Although the pathogenesis of endometriosis is not well understood, genetic factors have been considered to have critical roles in its etiology. Through a genome-wide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, we identified a significant association of endometriosis with rs10965235 (P = 5.57 x 10(-12), odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15, p16 and p14. A SNP, rs16826658, in the LD block including WNT4 on chromosome 1p36, which is considered to play an important role in the development of the female genital tract, revealed a possible association with endometriosis (P = 1.66 x 10(-6), odds ratio = 1.20). Our findings suggest that these regions are new susceptibility loci for endometriosis.

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs. Patient-derived tumour organoids have become important preclinical model systems in both cancer research and clinical settings 1. In contrast to patient-derived xenograft (PDX) mouse models that need a large amount of surgical specimen and 4-8 months for development 2 , organoids can be cultured from patient materials and can be expanded with high efficiency in a relatively short period (typically < 1 month). Organoids from mouse intestine, as well as from various other mouse and human tissues, including the colon, stomach, liver, lung, prostate, and pancreas, have been established 3,4. Patient-derived tumour organoids have also been generated from the colon, pancreas, prostate, breast, gastric, lung, oesophageal, bladder, ovarian, kidney, and liver tumour tissues 1. Organoids maintain the key genetic and phenotypic features of primary tumours, thereby, enabling their use in a broad range of applications, such drug development and identification of the best therapeutic regimen for each patient. Ovarian cancer is a devastating disease, with 295,000 new patients and 185,000 deaths each year, worldwide 5. The relative 5-year survival rate is 47% and has not apparently increased in the last 40 years. Debulking surgery with platinum-combination chemotherapy is usually administered to patients, irrespective of the histological

Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3.5%; BRCA2), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D), 2 (0.9%; ATM), 1 (0.4%; MRE11A), 1 (FANCC), and 1 (GABRA6). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2. Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

These results suggest that follicular LH or steroids do not affect PR expression, and full reduction of total PR expression on cumulus cells at the time of oocyte collection is associated with good morphology in human oocytes.

To probe the mechanism of the development of ovarian cancer from endometriosis, which is a multistep process that involves the activation of oncogenes and inactivation of tumor suppressor genes, we evaluated p53 mutations in solitary endometriosis and endometriosis coexisting with ovarian clear cell carcinoma (OCCA) and ovarian endometrioid carcinoma (OEC). We examined 7 cases of solitary ovarian endometriosis, 13 cases of OCCA, and 9 cases of OEC. Cancer tissue specimens that also contained endometriosis without atypia were chosen. Using a laser microdissection system, epithelial cells from the areas of endometriosis were isolated, and DNA was extracted. We amplified exons 5, 6, 7, and 8 of the p53 gene, and direct sequencing was performed. p53 mutation was observed in 4 (30.8%) of 13 specimens of endometriosis coexisting with OCCA, whereas no mutations were detected in solitary endometriosis or endometriosis coexisting with OEC. We thought that some genetic alterations, which induce p53 mutations in endometriosis, may affect malignant transformation of endometriosis into OCCA.