**8. Conclusion**

316 Endometriosis - Basic Concepts and Current Research Trends

(Wiegand 2010; Wiegand, 2011). Whether ARID1A mutation is an early or late event in endometriosis-associated ovarian cancers related to atypical endometriosis remains to be elucidated. Alterations of other genes, such as p53, p16, and PTEN, have been detected in a low percentage of endometriotic lesions (Martini, 2002; Nezhat, 2008). hMLH, a DNA mismatch repair gene, is another candidate for the malignant transformation of endometriosis (Nyiraneza, 2010 ; Ren F, 2011). hMLH is the causal gene of Lynch syndrome, in which the risk of developing endometrial and ovarian cancers is significantly increased (Schmeler&Lu, 2008). K-ras may also be important because mutated K-ras promotes endometriosis in a mouse model, suggesting that K-ras mutation may be an early event in the carcinogenesis of endometriosis-associated cancers (Cheng, 2011). Finally, a singlenucleotide polymorphism in the intron of ANRIL, a non-coding RNA that regulates p16 expression, has been recently reported to have a strong association with endometriosis (Uno, 2010). The molecular steps from endometriosis development to carcinogenesis remain

Recent studies have proposed classifying ovarian cancers into two categories: Type I tumors, which rarely harbor the p53 mutation and have an indolent clinical course, and Type II tumors, which feature the p53 mutation and are aggressive (Kurman&Shih, 2010). Within endometriosis-associated ovarian cancers, low-grade endometrioid adenocarcinoma and clear cell carcinomas are considered Type I, while high-grade endometrioid adenocarcinoma is included in the Type II category. However, p53 mutations are detected in both low- and high-grade endometriosis-associated ovarian endometrioid adenocarcinomas (Okuda, 2003), and PI3CA, PPP2R1A, and K-ras mutations are commonly detected in both endometrioid adenocarcinoma and clear cell carcinoma (Campbell, 2004; Jones, 2010 ; Kuo, 2009; McConechy, 2011 ; Mizuuchi, 1992). Recent evidence indicates that ovarian cancers arise from different cell lineages, such as preexisting cystadenomas, ectopic endometrium in endometriotic lesions, and epithelial cells of the Fallopian tubes (Bell, 2005; Kurman&Shih, 2011). Thus, it may be an oversimplification to divide all ovarian cancers into two groups. It may more accurate to categorize endometriosis-associated cancers into the same group, regardless of the

Numerous studies of expression microarray analyses have been published. Cytokines and chemokines, such as interleukin-1 and its downstream factor cyclooxygenase (COX)-2, interleukin-8, TNF-α and its downstream VEGF, TGF- α, and interleukin-6 have been reported to be involved in endometriosis and endometriosis-associated carcinoma (reviewed by (Nezhat, 2008)). An interesting study by Banz et al. revealed that SICA2, CCL14, and TDGF1 were specifically upregulated in both endometriosis samples and endometriosis-associated endometrioid adenocarcinomas, in contrast with serous adenocarcinomas or normal ovarian tissues (Banz, 2010). Another microarray study focusing on endometriosis-associated clear cell carcinoma showed upregulation of hepatocyte nuclear factor (HNF)-1β, versican, and other markers related to oxidative stress (Yamaguchi, 2010). HNF-1β is a transcription factor, involved in the regulation of glucose homeostasis and glycogen accumulation, normally expressed in the liver and other organs, which is assumed to have some role in the pathogenesis of clear cell carcinoma of the ovary (Kobayashi, 2009). Recently, a novel attempt to classify

to be further clarified.

histological subtype or tumor grade.

We have reviewed the literature on endometriosis-associated ovarian cancer. Further studies are awaited to clarify the exact role of oxidative stress in carcinogenesis.
