The SFRP1 gene on chromosome 8p11.2 encodes a Wnt signaling antagonist, and was recently demonstrated to be a new tumor suppressor that is inactivated by promoter methylation in human colon cancers. Here, we analyzed promoter methylation of the SFRP1 gene in human ovarian cancers, in which loss of heterozygosity in 8p is frequently observed and involvement of the Wnt signaling pathway has been suggested. Methylation-specific PCR (MSP) analysis showed that four of 13 ovarian cancer cell lines and two of 17 primary ovarian cancers had methylated SFRP1, while an immortalized ovarian epithelial cell line, HOSE, and seven ovarian endometrial cyst samples did not. In the four ovarian cancer cell lines with the methylation, SFRP1 was not expressed at all as determined by quantitative RT-PCR analysis. A cell line with SFRP1 methylation, MCAS, was treated with a demethylating agent, 5-aza-2'-deoxycytidine, and demethylation of the promoter and re-expression of SFRP1 were observed. These results show that SFRP1 is inactivated by promoter methylation in human ovarian cancers, as well as colon cancers. varian cancer is the most lethal gynecological malignancy, and is characterized by the diversity of its histology.1) The four major histological subtypes, serous, clear cell, mucinous, and endometrioid, constitute approximately 36, 19, 14, and 15% of the total, respectively, in Japan, 2) and all of these are considered to be derived from ovarian surface epithelium.3) As for genetic alterations, only limited information is available, such as mutations of β-catenin in 31% of endometrioid type 4,5) and c-erbB-2 amplification in serous type with poor prognosis.6) Due to promoter methylation, BRCA1, hMLH1, and RASSF1A are inactivated (silenced) in 10%, 7) 12.5%, 8) and 10-40% of ovarian cancers, 9, 10) respectively. Clarification of molecular alterations is important to identify novel diagnostic and therapeutic targets, and further investigations in ovarian cancers are necessary.Secreted frizzled-related proteins (SFRPs) are extracellular signaling molecules that antagonize the Wnt signaling pathway.11, 12) SFRP1 (8p11.2) is inactivated in colorectal cancers by promoter methylation [13][14][15] and also by infrequent mutations.15) Other members, SFRP2 (4q31.3) and SFRP5 (10q24.1), are also inactivated by promoter methylation in colorectal cancers.14) Strikingly, the inactivation of SFRP genes enhanced the constitutive Wnt signaling even in the presence of APC or β-catenin mutations.14, 15) In ovarian cancers, SFRP inactivation could also potentially be present for the following reasons. First, the Wnt signaling pathway can be affected in ovarian cancers, as indicated by the presence of β-catenin mutations in cancers of the endometrioid type. 4,5) Second, in the serous type, in spite of increased β-catenin accumulation, 16) β-catenin mutations are infrequent, 17) and abnormality in other genes in the Wnt signaling pathway is suggested.In this study, we analyzed methylation-associated silencing of the SFRP1 gene on chromosome 8p11.2...

No abstract

ObjectiveTo investigate the clinical significance of systematic retroperitoneal lymphadenectomy during interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients.MethodsWe retrospectively reviewed the medical records of 124 advanced EOC patients and analyzed the details of neoadjuvant chemotherapy (NACT), IDS, postoperative treatment, and prognoses.ResultsFollowing IDS, 98 patients had no gross residual disease (NGRD), 15 had residual disease sized <1 cm (optimal), and 11 had residual disease sized ≥1 cm (suboptimal). Two-year overall survival (OS) and progression-free survival (PFS) rates were 88.8% and 39.8% in the NGRD group, 40.0% and 13.3% in the optimal group (p<0.001 vs. NGRD for both), and 36.3% and 0% in the suboptimal group, respectively. Five-year OS and 2-year PFS rates were 62% and 56.1% in the lymph node-negative (LN-) group and 26.2% and 24.5% in the lymph node-positive (LN+) group (p=0.0033 and p=0.0024 vs. LN-, respectively). Furthermore, survival in the LN+ group, despite surgical removal of positive nodes, was the same as that in the unknown LN status group, in which lymphadenectomy was not performed (p=0.616 and p=0.895, respectively). Multivariate analysis identified gross residual tumor during IDS (hazard ratio, 3.68; 95% confidence interval, 1.31 to 10.33 vs. NGRD) as the only independent predictor of poor OS.ConclusionNGRD after IDS improved prognosis in advanced EOC patients treated with NACT-IDS. However, while systematic retroperitoneal lymphadenectomy during IDS may predict outcome, it does not confer therapeutic benefits.

No abstract