Common Dysregulated Genes in Endometriosis and Malignancies

► cancer ► endometriosis ► gene expression

Several authors have investigated the malignant transformation of endometriosis, which supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but there are few data about the pathways and molecular events related to this phenome- non. This review provides current data about deregulated genes that may function as key factors in the malignant transition of endometriotic lesions. In order to do so, we first searched for studies that have screen ed differential gene expression between endometriotic tissues and normal endometrial tissue of women without endometri- osis, and found only two articles with 139 deregulated genes. Further, using the PubMed database, we crossed the symbol of each gene with the terms related to malignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444 were studies about gene expres sion associated with speci fict y p e so ft u m o r .T h i s revealed that more than 68% of the analyzed genes are also deregulated in cancer. We have also found genes functioning as tumor suppressors and an oncogene. In this study, we present a list of 95 informative genes in order to understand the genetic components that may be responsible for endometriosis ’ malignant transformation. However, future studies should be conducted to con firm these findings. Resumo Vários autores têm estudado transformações malignas em endometriose que supor- tam a hipótese de um estado pré-neoplásico das lesões endometrióticas; contudo, existem poucos dados sobre as vias e eventos moleculares relacionados a este fenômeno. Esta revisão fornece dados atuais sobre genes desregulados que possam funcionar como fatores-chave para a transição maligna das lesões endometrióticas. Assim, inicialmente, estudos de expressão gênica diferencial em larga escala received November 19, 2015 accepted January 7, 2016 DOI http://dx.doi.org/ 10.1055/s-0036-1583293. ISSN 0100-7203. Copyright © 2016 by Thieme Publicações Ltda, Inc., Rio de Janeiro, Brazil THIEME Review Article 253

Endometriosis is a chronic gynecological disorder that af- fects nearly 10% of women in reproductive age worldwide.1 It is characterized by the existence of endometrial tissue outside the uterus, mainly ovary and pelvic peritoneum, and is related to pelvic pain and infertility symptoms in great part of the patients. 2,3 Although endometriosis is considered a benign disease, it shares some biological char- acteristics with cancer, like cell invasion, expansion of new blood vessels, unrestrained growth, resistance to apoptosis, potential to metastasize and occurrence of chronic inflammation. 4,5 Several investigations have focused on the malignant transformation of ectopic endometrial tissue, supporting the hypothesis of its pre-neoplastic state, predominantly in the ovary. 6–18 Studies have revealed that endometriotic lesions in endometriosis-associated ovarian cancer (and tumor) may go through multistep transition stages, from typical to atypical endometriosis, and then to carcino- ma.19,20 It has also been documented that the two major cancer histotypes related to the malignization of ovarian endometriosis are endometrioid and clear cell carcinomas, 21 and serous and mucinous carcinomas are encountered less frequently.22,23 Even though rare, the occurrence of the malignant transformation of endometriosis in other organs such as the colon and the rectum is reported, 24,25 including cases like endometriosis-associated abdominal wall cancer, which shows aggressiveness and poor prognosis. 21 Regarding the frequency, some authors have estimated the overall risk of 1% for the development of neoplasms from endometriotic tissue, but this percentage is supposed to be higher, since there are few studies of cancer arising from endometriosis available. 14,22 Besides, a great limita- tion to calculate the real risk of endometriosis ’ progression to malignancy is associated with the rigorous histopatho- logical criteria used to characterize this transition: proof of endometriotic foci close to the tumor; the carcinoma must arise from endometriosis, and not invade it from other sources; presence of tissue resembling endometrial stroma surrounding characteristic glands; and morphological dem- onstration of continuity between benign and malignant tissues within endometriosis. 26,27 Rarely all these stringent features are ful filled, leading to the underestimation of the malignant conversion of endometriotic tissue. 28 Moreover, another aggravating condition is that cancerous tissue probably destroys endometriotic foci, removing the histo- logical evidence of endometriosis ’ transformation to cancer. 28,29 Currently, molecular events that would clarify endome- triosis transformation into cancer are being researched. It is believed that epigenetic processes and somatic genetic changes in endometriotic implants could initiate tumorigen- esis. 5,30–32 Gogusev et al 33,34 showed that ectopic endome- trium in peritoneal implants and ovarian endometrioma have gain and loss of certain chromosomal regions that harbor genes representative of those involved in malignan- cies, such as oncogenes and tumor suppressors. However, the real frequency of these alterations and which genes really contribute to the benign –malign phenomenon in endome- triosis remain unknown. 28 The aim of this review is to identify in the literature deregulated genes in endometriotic lesions that may be involved with cancer pathways, explain malign transition from endometriosis, and bring new insights about the origin and development of endometriosis itself.

We performed two rounds of searches based on the survey of data available in PubMed (from 1985 to 2015) from articles published in English only. In the first round, we used the terms gene expression and endometriosis . The inclusion criteria were studies that have screened global differential gene expression (individual studies of a single gene expression were not included) and those that have compared endometriotic tissues and normal endometrial tissues of women without endometriosis. We did not consider the comparison between ectopic and eu- topic endometria of women with endometriosis since these tissues share biochemical and functional changes that are not detected in the endometria of women without endome- triosis. 35 We excluded from our search works in which: a) the absence and presence of endometriosis were not con firmed comparando tecido endometriótico e endométrio normal de mulheres sem endo- metriose foram procurados, e apenas dois a rtigos com 139 genes desregulados foram obtidos. Posteriormente, usando o banco de dados do PubMed, foram cruzados os símbolos de cada gene com termos relacionados à malignidade, como câncer e tumor,e 9.619 artigos foram obtidos, dos quais 444 eram estudos sobre expressão de genes associados a tipos especí ficos de tumor. Isto revela que mais de 68% dos genes analisados eram também desregulados em câncer. Também foram encontrados genes que funcionam como supressor tumoral e um oncogene. Este estudo apresenta uma lista de 95 genes informativos para compreender os componentes genéticos que possam ser responsáveis por transformações malignas na endometriose. Contudo, estudos futuros são necessários para con firmar estes achados. Palavras-chave ► câncer ► endometriose ► expressão gênica Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Common Dysregulated Genes Dentillo et al.254 by laparoscopy; and b) the patients had undergone hormonal therapy prior to the sample collection. In the second round, we crossed the symbol of each selected gene from the papers obtained in the first search with the terms: cancer, tumor, endometrioid carcinoma , clear cell carcinoma , serous carcinoma , mucinous carcinoma , onco- gene, and tumor suppressor gene . We just considered cancers and tumors in female organs, and genes with altered expres- sion in both endometriosis and cancer. Genetic polymor- phisms were not considered.

In the first search, we excluded 843 articles because we found just 2 studies that satis fied the established criteria. 36,37 Honda et al36 defined the profile of gene expression by serial analysis of gene expression (SAGE) using ovarian lesions as samples, and showed 34 deregulated genes. In another work published by our group, 37 we utilized samples of peritoneal lesions and ovarian endometriotic tissues and de fined 105 deregulated genes using rapid subtraction hybridization (RaSH). ITGB1, which encodes the integrin β-1 subunit, is the unique gene shared by both analyzed articles. In the two investigations, the control group of women and the endo- metriosis patients were at the proliferative phase of the menstrual cycle. In the second search, we obtained 9,619 articles that resulted from the match of each gene symbol with the specific terms. Among these articles, 444 of them were studies about gene expression associated with different types of tumor ( ►Table 1 ). We found that more than 68% of the genes deregulated in endometriosis were also deregu- lated in cancer. The list of genes with deregulated expression in the major cancer histotypes related to the malignization of endometri- osis is the following: clear cell carcinoma ( LDHA, RHOC, ILK, HLA-DRA, MMP2, ACTN4); endometrioid carcinoma ( ILK, HLA-DRA, MMP2, MMP7, ANAXA2 ); serous carcinoma (CRABP2, RHOC, SPARC, SP1, ILK, MMP2, MMP7, HLA-DRA, ACTN4, IGF2, ANAXA2 ); and mucinous carcinoma ( SP1, ILK, HLA-DRA). We have also found in the literature ENO1, TXNIP and SPARC acting as tumor suppressor genes and ID2 acting as an oncogene.

The investigations about the development of cancer from endometriosis initiated with Sampson (1925). 26 Since then, some publications and case reports have documented cancerous tissues forming within endometriotic lesions. 24,38–44 The majority of works that have tried to comprehend the malignant progression of endometriosis refers to the ovary, which is responsible for 80% of cases. 45 It is estimated that ovarian cancer develops in 1 to 5% of cases of ovarian endometriosis (10 to 20% endometrioid carcinoma and less than 5% clear cell carcinoma histotypes). 4,22,46 Nevertheless, if we take into account histological transition from benign to malign endometriosis, according to the description of Samp- son26 and Scott,27 its prevalence is estimated as 0.9%. Appar- ently, in patients with endometriosis the ovaries are more susceptible to malignization. 47,48 Findings from ultrasound assessment of carcinomas forming in endometrioid cysts point to some characteristics that are indicative of malignant transformation in the ovaries, 49 where a continuum of typi- cal and atypical endometriosis with transition to an inva- siveness condition was already found. 50 Indeed, the calculated risk of women developing ovarian cancer is two times higher compared with the general population, and after a follow-up period of over 10 years, this risk may increase 4.2-fold. 4,17 Although the ovary is the most affected organ by endometriosis-originated tumors, reports have recently showed that endometriosis is a risk factor for the development of endometrial cancer. 48,51 Even if infrequently, there have been reports of extra- ovarian sites affected by malignant transition from endo- metriotic implants. The organs most usually affected are the rectovaginal septum, the vagina, the urinary bladder and the colorectum (the last corresponding to 5%), but alterations in the pelvic ligaments, the umbilicus, the abdominal wall, the cervix, and the uterine tubes were also reported. However, no risk of ectopic endometrium conversion to cancer in these locations has been calculated. 21,22,52,53 The predicted incidence for ovarian and extraovarian malignization in endometriosis is an underestimate. Some of the reasons for this are: dif ficulty to ful fill Sampson’sa n d Scott’s criteria; excision of endometriotic foci is generally complete, and atypical unidenti fied lesions may be absent after surgery; the emerging cancerous cells can obliterate endometriotic lesions, removing the signs of a clear transi- tion of a benign to a malignant condition; some endometri- otic tissues are never treated surgically: they are only partially resected, preventing extensive sampling perfor- mance; and the number of investigations about the transi- tion between endometriosis and cancer is insuf ficient until now. 14,22,28,47,54 Even so, the cancerous potential of endometriosis should be carefully analyzed, for malignancy is often not recognized until a precise pathologic examination of the extirpated specimen. 54 Besides, in some cases malignancy can occur in residual remnant derived from an inadequate total endo- metriotic foci removal surgery. 55 In this way, most speci fi- cally for ovarian endometriosis, it is essential to run a detailed inspection and an effective surgical intervention, as epithelial ovarian cancer is the main cause of death among the female genital tract malignancies. 54 In patients with recurrent endometriosis, more incisive observation should be directed to a continued sampling of recurrences, once malignant transformation can take place. 56 Endometriosis ’ Malignant Transformation from the Molecular Point of View The malignization of endometriosis is considered according two main hypotheses. The first is that endometriotic lesions can directly go through cancerous transformation, maybe Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Common Dysregulated Genes Dentillo et al. 255 Table 1 Differentially expressed genes in endometriosis (endometr iotic lesions in comparison with endometrial tissue of women not affected by endometriosis) that have deregulated expression in cancer Symbol Locus Type of cancer or tumor Gene (Honda el at 36) RPS9 19q13.4 /C3 pancreatic, breast, brain ACTN4 19q13.2 /C3 breast, brain, bladder, oral, pancreas, ovary, liver, renal, esophageal, colorectal, lung, leukemia IGF2 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 nervous systems, rhabdomyosarcoma, esophageal, renal, gastric, uterine (cervix, endometrium and myometrium), liver, breast, ovary, head and neck, meninges, bone, lung, bladder, laryngeal, synovial, leukemia CHI3L1 1q32.1 brain, uterus (cervix and endo metrium), lung, breast, pancreas, gastric, lymphoma, renal, head and neck, melanoma, liver, colorectal, multiple myeloma, leukemia CEBPB 20q13.1 /C3 brain, gastric, bone, leukemia, lung, lymphoma, uterine cervix ITGB1 10p11.2 /C3 brain, gastric, rectal, oral, liver, lung, kidney, esophageal, leukemia EFEMP2 11q13.1 /C3 endometrium AXL 19q13.2 /C3 oral, bladder, breast, melanoma, thyroid, leukemia, liver, pancreas, ovary, esophageal, brain, renal, lung, gastric, bone, synovial, colorectal, uterus (endometrium, myometrium) DYNLRB1 20q11.22 liver PTBP1 19p13.3 /C3 brain, multiple myeloma JUND 19p13.11 breast, liposarcoma, oral, pancreas, brain, lung, lymphoma, colon, liver, melanoma, ovary PGK1 Xq21.1 liver, gastric, lung, pancreas, colon, renal SHC1 1q21.3 gastrointestinal, leukemia, breast, colon NNMT 11q23.2 /C3 bladder, renal, brain, oral, lung, liver, pancreas, colorectal, thyroid SMARCC2 12q13.2 /C3 lung ACTG1 17q25.3 /C3 bone, liver PPIE 1p32 /C3 brain, lung MRLC2 18p11.31 /C3 ovary HINT1 5q23.3 gastric, liver, colon RPS14 5q33.1 leukemia PAPSS2 10q23.2-q23.3 esophageal, gastric B3GNT5 3q28 /C3 brain ANXA2 15q22.2 pancreas, endometrium, liver, colon, breast, brain, multiple myeloma, lung, bone, leukemia GAPDH 12p13.31 ovarian, breast, brain, colorectal, lung, liver, thyroid, pancreas, renal, uterine cervix NUCB2 11p15.1 /C3 breast, gastric CAMLG 5q23 /C3 breast Gene (Dentillo et al 37) CRABP2 1q23.1 brain, head and neck, lung, oropharyngeal, renal, ovary, retina TH1L 20q13 /C3 breast, colorectal ATP5A1 18q21 /C3 colon, leukemia UBE1 Xp11.23 gastric, lymphoma, leukemia, multiple myeloma, lung TRIM28 19q13.4 /C3 breast, colorectal, gastric SOX17 8q11.23 liver, leukemia, breast, gastrointestinal, colorectal, gastric ENO1 1p36.2 /C3 gastric, thyroid, breast, lung, melanoma, brain, liver, colon, oral Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Common Dysregulated Genes Dentillo et al.256 Table 1 (Continued ) Symbol Locus Type of cancer or tumor XRCC5 2q35 /C3 liver, lung, uterine cervical, melanoma, multiple myeloma, breast PCBP1 2p13.3 pancreas, liver ID2 2p25 /C3 multiple myeloma, lung, lymphoma, liver, leukemia, breast, brain RNPS1 16p13.3 /C3 ovary LMO4 1p22.3 /C3 breast, pancreas, oral SMARCE1 17q21.2 /C3 breast PABPC1 8q22.3 /C3 esophageal, bladder PCBP2 12q13.13 oral FOSB 19q13.32 pancreas, colorectal, liver, breast, melanoma, endometrium, ovary IMPDH2 3p21.31 bone, colorectal, melanoma SRSF3 6p21 /C3 ovary, lymphoma SP1 12q13.13 breast, ovary, gastric, leukemia, pancreas, lung, melanoma, colorectal, endometrium, liver HNRPA1 12q13.13 colorectal, leukemia P4HB 17q25 /C3 endometrium PGK1 Xq13.3 gastric, pancreas, lung, colon PPIB 15q22.31 colorectal LDHA 11p15.1 /C3 retina, colorectal, uterine cervix PSAP 10q22.1 breast, bladder ACSL5 10q25.2 /C3 brain TCP1 6q25.3 colorectal LCMT1 16p12.1 /C3 brain TXNIP 1q21.1 head and neck, liver, gastrointestinal, breast, melanoma ACTG1 17q25 /C3 bone TP53I3 2p23.3 bladder RTN4 2p16.1 brain, liver HSPB1 7q11.23 /C3 head and neck, uterine cervix, leukemia, breast, ovary, liver, retina, gastric, brain, melanoma, pancreas, colorectal, esophageal, laryngeal DDAH2 6p21.3 /C3 ovary, breast NR2F2 15q26 /C3 lung, breast, lymphoma, salivary gland EIF4G2 11p15 /C3 brain, bladder TPT1 13q14 /C3 colon IFITM3 11p15.5 /C3 colon, rectal SERPINB6 6p25 /C3 colorectal RHOC 1p13.2 lung, tongue, uterine cervix, head and neck, breast, pancreatic, mela- noma, liver, renal, esophageal, gastric, colon, ovary, bladder TRAF3 1p34.2 /C3 pancreas GNB2L1 5q35.3 breast, lung, colon, oral, head and neck GNAS 20q13.3 /C3 ovary SPARC 5q33.1 lymphoma, brain, gastric, bladder, pancreas, lung, liver, ovary, melanoma, endometrium, colorectal STC1 8p21.2 colorectal, breast, ovary ECM1 1q21 /C3 breast, thyroid, esophageal, gastric, colorectal ID1 20q11 /C3 thyroid, lung, head and neck, ovary, gastric, breast, multiple myeloma CALM2 2p21 /C3 lymphoma (Continued ) Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Common Dysregulated Genes Dentillo et al. 257 after acquiring genetic alterations; in the second, it is specu- lated that endometriosis and cancer have common molecular mechanisms or share similar predisposing in fluences (such as genetic and immune deregulations, environmental fac - tors) that originate both diseases. 5,22,45 In any case, the genetic component is important, as it implies modi fications in cellular metabolism, which can lead to the malign state. Moreover, there are molecular genetics evidences that en- dometriosis is a precursor of ovarian carcinoma, even though all the genes and pathways implicated in this transition are yet unidentified. 57 Then, understanding the related process- es between endometriosis and cancer at a molecular level might clarify if the malignant condition can be a consequence of endometriosis or just a parallel phenomenon. The importance of this knowledge is directly related to the early diagnostics of malignancies in endometriosis patients as well as their prognosis, as it is reported that the risk of cancer may become greater in patients with a long history of endometriosis. 48,51,53,58 Furthermore, recognizing endo- metriotic lesions turning malignant would require different therapeutic management to treat adequately the two disor- ders concomitantly. 59 In reality, comprehending the malig- nant transformation of endometriosis would require a long- term survey of untreated cases, which is unfeasible for obvious reasons. 28 Due to that, finding other approaches that allow a reliable characterization of the endometriosis malignization occurrence would be desirable. Thereby, mo- lecular information can be a good tool. Previous works have shown that molecules like the in flammatory cytokine Il-1, growth factors and TNF- α are expressed in endometriosis, creating a condition comparable to the one found in malig- nancies. 4,17,60 Another work has detected overexpression of p53 in atypical endometriosis and cancer associated with endometriosis by immunohistochemistry. The authors con- cluded that the molecule may be used to identify endome- triosis with premalignant potential. 50 Additionally, genetic background obtained by observa- tions of endometriosis patients with familial cancer history suggests the role of genes favoring the onset of cancer. 61 Studies have also provided data which show that genomic instability in endometriosis may lead to mechanisms similar to those that cause carcinogenesis. 45,57 Using polymorphic Table 1 (Continued ) Symbol Locus Type of cancer or tumor EEF2 19p13.3 /C3 gastrointestinal, head and neck, lung HBB 11p15.5 /C3 breast ACTB 7p22 /C3 gastrointestinal, liver, lymphoma HSD3B2 1p12 /C3 adrenal, endometrium CFL1 11q13 /C3 breast, lung, colon, esophageal, leukemia, lymphoma CUL3 2q36.2 breast NGFRAP1 Xq22.2 ovary ITGB1 10p11.2 /C3 ovary, brain, gastric, rectal, oral, liver, lung, kidney, esophageal, leukemia CD81 11p15.5 /C3 brain, liver, multiple myeloma, lymphoma, leukemia ILK 11p15.4 bladder, colorectal, brain, lung, breast, ovary, head and neck, gastric, pancreas, thyroid H 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 SAT1 Xp22.1 /C3 bladder LGI1 10q24 /C3 brain, colorectal TMSB10 2p11.2 /C3 pancreas GSN 9q33 /C3 breast, leukemia PEBP1 12q24.23 pancreas, ovary, gastric, colorectal, liver, breast, melanoma, lymphoma, bladder ATP2A2 12q24.11 colon, lung, oral, colorectal TAGLN 11q23.2 /C3 colorectal, lung, bladder, esophageal, gastric HLA-DRA 6p21.32 liver, brain, breast, lung, ovary, lymphoma, melanoma, colon, leukemia MMP2 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 , renal, head and neck, breast, colorectal, thyroid MMP7 11q22.2 colorectal, breast, bladder, ovary, oral, pancreas, renal, lymphoma, lung, thyroid, endometrium, gastric, esophageal, colon Source: Data provided by the National Center for Biotechnology Information (NCBI) website. Note: /C3Indicates the loci (referring to breakpoints, loss or gain of the speci fic chromosomal region) that have been reported to be associated with every kind of cancer. Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Common Dysregulated Genes Dentillo et al.258 microsatellite markers from the 22 autosomal human chro- mosomes, Prowse et al offer indications that endometriotic lesions carry genetic changes that can originate cells with replicative advantages, equivalent to what happens in neo- plasms. 57 Another study from 2011 exposed common up and down-deregulated genes in both endometriosis and ovarian cancer.17 All of these findings put together denote a consis- tent link between endometriosis and cancer. Despite that, the precise groups of genes and molecules that may contrib- ute to endometriosis ’ malignant transformation are not completely elucidated. 62 A range of studies has evidenced clearly that the endome- trial tissue of women with endometriosis expresses a differ- ent repertoire of genes in relation to both ectopic endometrium and the endometrium of women not affected by the disease. 2,36,63–65 The paired comparison between eutopic endometrium versus endometriotic lesions has re- vealed an altered expression of some genes, such as CTGF, TP53 and MYC, which were already described as having a deregulating expression in cancer pathways as well. 2,66–69 However, the association of differentially expressed genes in a normal endometrium (without anatomical, histological and physiological alterations) and in endometriotic im- plants, evidencing their participation on cancerous process- es, has not been displayed until now. The result of our search shows a list of genes that exhibit different expression in endometriotic lesions and in the endometria of women without endometriosis. Of the total 139 gene sequences analyzed, we found that 95 (68.11%) also had altered expression in diverse types of cancer; moreover, a greater part of the genetic loci where the analyzed genes are has any relation to cancer ( ►Table 1 ). We think that these genes may participate in molecular pathways that generate cancer-like behavior in endometriosis, and are also related to endometriosis pathogenesis. Furthermore, these genes might also contribute to the malignization of endometriotic implants, as they play a role in carcinogenesis and could be used to explain the premalignant potential of endometriosis. One example is ITGB1, which is involved in cell adhesion, participates in the metastasis process and contributes to the malignant enhancement in ovarian cancer cells. 70–72 Obviously, for the description of a real involvement of these genes (presented in our work) with cancer one must do a direct comparison of cancerous and endometrial ectopic tissues. Moreover, for accurate results the use of suitable methodologies is essential, like real-time PCR, which cur- rently is the “gold standard” confirmative technique for gene expression investigation. However, the list of genes pre- sented here can trigger some insights regarding the path- ways or group of genes that should be include in studies related to endometriosis ’ malignization. We have also found genes deregulated in endometriosis and in the most frequent histotype of cancers, as well as genes that can function as tumor suppressors and oncogenes. These data expose the roles of some genes in cancerous processes in endometriosis, reinforcing its malignant trans- formation potential. Moreover, in our study some investigat- ed genes play roles related to cancer onset and development, such as cell invasion, metastasis enhancement (RHOC in melanoma and GNB2L1 in breast carcinoma), angiogenesis (PEPB1) and anti-apoptosis behavior ( HSPB1 in several can- cers, in which it was also referenced as a therapeutic tar- get). 73–76 Other genes are associated with more aggressive tumor behavior and poor clinical prognosis ( ID1 in breast, cervical and endometrial carcinomas, and ILK in a large number of malignancies). 77–81 The relationship of endometriosis and cancer in different types of organs does not imply that these tissues are in fact stricken directly by endometriosis. This statement aims to point to the frequency with which the genetic expression of each gene is deregulated in a variety of cancer types. At the same time, several authors have detected that having endo- metriosis itself may increase the risk of developing lympho- ma, melanoma and breast cancer, which are not associated with pelvic or abdominal organs. 22,82 However, this is based just on empiric observations and there is no available explanation about what mechanisms cause those elevated risks in women affected by endometriosis. Perhaps a tissue could have more susceptibility to malignant transformation or correlate better with certain organs depending on the biological microenvironment where endometriotic lesions implant themselves. 45

Endometriosis and cancer are complex, and heterogeneous disorders and malignization of endometrial ectopic im- plants must be considered particularly, as they might have more complicated provenance than each of the dis- eases individually. 45,83–85 Both entities can have their own proper pathogenesis associated with a particular gene or m 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 by a variety of environmental factors. Identifying genomic profiles that overlap in endometriosis and cancer in dis- tinct situations (such as stage and location) may provide clues to the understanding of the malignization of endo- metriotic lesions. 5,86 In our study, we ’ve presented a list of 95 informative genes in order to understand the genetic components responsible for endometriosis ’ malignant transformation. Conflict of Interest All authors declare that there are no con flicts of interest.

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