**3. Endometrioid and clear cell cancers (see figure 1)**

Women with CC and EC frequently present with endometriosis. In a review of 29 studies, Van Gorp *et al* [43] found a statistical association between endometriosis and endometriosisassociated ovarian cancers (EAOC): 36% of clear cell carcinoma were associated with endo‐ metriosis (11-70%), and 10% in case of endometrioid carcinoma (5-43%). A precursor lesion called atypical endometriosis was proposed. Atypical endometriosis (AE) is defined by the presence of hyperplasia or cytological atypia, increased nuclear/cytoplasmic ratio, mild hyperchromosomia, mild to moderate pleomorphism, crowded and occasionally stratified epithelial cells. AE has been identified adjacent to concomitant EAOC, with a demonstrated transition from benign endometriosis through AE to EAOC. At the molecular level, AE and EAOC share common molecular abnormalities such as PTEN and PIK3CA mutations, HNF 1b up-regulation, MET amplification and loss of ARID1A [44].

ARID1A (loss or mutation) and PIK3CA are early events and likely occur in precursor lesions as well as in EAOC: mutation of ARID1A gene (AT rich interactive domain 1A) was found in 41 to 57% of clear cell cancers and 30 to 48% of endometrioid cancers [31, 45-47]. ARID1A is a tumour suppressor gene and encodes BAF 250a protein that is involved in the multi-protein SWI/SNF chromatin-remodelling complex.

It has been well established that the SWI/SNF complex is involved in DNA repair through cell cycle arrest and apoptosis, cell survival after DNA damage (particularly by promoting γH2AX induction) and genomic stability. ARID1A has recently been demonstrated to act as a negative regulator of the cell cycle through interaction with TP53 and its mutation may lead to cellular dysfunction as dysregulation of chromatin remodelling [48]. Moreover, loss of expression of this gene was recently found in benign endometriosis (20%) and AE (38.5%) adjacent to malignant lesions (57.7%), suggesting a chronological association from benign through atypical endometriosis to AEOC [44]. Samartzis et al [49] found also loss of ARID1A/ BAF 250a expression in presumably benign ovarian endometriomas (n=3/20, 15%) particularly in the form of cell clusters that could suggest a clonal loss of BAF 250a and a risk of carcinogenic transformation [31].

Finally tubal ligation is protective against AEOC suggesting passage of endometriosis through the tube as a key oncogenic step with potential clinical implications (see below).
