Human Reproduction Update Advance Access originally published online on September 19, 2005
Human Reproduction Update 2006 12(1):77-89; doi:10.1093/humupd/dmi037
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Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis
Department of Obstetrics, Gynecology and Neonatology, Fondazione ‘Policlinico–Mangiagalli–Regina Elena’, Milan, Italy
1 To whom correspondence should be addressed at: Department of Obstetrics, Gynecology and Neonatology, Fondazione ‘Policlinico–Mangiagalli–Regina Elena’, Via Commenda 12, 20122 Milan, Italy. E-mail: paola.vigano{at}unimi.it
Submitted on June 1, 2005; accepted on July 29, 2005
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Abstract |
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 TOP Abstract IntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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Although population-based studies have unequivocally reported an increased risk of ovarian cancer in women with endometriosis, the biological evidence supporting the idea of endometriosis as a preneoplastic condition is scanty and not well substantiated. The fundamental features of human neoplasms (monoclonal growth, genetic changes, mutations in tumour suppressor genes and replicative advantage) have been evaluated in endometriotic lesions but results obtained are discordant. It is plausible that ectopic glands may expand monoclonally but the entity of this phenomenon is debated. According to some allelotyping studies, from one-third to one-half of endometriosis lesions would harbour somatic genetic changes in chromosomal regions supposed to contain genes involved in ovarian tumourigenesis, especially for the endometrioid histotype. These findings would be consistent with the progression model for carcinogenesis from the benign precursor to ovarian cancer but they could not be unequivocally replicated. Gene mutational studies are rare in this context. A single group has found missense mutations and deletions of PTEN gene in about 20% of ovarian endometriotic cysts. Moreover, in a model of genetically engineered mice harbouring an oncogenic allele of K-ras resulting in benign lesions reminiscent of endometriosis, a conditional deletion of PTEN caused the progression towards the endometrioid tumour. Based on these data, the causal link between endometriosis and ovarian endometrioid/clear cell carcinomas remains to be defined both in terms of entity of association and of undelying molecular mechanisms.
Key words: endometriosis / malignant transformation of endometriosis / molecular mechanisms
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Introduction |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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The relationship between endometriosis and ovarian cancer is an intriguing and still poorly investigated issue. It has been suggested that endometriosis may be associated with a definitive risk of malignancy (Ness, 2003
). Specifically, histological findings indicate an association between endometriosis and endometrioid/clear cell carcinoma of the ovary (Vercellini et al., 1993) and recent large population-based cohort studies have reported a slightly higher incidence of ovarian cancer in women with endometriosis with standardized incidence ratio varying between 1.3 and 1.9 (Brinton et al., 1997; Brinton et al., 2004). However, confounders have not been always controlled adequately so that a precise estimation of the prevalence of these associations is still lacking. More importantly, current evidence is insufficient to deduce a causative relationship between endometriosis and ovarian cancer. Indeed, scientific attention has been focussed on the potential development of cancer from pre-existing endometriosis but the scenario can well be broader, as endometriosis and cancer may share similar risk factors and/or antecedent mechanisms.
Studies addressing the malignant potential of endometriosis are utterly needed but very troublesome. Although epidemiological studies have to face the difficulty in determining the exact incidence of endometriosis in the general population (Holt and Weiss, 2000; Zondervan et al., 2002), problems of cellular heterogeneicity and sample collection hamper the molecular analysis of perturbations at specific causative loci common to endometriosis and cancer, which should eventually confirm the existence of a mechanism of tumourigenesis conforming to a progression model. The result is that we are years of research away from knowing the entity of the risk for endometriosis to undergo malignant transformation, to understand the molecular bases and even less to have a cellular marker for this event.
This review aims to represent a comprehensive tool for those approaching this problem. It describes the molecular studies performed so far to evaluate the malignant potential of endometriosis. To give the reader a useful instrument, a critical analysis of problems and limits related to these studies will be also reported. Finally, different explanations for the association between endometriosis and ovarian cancer will be offered.
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Clonality of the endometriosis lesions |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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Clonal outgrowth is thought to be a fundamental feature of all human neoplasms (Levy, 2001
). One cancer cell gives rise to daughter cells, all of which exhibit the same change that initially provided a growth advantage to the parent cells. Accumulation of further genetic changes in subsequent daughter cells, each providing an additional growth advantage has been well documented in human cancer. Therefore, the clonality of a cellular expansion is taken to be a valuable tool capable of distinguishing an irreversible and potentially inexorably progressive process induced by an intracellular insult, from a possible reversible or self-limiting trophic response to environmental signals (Levy, 2001). Although the dogma surrounding the monoclonal origin of cancers is well entrenched (for definition of terminology see Table I), many technical constraints and sources of experimental bias associated with clonality analyses often confound the appropriate interpretation of the information obtained (Sidransky, 1995; Levy, 2001).
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Most of the methods used to establish clonal architecture in tissue are based on the principle that, at around the time of implantation during early female embryogenesis, each cell randomly but permanently inactivates genes on either the maternally or paternally derived X chromosome by cytosine methylation of promoter regions. Once methylated, the pattern of functional inactivation is stably inherited by the progeny of each cell throughout the lifetime, even when the cell becomes neoplastic. Thus, all adult female tissue should consist of a mosaic of cells in each of which genes on either the maternal or paternal X chromosome have been inactivated. In contrast, a cellular expansion characterized by the inactivation of a unique X chromosome must represent the progeny of a single cell (Levy, 2001). Therefore, clonality analysis depends firstly on being able to distinguish between different X chromosome alleles in a heterozygote and secondly on being able to establish which of the two X chromosomes is active on the basis of their methylation pattern. Genes located on the X chromosome characterized by a polymorphism and harbouring a restriction site for a methylation-sensitive endonuclease can be used to reveal the clonality status, such as those encoding phosphoglycerate kinase (PGK) and hypoxanthine phosphoribosyltransferase (HPRT), for which over 50% of females are informative (Vogelstein et al., 1987; Levy, 2001). More recently, methods were developed that exploited X-linked DNA polymorphisms consisting of variable number of tandem repeats. Of these polymorphisms, the human androgen receptor gene (HUMARA) has a highly polymorphic trinucleotide CAG repeat in the first exon that is 90% informative for female specimens evaluated (Levy, 2001).
The technical issues potentially confounding interpretation of clonality data include the fact that tumours are a mixture of tumour cells and other non-tumour elements, which together skew the methylation pattern towards polyclonality (Levy, 2001). A further bias may depend upon the average patch size of the native tissue being assessed that, if large relative to sample size, may mask a polyclonal cellular expansion. Finally, clonal assessment is based on the assumption that the methylation pattern is essentially conserved even during the neoplastic change which is not necessarily the case because the expression of the gene encoding DNA methyltransferase is regulated with the proliferative state of the cells and also potentially up-regulated by cellular oncogenic pathways (Levy, 2001). The HUMARA gene locus, in particular, is thought to display an unstable methylation pattern even in non-malignant cells thus representing a poorly adequate marker of X chromosome inactivation (Jang and Mao, 2000; Sakurazawa et al., 2000). It is probably for all these technical issues that the question regarding the clonality of endometriosis lesions remains still controversial.
Eight studies have addressed the clonality status of endometriosis lesions so far (Nilbert et al., 1995; Jiang et al., 1996; Jimbo et al., 1997, 1999; Tamura et al., 1998; Mayr et al., 2003; Nabeshima et al., 2003; Wu et al., 2003). Table II summarizes polymorphic markers used and number/type of endometriotic tissues evaluated by the different studies. Because in studies on endometriosis all patients are naturally female, clonality can be easily determined by analyzing the X chromosome inactivation pattern; four of these studies used the HUMARA gene as an X-linked polymorphic marker, three used PGK and one used both. In general, the studies support the monoclonal origin of endometriosis lesions. However, the first studies have been criticized for the limited number of samples evaluated. Others might have suffered of some contamination of the samples. Indeed, since it is a general agreement that the stromal components of the ectopic endometrium are polyclonal (Jimbo et al., 1997), the precise capture of epithelial cells from the lesion lining is critical to the accuracy of the analysis. Thus, some degree of contamination from stromal cells might have hampered a correct clonal evaluation of the epithelial component.
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More recently, the idea of the monoclonal origin has been challenged. Indeed, the two studies that have evaluated by far the largest number of sample size and that have been particularly cautious in the separation of the epithelial component have both been published in 2003 and they are in complete disagreement (Mayr et al., 2003; Wu et al., 2003). The study protocols were similar between the two: laser capture microdissection was used to harvest epithelial cells from single or multiple foci which were located in various sites other than ovary and derived from paraffin-embedded or frozen tissues. The main difference was the clonality assay being HUMARA-based in the study of Wu et al. (2003) and PGK-based in that of Mayr et al. (2003). Wu et al. (2003) have analysed 38 specimens from 18 informative patients and found that all these lesions were monoclonal; in case of multifocal foci, different foci had independent origins. Mayr et al. (2003) have analysed 32 samples from 13 informative patients. Thirty of the 32 samples assayed displayed a polyclonal restriction pattern, the remaining two being monoclonal. Therefore, only 15.4% of all informative patients analysed in the study beared monoclonal tissue (Mayr et al., 2003). The more recent study by Nabeshima et al. (2003) has used both PGK and HUMARA as clonal markers and has reported intriguing and again different results. Microdissected individual glands of any peritoneal endometriotic lesion evaluated showed a monoclonal pattern while adjacent glands within the same lesion showed a polyclonal origin (Nabeshima et al., 2003)
Studies on clonality of endometriosis may also shed light on the aetiologic mechanisms of the disease. According to the monoclonal model of pathogenesis proposed by Wu et al. (2003), from a piece of shed endometrium regurgitated in peritoneum, polyclonal in origin, a single cell could grow into a focus of ectopic tissue. Conversely, according to the polyclonal model of pathogenesis by Mayr et al. (2003), an originally polyclonal piece of endometrium regurgitated in peritoneum would establish polyclonal endometriotic foci. Finally, the pattern proposed by Nabeshima et al. (2003) is consistent with both the developing of endometriosis lesions from multiple precursor cells and with the potential ability of ectopic endometrial glands to grow as a single-cell derivation (Nabeshima et al., 2003).
This issue has to be resolved unequivocally by additional studies although it is plausible that ectopic glands may expand monoclonally. On the other hand, it has to be underlined that it is not justified to equate monoclonality with premalignant potential per se since even areas of normal tissue can be monoclonal (Ponder et al., 1985; Tiltman, 1997). Along this line, evidence of a monoclonal composition has been recently provided for normal endometrial glands with glands located within a 1 mm2 area that share clonality status (Tanaka et al., 2003).
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DNA abnormalities in ectopic endometrium |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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The emergence of all cancers from normal precursor tissues is governed by a stepwise accumulation of genetic changes that liberates neoplastic cells from the homeostatic mechanisms that govern normal cell proliferation. In humans, at least four to six mutations are required to reach this state (the ‘multi-hit’ model) (Han and Weinberg, 2002
). In endometriosis two possible scenarios may be envisioned:
- The initial DNA variants might involve genes that increases predisposition to implantation of refluxed menstrual endometrial tissue (Simpson et al., 2003). These hits might be somatic or germline and might involve genes able to regulate cellular attachment or apoptosis or growth or escape from the immune system or metabolism of chemicals and/or toxins. Further somatic mutational events involving tumour suppressor genes and/or oncogenes might confer to the cells the invasive features and the malignant potential characteristics of cancer. According to this view, endometriosis would be the precursor of some, if not all, ovarian cancers of endometrioid and clear cell histologic types (Bischoff et al., 2002).
- Alternatively, endometriosis and ovarian carcinoma might represent two distinct biological entities characterized by a different set of causative molecular events and their relative frequent coexistence may derive from the sharing of some risk factors or antecedent mechanisms (genetic predisposition, immune dysregulation, environmental factors).
If ovarian carcinomas do arise from endometriosis, one would expect to find genetic alterations common to both endometriosis and malignant tumours (Thomas and Campbell, 2000a,b; Simpson et al., 2003). Conversely, if endometriosis represents a distinct entity then one would expect to find alterations unique to the pathway that leads to this pathology.
Different techniques have been employed to detect acquired chromosome-specific alterations in endometriosis with the aim to verify whether endometriosis lesions may be associated with genetic defects such as loss of heterozygosity (LOH), chromosomal loss or gain, microsatellite instability and increased heterogeneity of chromosome 17 aneuploidy that are frequently involved in the stepwise pathway of cellular transformation (Table I) (Diebold, 1999). Results from these techniques are described below. Similarly to what is observed for cancer, chromosomal rearrangements in endometriotic tissue may uncover candidate chromosomal loci and, ultimately, causative genes.
Evaluation of chromosomic aberrations by conventional cytogenetic analysis
No specific chromosomal abnormalities have been identified by karyotypic analysis applied to pelvic endometriosis implants and endometriotic cysts (Dangel et al., 1994; Tamura et al., 1998). The limited information yielded by these studies may depend upon the limitations related to the culture of endometriotic tissue (e.g. contamination from inflammatory infiltrate or surrounding normal tissue, selection against aneuploid cells because of the methods employed such as the collagenase treatment) and those inherent to the technique itself. Indeed, the genetic changes might take place at the molecular level and might not result in structural or numerical chromosome rearrangements. Evidence against this hypothesis comes from fluorescence in-situ hybridization (FISH) analysis.
Evaluation of chromosomic aberrations by FISH analysis
FISH analysis has the advantage that culturing of endometriosis cells is unnecessary since it can be performed on fresh or fixed tissue. Three studies employing the FISH strategy have been performed by the group of Simpson and Bischoff (Shin et al., 1997; Kosugi et al., 1999; Bischoff et al., 2002). In the first study, aneuploid frequency was significantly higher in three out of four preparations of fresh endometriosis specimens derived from women affected by advanced stage disease (8.8 and 14.8% respectively for chromosome 16 and 17 monosomy in one case; 14.8% for chromosome 11 trisomy in the second case and 14.1% for chromosome 16 monosomy in the third case) when compared to the mean background frequency observed in normal specimens (3.4%, range 2.2–5.8%, for monosomy and 1.2%, range 0–1.9%, for trisomy) (Shin et al., 1997). In the subsequent study, the authors reported an increased frequency of chromosome 17 aneuploidy in endometriosis specimens versus normal endometrial tissue (Kosugi et al., 1999). Somatic alterations involving chromosome 17 or mutations in the tumour suppressor gene (TSG) TP53, localized on chromosome 17, are frequently observed in premalignant and malignant tissues and play the most significant role in ovarian tumour development (Jacobs et al., 1992). As a further confirmation, the same authors have employed the FISH analysis to examine fresh and fixed endometriosis specimens obtained from women with advanced stage disease, to detect monosomy for the chromosome 17 as well as for the TP53 locus (17p13.1). They have demonstrated heterogeneity for loss of chromosome 17 in all 14 endometriosis specimens studied. In 12 out of 14 specimens, from 8 to 42% of the cells not only were monosomic for chromosome 17-centromere but also showed loss of TP53 locus. In the two remaining cases, only TP53 loss was significant, observed in 8 and 14% of cells (Simpson et al., 2003). Although these studies have investigated a limited number of chromosomes, they, however, support the involvement of somatic mutations in the process of endometriosis progression.
Few studies have evaluated LOH events (also termed allelic imbalance) on DNA obtained from endometriotic tissues (Jiang et al., 1996, 1998; Sato et al., 2000; Goumenou et al., 2001a; Nakayama et al., 2001a). The specific method consists in a polymerase chain reaction-based microsatellite analysis of different chromosomal regions with the aim to evaluate potential inactivation in candidate genetic loci involved in susceptibility to a disease. Allelotyping studies have the disadvantage that the correct gene or region must be selected and that perturbation must be detectable by the method chosen. In addition, they are limited by the necessity to evaluate endometriotic tissue with minimal contaminating tissue and normal endometrial samples from the same patient as a control. In view of the potential association of endometriosis with ovarian cancer, Jiang et al. (1996) set up a study aimed to evaluate in endometriosis samples any potential DNA deletions present on chromosome arms 6q, 9p, 11q, 17p, 17q and 22q that were identified as harbouring TSGs important for ovarian tumourigenesis and, more particularly, for the endometrioid histotype. DNA was derived from 40 samples of endometriosis glands and stroma microdissected from frozen or fixed lesions. In 27.5% of the cases, endometriotic tissue showed LOH at one or more loci on chromosomes 9p (18%), 11q (18%) and 22q (15%). No LOH was observed for chromosome 17. Moreover, the same authors could not demonstrate any LOH in normal endometrium (Thomas and Campbell, 2000b; Campbell and Thomas, 2001). In a subsequent study, the same group examined 14 cases of endometriotic tissue synchronous with ovarian cancer for LOH events on 12 chromosome arms (2q, 4q, 5p, 5q, 6q, 7p, 9p, 11q, 17p, 17q, 22q and Xq) and observed that 9 of these cases (64%) showed LOH at one or more loci (Jiang et al., 1998). Common LOH events were detected in 9 of 11 cases of ovarian endometriosis adjacent or contiguous to endometrioid ovarian carcinoma. These LOH events involved chromosome regions 9p21 (31%), 11q23 (20%) and 22q13 (31%) but also regions 4q (8%), 5q13-q14 (25%) and 6q14-q15 (27%). Again, no LOH was observed for chromosome 17. LOH on these chromosome regions has been shown to be very common in endometrioid ovarian cancers, especially of early-stage and/or low grade (Tibiletti et al., 1996; Saretzki et al., 1997; Watson et al., 1998; Zborovskaya et al., 1999). A comparative assessment of the alterations found by LOH at specific chromosome arms in endometriosis and in endometrioid ovarian cancer is shown in Table III (Jiang et al., 1998; Diebold, 1999; Obata and Hoshiai, 2000; Sato et al., 2000). From these data, it can be observed a trend of increasing LOH frequencies when comparing solitary endometriosis lesions, endometriosis-associated carcinoma and endometrioid ovarian tumour. Most of the genes targeted by LOH have not yet been identified; however, the 9p21 genetic locus is known to harbour the TSG regulator of the cell cycle p16Ink4, the progesterone receptor gene is located in chromosome region 11q22–q23, whereas the estrogen receptor gene and the TSG superoxide dismutase gene 2 map on 6q although the minimal region deleted seems to be different from that described in the study by Jiang et al. (1998).
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LOH in the chromosome 10q23.3 region has been demonstrated in 56.5% of 23 cases of endometriotic cysts (Table III) (Sato et al., 2000). Reported frequency of LOH in this region for ovarian endometrioid carcinomas and clear cell carcinomas was 42.1 and 27.3%, respectively. Again in this study, common LOH events were detected in cases of endometriosis synchronous with ovarian tumours. Of five cases of endometrioid carcinomas associated with endometriosis, 3 displayed common events, one displayed an event only in the tumour and one displayed no event in either lesions. Of seven cases of clear cell carcinomas associated with endometriosis, three displayed common events, one displayed an event only in the tumour and 3 displayed no event. In no cases was LOH detected only in the endometriosis. Moreover, none of the 12 specimens of normal endometrium showed LOH at this region. Importantly, the TSG PTEN is located in this specific region and, as better outlined beyond, it is well known that loss of function of just a single allele of PTEN is sufficient to confer a growth advantage because of the gene inactivation (Di Cristofano and Pandolfi, 2000). LOH events on chromosomes 5q, 6q, 10q, 11q and 22q have been subsequently confirmed by others (Obata and Hoshiai, 2000).
Along this line, Goumenou et al. (2001a) assayed 22 samples of endometriotic cysts for LOH based on the use of 17 microsatellite markers correspondent to specific chromosomal regions in which candidate genes implicated in limiting malignant transformation that have been mapped. LOH in at least one locus was observed in 36.4% of the samples. Loci 9p21 where the TSG p16Ink4 has been mapped, 1q21 where apolipoprotein A2 (APOA2) is located and 17p13.1 correspondent to TP53 exhibited imbalance in 27.3, 4.5 and 4.5% of the cases, respectively. Interestingly, occurrence of these alterations increased 3-fold from stage II to more severe stages of the disease, suggesting that LOH events accumulate as the disease progresses.
Finally, Bischoff et al. (2002) have evaluated allelic imbalance for polymorphic markers on chromosome 17 in 15 advanced stage endometriosis samples and were unable to detect LOH at the 17p13 locus while in four cases (27%) losses were observed for 17q loci where other TSGs such as BRCA1 are mapped.
Importantly, most of these data has been recently severely challenged by Prowse et al. (2005). They sought to identify genetic alterations by performing LOH analysis on 17 archival ovarian endometriotic samples. Each sample was microdissected using a laser capture microscope to separate the endometriotic epithelium, the adjacent stroma and surrounding normal tissue. LOH analysis was performed based on a fluorescence-based technology. Twelve polymorphic microsatellite markers around p16Ink4, TP53, APOA2, PTEN and other potentially important genes were chosen because LOH had been previously detected at these loci in endometriosis. In most of lesions, LOH was absent, and the allelic ratios in the endometriotic samples were generally very similar to those in the normal tissue, providing no evidence to suggest that allelic loss had been masked by contaminating normal tissue. One lesion showed LOH, and this was at just one microsatellite marker correspondent to 8p22 chromosomal region (Prowse et al., 2005).
Evaluation of chromosomic aberrations by comparative genomic hybridization
Comparative genome hybridization (CGH) allows screening of the entire genome with the aim to discover and map chromosomal gains or losses. Gogusev et al. (1999, 2000) examined 18 endometriosis lesions obtained from advanced stage patients by CGH. Recurrent gene copy number alterations were found in 15 out of 18 cases (83%). The average number of copy alterations was 3.1 per lesion, which is low compared to malignant tissue and in line with that demonstrated in other benign proliferations such as pituitary adenomas (Daniely et al., 1998). Loss of genomic material in chromosome 1p and 22q were detected in 50% of the cases. Additional common losses occurred on chromosomes 5p (33%), 6q (27%), 7p (22%), 9q (22%) 16 (22%) and 17q in one case. Gain of DNA sequences were seen at 1q, 6q, 7q and 17q in four cases. The molecular cytogenetic aberrations identified by CGH only partially match molecular allelotyping findings (Table III). CGH analysis was also applied to compare genetic alterations between endometriosis and the associated tumour in a very limited number of cases of carcinomas arising in endometriotic cysts. A gain in the long arm of chromosome 8, which harbours the oncogene c-myc, has been observed (Mhawech et al., 2002; Noack et al., 2004).
In conclusion, from results of these different techniques it is evident that poor consistency exists in relation to the DNA abnormalities present in endometriotic samples. According to some studies, a significant proportion (from about one-third to one-half for allelotyping and more than two-third for CGH) of endometriosis lesions harbours somatic genetic changes in chromosomal regions supposed to contain genes involved in tumourigenesis, especially for endometrioid carcinoma (Table III). Since the frequency of LOH in ovarian endometrioid cancers is estimated between 60 and 90% (Diebold, 1999), these results would be consistent with the progression model for carcinogenesis where some ovarian tumours are expected to harbour a greater number of genetic alterations than their benign precursors (Roy et al., 1997). Moreover, the frequency of genetic aberrations seems to increase for cases of endometriosis adjacent or contiguous to ovarian cancer and, more importantly, these cases tend to share the same genetic changes, which supports idea of a common developmental pathway through the inactivation of the same TSGs.
On the other hand, other studies cannot replicate these findings and fail to detect evidence supporting the concept that endometriosis may be a preneoplastic condition (Prowse et al., 2005).
These controversial findings are even more emphasized by data obtained for 17p13 region. Aberrations on chromosome 17 are the most prevalent in ovarian tumour development (Diebold, 1999) but LOH at 17p13 is rare in benign ovarian lesions and borderline tumours supporting the accepted concept that inactivation of TP53 is usually a late event during ovarian carcinogenesis, and, particularly for the endometriod type, it is associated with tumour progression. The failure to detect a significant frequency of 17p13 alterations in endometriosis by molecular means is consistent with the idea that these changes are uncommon in endometriosis or rather occur at a late stage of transformation. On the other hand, the frequent perturbations of chromosome 17 detected in severe stage disease by FISH analysis (Bischoff et al., 2002) argue against this view.
There are different explanations for these disagreements: (i) a problem may reside in the cellular heterogeneity of endometriotic tissue that represents the critical caveat for all these techniques; (ii) methodological differences may be related to the specific technique employed that can be either based on a direct visual inspection rather than on more automated procedures; (iii) the number of lesions evaluated in the various studies was limited and it cannot be excluded that different cysts are at different stage of endometriosis progression. Unfortunately, very few studies have evaluated genetic changes in histologic forms of atypic endometriosis. Moreover, we have to consider that there might be a ‘publication bias’ related to the tendency in reporting and publishing only positive results.
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Expression of oncogenes and tumour suppressor genes |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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It is widely accepted that malignancies arise only after the accumulation of mutations in oncogenes and TSGs because of the clonal expansion of successively more genetically damaged cells. If malignancy arises from endometriosis, some endometriotic lesions are likely to harbour mutations in genes and aberrant expression of proteins that are involved in the early step of carcinogenesis (Campbell and Thomas, 2001
). We have decided to provide a detailed description of the studies set up to investigate this aspect of the problem, although the general impression here is that very few data can substantiate the hypothesis that specific genes are involved in endometriosis progression towards malignancy.
Activation of the PI-3 kinase pathway is a pivotal event in the development of a tumour. Many oncogenes stimulate tumour growth by activating this pathway. PI-3 kinase-generated phosphoinositides are perceived as second messengers, such as phosphatidyilinositol-3,4,5-triphosphate [PtdIns(3,4,5)P3], which is responsible for protection against apoptosis. The major route for removing PtdIns(3,4,5)P3 in cells has been shown to occur through PI-5- and PI-3- phosphatases. By virtue of its phosphatase activity, PTEN, whose gene is located on chromosome arm 10q (10q23.3), is a major negative regulator of the PI-3 kinase pathway and has been isolated as a tumour suppressor in a variety of malignancies (Myers et al., 1997).
High frequency of LOH at 10q23.3 and mutations of the gene have been reported in glioma, endometrial carcinoma of the uterus and ovarian endometrioid carcinoma (Obata et al., 1998). In particular, Mutter et al. (2000) have recently emphasized that loss of PTEN function is an early event in endometrial tumourigenesis. While no normal endometria showed PTEN mutations, a mutation rate of 83% was found in endometrioid endometrial adenocarcinomas and of 55% in premalignant endometrial intraepithelial lesions. Moreover, endometrioid endometrial adenocarcinomas showed at least some diminution in PTEN protein expression in 97% of the cases thus suggesting that other mechanisms at transcriptional and translational levels beyond the observed mutations are responsible for PTEN inactivation (Mutter et al., 2000). As mentioned above, a significant proportion of LOH events at 10q23.3 locus have been also demonstrated in endometriotic cysts (Sato et al., 2000). Three studies have specifically evaluated the potential inactivation of PTEN in endometriosis and results for frequency of mutations and alteration of protein expression are reported in Table IV (Obata and Hoshiai, 2000; Sato et al., 2000; Martini et al., 2002). Sato et al. (2000) used a laser-assisted microdissection system to detect mutations in PTEN gene. They found missense mutations and deletions in 7 of 34 (20.6%) solitary ovarian endometriotic cysts and five of these seven cases were accompanied by LOH at 10q23.3. Somatic mutations in PTEN gene were also detected in 20% ovarian endometrioid carcinomas and in 8.3% clear cell carcinomas. For clear cell carcinomas and endometriotic cysts, mutations were concentrated around the phosphatase domain of the gene.
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A very strong support for a role of PTEN in the malignant transformation of endometriosis came recently from a mutagenesis approach in genetically engineered mice (Dinulescu et al., 2005). In mice harbouring an oncogenic allele of K-ras resulting in the development of benign lesions reminiscent of endometriosis, a conditional deletion of PTEN caused the progression towards the ovarian tumour. In these mice with a combined mutation of K-ras and PTEN, all the tumours appeared to originate from the ovarian epithelium with a disease latency of only 7 weeks, extended into the stroma through a process of infiltrative growth and were diagnosed as endometrioid subtype. It has to be noted that, although the oncogenic activation of K-ras did result in the development of both peritoneal and ovarian lesions with endometrioid morphology, this mouse model is probably not perfect as a genocopy of endometriosis. Indeed, lesions in the ovary showed proliferations of glands but lack a surrounding endometrial-like stroma. However, even if these observations need to be confirmed, this elegant study represents one of the most convincing pieces of evidence supporting a continuum between endometriosis and cancer. Results obtained, based on the combination of two mutations in tumour-related genes, suggest the potential existence of a mechanism of tumourigenesis conforming to a progression model from the benign lesion to the malignant ovarian disease.
These very few data prompt consideration of the implication of the PTEN gene, more than others, in the progression of endometriosis towards a more severe and invasive form.
The TP53 gene, which is found on the short arm of chromosome 17, encodes for the nuclear protein p53 that lies at the heart of stress response pathways that prevent the growth and survival of potentially malignant cells. Activation of p53 can induce several responses in cells including differentiation, senescence, DNA repair and the inhibition of angiogenesis but best understood is the ability of p53 to induce cell cycle arrest and apoptotic cell death (Schuijer and Berns, 2003). Mutations of the TP53 gene are frequently related with allelic loss at 17p13 and overexpression of non-functional p53 protein. Wild-type p53 loses its antigenicity during tissue processing and can hardly be detected by the immunohistochemical technique. By contrast, mutated p53 accumulates within the nuclei and is regularly detected by immunohistochemical staining because of its increased stability and prolonged half-life time (Nezhat and Kalir, 2002; Nezhat et al., 2002; Schuijer and Berns, 2003). TP53 gene mutations or protein overexpression of p53 are the most common genetic alterations detected thus far in ovarian cancer with mutations being present especially in serous tumours but also in about 30 and 10% of endometrioid and clear cell carcinomas, respectively (Schuijer and Berns, 2003). Therefore, several studies have investigated whether the development of endometriosis and its potential malignant transformation to endometrioid/clear cell ovarian carcinoma may involve mutations in this gene (Table V). As mentioned above, evaluation of chromosome 17 aberrations by FISH and allelotyping has revealed controversial findings. No mutation in exons 5–9 of the TP53 gene was found in endometriosis lesions by single strand conformational polymorphism (SSCP) analysis (Vercellini et al., 1994; Jiang et al., 1996; Okuda et al., 2003). A single TP53 mutation (Tyr-to Cys in codon 220) was detected in one case of endometriosis adjacent to endometrioid ovarian carcinoma but was not detected in the adjacent tumour (Jiang et al., 1998). In line with these findings, most authors agree that p53 immunoreactivity is undetectable in samples of endometriosis not associated with carcinomas (Table V) (Vercellini et al., 1994; Schneider et al., 1998; Bayramo and Duzcan, 2001; Nezhat and Kalir, 2002; Okuda et al., 2003).
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Only three studies showed expression of p53 in endometriotic lesions not complicated by cancer. Nakayama et al. (2001b) failed to detect any mutation in TP53 gene in both ectopic and eutopic endometrium but found that 20% of endometriotic lesions were positive for the protein in the nuclei of epithelial cells. Among the 13 positive lesions, two were associated with ovarian carcinomas. However, since the DNA analysis did not detect genetic alterations in p53-positive samples, the authors suggested that, similarly to what observed in endometrial cancer, the p53 expression recognized in some endometriotic epithelia could be due to an excessive production of the wild-type protein (Bayramo and Duzcan, 2001). Fauvet et al. (2003) found that the percentage of p53-positive samples were higher among endometriomas than in benign ovarian tumours but not malignant cancers although the percentage of positive cells in endometriomas was only around 2%. A very low percentage of p53 positive cells in endometriosis was also detected by Beliard et al. (2004) but only in the late secretory phase when a limited percentage of eutopic endometrial cells also stained for the protein.
The expression of p53 in endometriotic lesions next to carcinomas as a potential sign of a continuum from endometriosis to cancer is much more debated. Studies describing sporadic occurrence of endometriosis adjacent to malignant carcinomas consistently failed to demonstrate p53 expression in the endometriotic areas and consistently found a staining for p53 in all malignant tumours (Table V) (Han et al., 1998; Horiuchi et al., 1998; Mhawech et al., 2002; Noack et al., 2004). In contrast, other authors have detected the protein in benign endometriotic areas adjacent to ovarian cancers (Nezhat et al., 2002). A clear increase in p53 overexpression from typical endometriosis to atypical endometriosis to cancer has been observed by Saintz de la Cuesta et al. (2004) (Table V).
Data from Prefumo et al. (2003) would be consistent with the occurrence of ovarian endometrioid carcinomas by different molecular pathways, one of which would imply the malignant transformation of endometriosis involving p53. They have compared the immunohistochemical expression of p53 protein in ovarian endometrioid carcinomas associated or not with endometriosis. A higher percentage of positive cells were found in cases of tumours associated with the disease. More interestingly, in these cases, the expression of p53 in the malignant epithelium was compared with the expression in the adjacent benign endometriotic epithelium and a significant degree of concordance was observed (Spearman’s p of 0.96) (Prefumo et al., 2003).
In ovarian carcinomas, TP53 mutations and p53 accumulation occur late in carcinogenesis (Diebold, 1999). On this basis, absence of mutations and accumulation in most of the isolated endometriotic lesions is not an entirely unexpected finding and p53 presumably exerts its physiological function in endometriosis. Studies on p53 expression in areas associated with carcinomas do not unequivocally clarify whether the protein alterations could be a step in the molecular mechanisms involved in the malignant transformation of endometriosis rather than a random and independent event. The lack of mutation analysis of the TP53 gene in endometriosis limits the value of these studies.
Bcl-2, a protooncogene located on chromosome 18q21.3, codes for the bcl-2 protein, which is important in determining whether a cell will be irreversibly committed to apoptosis (Pezzella et al., 1993). Bcl-2 belongs to a growing family that is often divided into two different categories: inhibitors of apoptosis such as Bcl-2 and bcl-xl, and accelerators or promoters such as Bax (Nezhat and Kalir, 2002; Nezhat et al., 2002). The ratio of Bcl-2 to Bax is important in determining susceptibility to apoptosis (Korsmeyer, 1992; Reed, 1994). High levels and aberrant patterns of Bcl-2 expression have been found in a variety of human cancers (Alderson et al., 1995; Diebold et al., 1996; Chan et al., 2000). Endometrioid ovarian carcinomas show strong expression of the Bcl-2 oncoprotein (Diebold, 1999). In a normal endometrium Bcl-2 expression varies with menstrual cycle phase being higher in proliferative glandular epithelium consistent with a positive regulation by estrogens (Bozdogan et al., 2002; Jones et al., 1998). Modest levels of Bax protein are present in proliferative phase and increase in the secretory phase. Studies evaluating immunohistochemical Bcl-2 expression in endometrial tissue from patients with and without endometriosis and in the ectopic versus the eutopic endometrium resulted in conflicting conclusions (Jones et al., 1998; Meresman et al., 2000; Beliard et al., 2004). However, data from different groups concerning Bcl-2 expression in ectopic endometrium are generally in keeping with the observation that this tissue does not present significant cyclical variations for both Bcl-2 and Bax such as those observed in eutopic endometrium (Goumenou et al., 2001b, 2004; Beliard et al., 2004).
Controversial findings have been also reported for the expression of the oncoprotein in endometriosis tissue adjacent to carcinomas (Han et al., 1998; Mhawech et al., 2002; Noack et al., 2004; Saintz de la Cuesta et al., 2004). Nezhat et al. (2002) compared staining patterns for Bcl-2 in benign endometriotic cysts, ovarian tumours and endometriosis areas associated with the tumours, in an attempt to identify sequential or aetiologic correlation. Only 23% of the endometriotic cysts stained positively for Bcl-2, whereas 67% of the endometrioid tumours and 74% of the clear cell carcinomas resulted positive. Of the twelve endometriosis areas adjacent to the endometrioid carcinomas and 11 endometriosis samples adjacent to clear cell neoplasms 42 and 73% express Bcl-2, respectively.
Potential involvement of these proteins in early carcinogenesis warrants further investigations.
Other components of the cell cycle machinery and oncogenes
Table VI summarizes results from different studies evaluating potential mutations and alterations of protein expression for various components of the cell cycle regulation and genes able to produce aberrant growth-control signals (Bergqvist et al., 1991; Vercellini et al., 1994; Jiang et al., 1996; Han et al., 1998; Schneider et al., 1998; Matsuzaki et al., 2001; Martini et al., 2002; Mhawech et al., 2002; Fauvet et al., 2003; Okuda et al., 2003; Noack et al., 2004; Saintz de la Cuesta et al., 2004). Data are inconclusive.
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Association between endometriosis and cancer-related genotypes |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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Endometriosis does share some risk factors with ovarian cancer; nulliparity and menstrual characteristics (early age at menarche, regular menstrual cycles) are determinants of the risk for both the conditions (Signorello et al., 1997
; Riman et al., 1998). A common genetic predisposition, rather than a cause-effect relationship, may be also considered to explain the potential association between endometriosis and ovarian cancer. At present, only two specific types of genetic variants deserve to be mentioned, although no conclusive data exist in this regard. Progesterone receptor gene PROGINS polymorphism
A germline TaqI restriction fragment length polymorphism in the hormone-binding domain of the progesterone receptor gene is the result of an Alu sequence insertion in intron G of the gene (Fabjani et al., 2002). This insertion seems to have consequences for the integrity of the regulatory functions of the gene (Agoulnik et al., 2004). Two other polymorphisms, a G to T substitution in exon 4 causing a valine to leucine change in the hinge region of the receptor and a synonymous C to T substitution in exon 5 are in complete linkage disequilibrium with the Alu insertion and together these three variants have been designated as PROGINS (Kurz et al., 2001; Donaldson et al., 2002; Modugno, 2004). PROGINS has been related to sporadic ovarian carcinoma, albeit not consistently (Kieback et al., 1995; Risch et al., 1996; Lancaster et al., 1998; Tong et al., 2001) An increased risk was found in the German and pooled German/Irish Caucasian population for both homozygotes and heterozygotes (McKenna et al., 1995) and a study of BRCA1 and BRCA2 mutation carriers found that the PROGINS allele was associated with a 2.4-times (95% CI = 1.4–4.3) higher risk of developing ovarian cancer among the subgroup that had never used oral contraceptives (Runnebaum et al., 2001). Conversely, no association was found in the Caucasian populations from North America and England (McKenna et al., 1995; Lancaster et al., 1998; Runnebaum et al., 2001; Tong et al., 2001; Lancaster et al., 2003).
An increased frequency of the PROGINS mutated allele has been also reported for women with endometriosis in both Austrian (OR = 2.4; 95% CI = 1.3–4.5) (Wieser et al., 2002) and Italian (OR = 1.7; 95% CI = 1.0–2.8) (Lattuada et al., 2004) Caucasian populations. This finding is in line with the recent evidence supporting the idea that an alteration in the status of the progesterone receptor may be involved in the molecular mechanisms underlying endometriosis development, from cellular implantation to invasion (Gurates and Bulun, 2003).
The genetically variable biotransformation enzymes, cytochromes P450 (CYP), epoxide hydrolase and glutatione S-transferase (GST) metabolize drugs, carcinogens and natural products (Brockmoller et al., 1998). Individual effectiveness in the detoxification of environmental carcinogens influences susceptibility to malignant disease since a high percentage of human cancers results from exposure to these chemicals. The phase I detoxification enzyme CYP1A1 catalyses the oxidation of polyclyclic aromatic hydrocarbons (PAHs) to epoxides and is inducible by PAH. The polymorphic CYP1A1 gene is located on chromosome 15 (15q22-q24) and its genetic polymorphism in the 3'-flanking region (MspI site) has been associated with increased inducibility of CYP1A1 and with an elevated risk of lung cancer and colorectal cancer in an oriental population (Sarmanova et al., 2001). The phase II enzymes GSTs are critical for the detoxification of the products of oxidative stress, various carcinogenic electrophils, the residues of reactive oxygen species (ROS)-damaged DNA and metabolism of dioxin (Brockmoller et al., 1998) The biological consequences of failure to express these functional proteins may result in rapid accumulation of genetic damage and increase susceptibility to some types of cancer. GSTM1 gene is located on chromosome 1 (1p13.3) and the GSTM1 null genotype was associated with increased risk of ovarian endometrioid/clear cell invasive cancer (Spurdle et al., 2001).
In relation to endometriosis, for both GSTM1 deficiency and CYP1A1 MspI variant studied alone, data from different groups are discordant (Baranova et al., 1999; Arvanitis et al., 2001; Baxter et al., 2001; Hsieh et al., 2004; Babu et al., 2005; Hur et al., 2005) but the combination of both mutations was found to be associated with a small increased risk of disease development in an English study. A RR of 4.7 (95% CI = 1.1–19.6) was found for familiar cases with the genotype combination versus the proportion of male controls (Hadfield et al., 2001). It has to be noted that a significant interaction between GSTM1 deficiency and high CYP1A1 inducibility has been reported in other contexts (Brockmoller et al., 1998; Krajinovic et al., 1999; Lear et al., 2000). The presence of the CYP1A1 MspI polymorphism in combination with the absence of activity in a phase II enzyme could result in an excess of reactive intermediates which may in turn be involved in both endometriosis and cancer aetiology.
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Conclusions |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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The biological plausibility at the basis of the idea that endometriosis may be the precursor of some, if not all, ovarian endometrioid/clear cell tumours is not well substantiated. While endometriosis does share some aspects of malignancy such as increased growth and vascularization and tissue invasion, the pivotal characteristics of cancer (monoclonal expansion, genetic abnormalities, replicative advantage) remains to be defined (Figure 1). Although the monoclonal outgrowth of ectopic glands has been demonstrated, the entity and the details of the phenomenon are unknown. Further studies on many highly isolated eutopic and ectopic endometrial glandular samples are needed. Controversial data have been reported for the presence and positions of genetic changes and for the inactivation of specific TSGs in endometriosis (Figure 1). Studies reporting results of mutational analysis are very few in this field. Presence of gene mutations has to be extensively investigated not only in cases of endometriosis concomitant to ovarian cancer or to histologic transition forms but also in isolated endometriotic cysts. A molecular continuum between the benign affection and the malignant entity requires more strong evidence of common mutational events. Epigenetic changes, recognized as an important mechanism of gene inactivation in ovarian cancer, have to be explored also in endometriosis (Cvetkovic, 2003
). Similarly, as the expression of telomerase enzyme is a molecular change shared by borderline and malignant but not benign ovarian tumours, it would be also interesting to evaluate this aspect (Cvetkovic, 2003). Another useful instrument of research is represented by the further development or improvement of experimental models of endometriosis transformation into cancer. Finally, other explanations rather than a causal relationship should be taken into consideration to explain the increased risk of ovarian cancer in women with endometriosis. At present, a cautious attitude is advisable when addressing endometriosis as a preneoplastic condition.
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References |
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TOPAbstractIntroductionClonality of the endometriosis...DNA abnormalities in ectopic...Expression of oncogenes and...Association between...ConclusionsReferences |
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