to the understanding of the malignization of endo-\nmetriotic lesions.\n5,86 In our study, we ’ve presented a list of\n95 informative genes in order to understand the genetic\ncomponents responsible for endometriosis ’ malignant\ntransformation.\nConflict of Interest\nAll authors declare that there are no con flicts of interest.\nReferences\n1 Fourquet J, Báez L, Figueroa M, Iriarte RI, Flores I. Quanti fication\nof the impact of endometriosis symptoms on health-related\nquality of life and work productivity. Fertil Steril 2011;96(1):\n107–112\n2 Meola J, Rosa e Silva JC, Dentillo DB, et al. Differentially expressed\ngenes in eutopic and ectopic endometrium of women with\nendometriosis. Fertil Steril 2010;93(6):1750 –1773\n3 Michaud N, Al-Akoum M, Gagnon G, et al. 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Fertil\nSteril 2005;83(Suppl 1):1134 –1143\nRev Bras Ginecol Obstet Vol. 38 No. 5/2016\nCommon Dysregulated Genes Dentillo et al. 261","source_license":"CC-BY-4.0","license_restricted":false}