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Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC.

Glycosylation is an important post-translational modification, in which attachment of glycans to proteins has effects on biological functions and carcinogenesis. Analysis of human chorionic gonadotropin, a glycoprotein hormone produced by placental trophoblasts and trophoblastic tumors, has contributed to the diagnosis and treatment of trophoblastic disease, resulting in reduced incidence and mortality. However, alterations of the glycan structure itself in choriocarcinoma have not been characterized. We established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC3-1), which mimics the clinical pathohistology in vivo, to examine the tumorigenesis and pathogenesis of choriocarcinoma. In this study, the alterations of glycan structures in the development of choriocarcinoma were examined by performance of comprehensive glycan profiling in clinical samples and in iC3-1 cells using a conventional microarray and the recently introduced lectin microarray. Microarray comparison showed significant upregulation of several characteristic glycogenes in the iC3-1 cells as compared to the parental HTR8/SVneo cells. The lectin array showed increased α-2-6-sialic acid, Galβ1-4GlcNAc, GlcNAcβ1-3GalNAc, and decreased α-1-6 core fucose, high mannose, GalNacβ1-4Gal, GALNAc (Tn antigen) and Galβ1-3Gal in choriocarcinoma tissue compared to normal villi. This is the first report of a lectin array analysis in choriocarcinoma and provides useful information for understanding of the disease.

Chemotherapy and surgery are important treatment strategies for gynecologic malignant tumors such as ovarian, cervical and endometrial cancer. However, many anticancer drugs currently available are cytotoxic and cause strong adverse reactions in patients. Aurora kinases have attracted increasing attention in recent years as serine/threonine kinases with various roles in cell division, including chromosomal agglutination and segregation, functions of centromeres, centrosomal maturation, spindle formation and cytokinesis. Aurora kinases are overexpressed in a number of cancers and recent studies have shown that they are involved in onco genesis and cause an aberrant increase in centrosome number, emergence of polykaryocytes and failure of cancer inhibition mechanisms. Thus, drugs that inhibit Aurora kinases are likely to exert anticancer effects in various fields, including the gynecologic field. Aurora kinase inhibitors exert antitumor effects in monotherapy and synergistic effects in combination therapy with taxane-based anticancer agents for gynecologic tumors and are likely to increase the efficacy of existing anticancer drugs. Current Aurora kinase inhibitors include ZM447439, Hesperadin, VX-680/MK-0457, AT9283 and Barasertib, and clinical trials are ongoing to verify the effects of these inhibitors.

The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers.

Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur. Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. Epimutation has been shown for many tumor suppressor genes, including RB, VHL, hMLH1, APC and BRCA1, in sporadic cancers. Methylation has recently been shown in DNA from normal tissues and peripheral blood in cases of sporadic colorectal cancer and many studies show constitutive epimutation in cancers. Epimutation of DNA mismatch repair (MMR) genes (BRCA1, hMLH1 and hMSH2) involved in development familial cancers has also been found. These results have led to a focus on epimutation as a novel oncogenic mechanism.

The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use.

Progestin preparations are made of synthetic progesterone and have often been used for hormone therapy in gynecological patients with endometriosis or endometrial cancer. Hormone therapy using progestin is considered to be one of the effective means of treatment particularly when dealing with endometrial cancer (an estrogen-dependent tumor). Numerous reports have been published concerning its efficacy in advanced or recurrent cases of atypical endometrial hyperplasia or endometrial cancer. Dienogest has been developed as a fourth-generation progestin for hormone therapy for endometriosis that can be used with high safety for long periods of time. In Japan, dienogest has been recommended as a first-line drug for endometriosis-associated pain. However, its antitumor activity has also been attracting close attention following a report that this drug suppressed the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterine acetate (MPA). The mechanism for antitumor activity of dienogest is considered to differ from the mechanism for antitumor activity of conventional progestin preparations used for treatment of endometrial cancer. This drug is expected to be clinically applicable as a new drug for the treatment of endometrial cancer.

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.