**6. Future scope**

430 Endometriosis - Basic Concepts and Current Research Trends

High frequency of p53 locus deletion was observed in the endometriosis specimens (Bischoff et al., 2002). The p53 protein abnormalities and chromosomal aberrations may be involved in malignant transformation of ovarian endometriosis (Mhawech et al., 2002). In contrast, some investigators have demonstrated the undetectable expression of p53 in the

Although the real role of p53 polymorphism has not been clarified, it deserves more attentions in the study of endometriosis and the development of gene therapy. However, the real roles of these p53 gene polymorphisms upon endometriosis remain to be clarified. Lager cohort recruitment is request for its further clarification. After the elucidation of these issues, some tumour suppressor gene polymorphisms might become useful markers to predict the future development of endometriosis as well as the development and

Some genetic polymorphisms, involved in sex steroids biosynthesis and metabolism, may be reasonably associated with an increased risk of endometriosis. Specific genes with polymorphisms have been investigated for an association with endometriosis. Some association studies implicated GALT (a gene involved in galactose metabolism) and GSTM1 and NAT2 (genes encoding for the detoxification enzymes) as possible disease susceptibility genes. Recent finding have added to the evidence for the involvement of GSTM1 and NAT2, but have cast doubt on the role of GALT. The CDKN1A gene codon 31-arginine/serine polymorphism is not associated with endometriosis. Polymorphisms of the arylhydrocarbon receptor (AHR) gene and related genes were examined, and in at least one study, no

The endometriosis regresses after menopause or ovariectomy, suggesting it could depend on the production and metabolism of sex steroids (Kitawaki et al., 2002): high concentrations of estrogens were found in the endometriotic lesions, which grow and regress in an

The inheritable susceptibility to endometriosis justifies the growing interest in identifying genes and/or genetic polymorphisms that could lead to an increased risk of disease. Identifying these polymorphisms may open to their use as genetic biomarkers of endometriosis **(**Vietri et al., 2007a, 2007b). Some genetic polymorphisms, involved in sex steroids biosynthesis and metabolism, may be reasonably associated with an increased risk of endometriosis, like progesterone receptor (PR), AR, oestrogen receptor (AR), 17betahydroxysteroid dehydrogenase type 1 (HSD17B1), cytochrome P450 subfamily 17 (CYP17) and cytochrome P450 subfamily 19 (CYP19) (Guo, 2006). No doubt this list is likely to increase over the years. The most widely used approach for the identification of endometriosis-predisposing genetic polymorphisms are the genetic association studies, by which genetic susceptibility polymorphisms are identified through the identification and assessment of the difference in allele/genotype frequencies between patients and control

The **CYP17 genotype** contains a single nucleotide T>C polymorphism situated 34bp upstream of the translation initiation site. C allele may have great promoter activity, increasing the transcription of P450c17 alpha enzyme. This effect amplifies the production of

endometriosis specimens.

intervention of genetic therapy.

**5.3 Polymorphisms** 

association was found.

oestrogen-dependent way.

subjects.

Endometriosis is associated with genetic and immunological influences and exposure to environmental factors. It seems to result from a complex sequence of events in which multiple gene loci interact with each other and the environment to produce the disease phenotype, but thus far little is known about the candidate genes involved (Balow & Kennedy 2005). Because of this complexity, endometriosis is ideally suited as a target for genome wide scanning. Mutations and single-nucleotide polymorphisms (SNPs) have been identified in a number of genes that might confer susceptibility to endometriosis, but their precise role remains to be determined.

**Proteome analysis** is now widely accepted as a complementary technology to genetic profiling and together enables a better understanding of diseases and the development of new treatments. Proteomics allows the simultaneous observation of alterations in protein expression that may be either a precursor to or causative in disease development or a consequence of the disease. These techniques check and identify proteins that are expressed differently in patients with endometriosis versus normal controls. More recently, protein arrays using antibodies enable the screening of thousands of proteins against one sample. In future, such arrays could measure the expressions of multiple proteins to reveal changes in their regulation and expression in disease states. Furthermore, by using protein chip arrays, differential analysis of protein expression in women with and without differential protein profiling technology can be developed into a powerful tool for endometriosis research.

Current Insights and Future Advances in Endometriosis Diagnostics 433

technique for evaluating and monitoring endometriosis. Even so, microscopic or occult endometriosis may be misdiagnosed because of the inability to visualize some lesions. Attempts for early diagnosis and treatments of endometriosis have been weighed down by lack of proper methods to study and manage the disease. Furthermore, the need for noninvasive diagnostic methods is evident because the laparoscopy is a surgical procedure with

At present, there are no reliable markers for the diagnosis and prognosis of endometriosis and identification of serum and endometrial markers is decisive for disease diagnosis and

The diagnostic laboratories are using new genomic and proteomic technologies to develop novel diagnostic and therapeutic approaches for endometriosis. These technologies will facilitate the generation of molecular expression profiles and then identifying potential gene and protein targets. This will lead to available markers with high sensitivity and specificity for screening of endometriosis, then to the development of serum diagnostic tools,

The combination of immunological discoveries and recent advances in DNA technologies may provide the long sought screening tool with the desirable diagnostic accuracy for this

The identification of specific genetic alterations and protein profiles associated with endometriosis offers a unique opportunity to develop assays for early diagnosis and/or treatment. By identifying proteins in biological samples, a minimally invasive tool should be feasible to assess the presence of disease and monitor response to treatment and/or disease

The promise for gene-based diagnostic tests for endometriosis and rational development of genetically targeted and molecular therapeutic strategies is, in principle, excellent. The evolving genomic and proteomic technologies remain poised to revolutionize the diagnosis and treatment of endometriosis, but have not yet lead to a single new therapy or tested biomarker. Many problems remain to be resolved and, while some of these are technical in nature, the most intractable ones have mainly to do with the complex and multifactorial

Akahane, T., Sekizawa, A., Purwosunu, Y., Nagatsuka, M. & Okai, T. (2007). The role of p53

Balow, D.H. & Kennedy, S. (2005). Endometriosis: new genetic approaches and therapy, *Ann* 

Barcelò, B., Pons, J., Fuster, A., Sauleda, J., Noguera, A., Ferrer, J.M. & Agustì, A.G. (2006).

Bedaiwy, M.A., Falcone, T., Sharma, R.K., Goldberg, J.M., Attaran, M., Nelson, D.R. &

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mutation in the carcinomas arising from endometriosis, *Int J Gynecol Pathol,* Vol. 26,

Intracellular cytokine profile of T lymphocytes in patients with chronic obstructive pulmonary disease, *Clin Exp Immunol,* Vol. 145, No. 3, (September 2006), pp. 474-

Agarwal A. (2002). Prediction of endometriosis with serum and peritoneal fluid

potentially dangerous risks.

therapeutic strategies and prognosis markers.

follow-up of patients.

puzzling disorder.

progression.

**8. References** 

character of the disease itself.

479, ISSN 0009-9104

The study of protein function and protein-protein interaction can clarify the biology of the disease more so than the application of genomics. This is because gene expression and biological effects are linked via complex protein synthesis and gene interaction pathways.

**Genomics** includes hybridization techniques (e.g. differential colony hybridization), subtractive techniques (e.g. hybridization and representational difference analysis), gelbased techniques (e.g. RNA arbitrarily primed or differential display), and sequencing based techniques (e.g. expression sequence tags and serial analysis of gene expression). Furthermore, the use of DNA microarrays allows the search for new gene expression markers of endometriosis by identifying differentially expressed genes in endometriosis implants compared with endometrial tissue. The aim of the technique is to identify changes in gene expression characterizing the disease state so that we can understand the disease's progression and identify novel therapeutic targets.

Apart from the better understanding of the pathophysiology and the metabolic pathways that lead to potential biomarkers for endometriosis, there are still issues to be clarified and applications to be achieved. Once a protein or small number of proteins have been shown to be differentially expressed in endometriosis, the next step will be to use this information to try to develop a non-invasive diagnostic test for endometriosis. This diagnostic test should ideally have good sensitivity and specificity as well as satisfactory positive and negative predicative values for the detection of endometriosis, and also be cost effective and readily available.

Genetic markers that are prognostic for endometriosis can be genotyped early in life and could predict individual response to various risk factors and treatment. Genetic predisposition revealed by genetic analysis for susceptibility genes can provide an integrated assessment of the interaction between genotypes and environmental factors, resulting in synergistically increased prognostic value of diagnostic tests. Thus, presymptomatic and early symptomatic genetic testing is expected to be the cornerstone of the paradigmatic shift from late surgical interventions to earlier preventative therapies. Thus, there is an urgent need for novel genetic markers that are predictive of endometriosis and endometriosis progression, particularly in treatment decisions for individuals who are recognized as having endometriosis.

Such genetic markers may enable prognosis of endometriosis in much larger populations compared with the populations that can currently be evaluated by using existing risk factors and biomarkers.

The availability of a genetic test may allow, for example, early diagnosis and prognosis of endometriosis, as well as clinical intervention to mitigate progression of the disease. The use of these genetic markers will also allow selection of subjects for clinical trials involving novel treatment methods.

The discovery of genetic markers associated with endometriosis will further provide novel targets for therapeutic intervention or preventive treatments of endometriosis and enable the development of new therapeutic agents for treating endometriosis.
