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Intraindividual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The aim of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling and DNA methylation profiling of four OSC genomes by using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, eight shared and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency, and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA and RB1 were also identified. It is of note that the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that, despite ITH, somatic mutations, CNAs and DNA methylations in both 'common' category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource for discovering somatic mutations of primary OSC with diagnostic and therapeutic relevance. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

INTRODUCTION The aim of this study was to investigate the association between Toll-like receptor 2 (TLR2) gene polymorphisms and human papillomavirus (HPV)-related cervical neoplasia in Korean women. MATERIAL AND METHODS Peripheral blood samples collected from 127 patients with HPV-related cervical neoplasia and 175 healthy women were genotyped for the TLR2 -16934, +1350, intron1, and 3' untranslated region (UTR) polymorphisms using the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS The TLR2 -16934 A/A, intron1 A/A, and +1350 T/C genotypes were more frequent in patients than in controls [odds ratio (OR) = 2.1, 95% CI = 1.302-3.475, p = 0.002; OR = 1.9, 95% CI = 1.168-3.169, p = 0.010; and OR = 1.9, 95% CI = 1.211-3.123, p = 0.006, respectively]. The frequencies of the TLR2 + 1350 C and 3'UTR G alleles were also higher in patients (OR = 2.0, 95% CI = 1.236-3.121, p = 0.004 and OR = 1.7, 95% CI = 1.005-3.076, p = 0.046, respectively). The genotype frequencies of TLR2 -16934 A/A and intron1 A/A increased with increasing oncogenic risk of the HPV genotype, as follows. low-risk type < high-risk type < HPV-16 and/or HPV-18 type (p = 0.008). CONCLUSIONS Our study provides the first evidence that TLR2 gene polymorphisms are associated with high-risk type HPV-related cervical neoplasia and may play an important role in susceptibility to HPV infection. Further large-scale and functional studies are needed to confirm the role of TLR2 gene polymorphisms in HPV-related cervical neoplasia.

Aim The aim of this study was to compare Affirm VPIII Microbial Identification Test results for Korean women to those obtained for Gardnerella vaginalis through Nugent score, Candida albicans based on vaginal culture and Trichomonas vaginalis based on wet smear diagnostic standards. Methods Study participants included 195 women with symptomatic or asymptomatic vulvovaginitis under hospital obstetric or gynecologic care. A definite diagnosis was made based on Nugent score for Gardnerella, vaginal culture for Candida and wet prep for Trichomonas vaginalis. Affirm VPIII Microbial Identification Test results were then compared to diagnostic standard results. Results Of the 195 participants, 152 were symptomatic, while 43 were asymptomatic. Final diagnosis revealed 68 (37.87%) cases of Gardnerella, 29 (14.87%) cases of Candida, one (0.51%) case of Trichomonas, and 10 (5.10%) cases of mixed infections. The detection rates achieved by each detection method (Affirm assay vs diagnostic standard) for Gardnerella and Candida were not significantly different (33.33% vs 34.8% for Gardnerella, 13.33% vs 14.87% for Candida, respectively). The sensitivity and specificity of the Affirm test for Gardnerella compared to the diagnostic standard were 75.0% and 88.98%, respectively. For Candida, the sensitivity and specificity of the Affirm test compared to the diagnostic standard were 82.76% and 98.80%, respectively. The number of Trichomonas cases was too small (1 case) to be statistically analyzed. Conclusions The Affirm test is a quick tool that can help physicians diagnose and treat patients with infectious vaginitis at the point of care.

This study investigated whether killer-cell immunoglobulin-like receptor (KIR) genes and human leukocyte antigen (HLA)-C alleles, receptors and ligands of natural killer cells are associated with the development of human papillomavirus (HPV)-related cervical disease in Korean women. Blood samples from 132 women with HPV-related cervical disease and 159 women without HPV infection were collected for genotyping of KIR genes and HLA-C alleles. Although no relationship was found between KIR genes and HPV-related cervical disease, a significant relationship was found between HLA-C alleles as ligands of KIR and HPV-related cervical disease. Women with HPV-related cervical disease were found to be significantly more likely to carry HLA-C*0303, particularly those with HPV 16 or 18 infection, and less likely to carry HLA-C*01 compared to women without HPV infection. HLA-C*0303 was found to confer susceptibility to HPV-related cervical disease, whereas HLA-C*01 was found to confer a protective effect against HPV-related cervical disease.

Aim: The aim of this study was to evaluate the behavior of low-grade squamous intraepithelial lesion (LSIL) in Korean women infected with human papillomavirus (HPV) in relation to the immunocytochemical detection of the HPV L1 capsid protein. Material and Methods: From January 2006 to December 2007, a total of 353 immunocytochemistry tests were performed on specimens from HPV-infected patients with LSIL. Due to exclusions, the study population was reduced to 318. Subjects were monitored at 4–6 month intervals. The regression, persistence, and progression of the cytologic abnormalities of the 318 cases were compared with the results of HPV L1 capsid protein immunocytochemical detection. Results: Of the 137 patients negative for the HPV L1 capsid protein, 38 (27.7%) showed progression to high-grade lesions, 50 (36.5%) showed persistence, and 49 (35.8%) showed regression to normal cytological features. In contrast, of the remaining 181 patients positive for the HPV L1 capsid protein, 15 (8.3%) showed progression to high-grade lesions, 74 (40.9%) showed persistence, and 92 (50.8%) showed regression. The results of immunocytochemical testing for the HPV L1 capsid protein show a linear association with the progression or regression behavior of low-grade cervical cytology in patients infected with HPV (linear by linear association test, P

Although endometriosis is a common disease in women of reproductive age, rectal endometriosis is rare and lymph node involvement by endometriosis is considered uncommon. We report a 37-year-old woman who had irregular lower abdominal pain and changes in bowel habits. She was operated on with suspected rectal cancer, but the histological diagnosis was rectal endometriosis with lymph node involvement. In women who suffer from digestive complaints, endometriosis should be considered in differential diagnosis. Rectal endometriosis has the ability to invade adjacent tissue as true malignant tumors. Therefore, lymph node involvement should be considered in rectal endometriosis.

Park SW, Hur SY, Yoo NJ, Lee SH. Somatic frameshift mutations of bone morphogenic protein receptor 2 gene in gastric and colorectal cancers with microsatellite instability. APMIS 2010; 118: 824–9. Mounting evidence exists that perturbation of bone morphogenic protein (BMP) signaling is involved in cancer development, especially in gastrointestinal cancers. However, somatic mutations of the genes encoding BMP and BMP receptors have not yet been discovered in human cancer tissues. By analyzing a public database, we found that BMP receptor 2 (BMPR2) and BMP1 genes had mononucleotide repeats in their coding sequences that could be mutation targets in cancers with microsatellite instability (MSI). In this study, we analyzed the mutation of BMPR2 and BMP1 genes in gastric (GC) and colorectal cancers (CRC) with MSI [31 GC with high MSI (MSI-H), 13 GC with low MSI (MSI-L), 38 CRC with MSI-H and 15 CRC with MSI-L] by single-strand conformation polymorphism analysis and DNA sequencing. Overall, we found seven frameshift mutations in the BMPR2 gene, but not in the BMP1 gene. The mutations were an identical deletion mutation of one base in the repeats (c.1748delA) that would result in premature stops of the amino acid synthesis (p.Asn583ThrfsX44). The BMPR2 mutations were detected in 6.5% of GC and 13.2% of CRC with MSI-H. All the cancers with the BMPR2 mutation showed loss of BMPR2 expression. Our data indicate that frameshift mutation of BMPR2 gene occurs in GC and CRC with MSI-H, and suggest that the BMPR2 mutation might contribute to cancer pathogenesis by inactivating BMPR2-mediated BMP signaling.

Yoo NJ, Hur SY, Kim MS, Lee JY, Lee SH. Immunohistochemical analysis of RNA-induced silencing complex-related proteins AGO2 and TNRC6A in prostate and esophageal cancers. APMIS 2010; 118: 271–6. Evidence exists that microRNA (miRNA), which regulates gene expression, is frequently deregulated in cancers. A mature miRNA directs a RNA-induced silencing complex (RISC) to its target messenger RNA, and causes inhibition of gene transcription. Ago proteins and TNRC proteins are main components of the RISC and participate in miRNA-induced gene silencing. However, expression status of Ago and TNRC proteins has not yet been studied in human cancer tissues. In this study, we attempted to explore whether expressions of Ago2 and TNRC6A are altered in prostate carcinomas (PCA) and esophageal squamous cell carcinomas (ESCC). We analyzed the expression of Ago2 and TNRC6A in 107 PCA and 58 ESCC tissues by immunohistochemistry using a tissue microarray (TMA) method. In the prostate, Ago2 was not expressed in normal glandular cells, while it was expressed in 50.0% of prostate intraepithelial neoplasia (PIN) and 57.0% of the PCA. TNRC6A was not expressed in normal prostate cells, while it was expressed in 55.0% of the PIN and 63.6% of the PCA in cytoplasm and nucleus. In the esophagus, neither Ago2 nor TNRC6A was expressed in normal squamous cells, while Ago2 and TNRC6A were expressed in 58.6% and 62.1% of the ESCC, respectively. However, neither the expression of Ago2 or TNRC6A was associated with pathologic characteristics of the cancers, including age, sex, Gleason score (PCA) and stage. The increased expressions of Ago2 and TNRC6A in both PCA and ESCC compared with their normal cells suggested that over-expression of these proteins may be related to miRNA functions and might play a role in tumorigenesis of PCA and ESCC.

A missense somatic mutation in the FOXL2 gene affecting codon 134 has recently been reported in granulosa cell tumour (GCT) and thecoma of the ovary. Such a recurrent nature of the mutation strongly suggests that the FOXL2 mutation may play an important role in the development of ovarian sex cord-stromal tumours. The aim of this study was to characterize the FOXL2 mutation in human tumour tissues. We analysed 1353 tumour tissues from various origins, including ovarian tumours and other common cancers, by single-strand conformation polymorphism analysis. We found the FOXL2 codon 134 missense mutation in 53 of 56 adult GCTs (94.6%) and two of the 16 thecomas (12.5%), but none in other tumours. Histologically, FOXL2 mutation-negative adult GCT showed that GCT cells were admixed with fibrothecomatous cells, and FOXL2 mutation-positive thecomas showed that luteinized theca cells were predominant. However, immunostaining of either inhibin alpha or FOXL2 did not differentiate the FOXL2 mutation status of adult GCTs and thecomas. There was no FOXL1 mutation and no common oncogenic mutation in the adult GCTs and thecomas. Our data indicate that the FOXL2 codon 134 mutation occurs exclusively in GCT and thecoma, and suggest the possibility that the development of most GCTs and a fraction of thecomas may be dependent on this mutation. Our data also suggest that the FOXL2 mutation status, as well as some histological features, may be important in the diagnosis of ovarian sex cord-stromal tumours.

Background We evaluated the efficacy and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) using paclitaxel as consolidation therapy in patients with epithelial ovarian cancer. Methods Between November 1999 and January 2004, 18 patients with a negative second-look and 1 patient with positive peritoneal cytology only with stage Ic–IIIc epithelial ovarian cancer received consolidation intra-operative HIPEC using paclitaxel. The HIPEC was performed with open-abdomen technique, using 6 L of lactated Ringer's solution containing paclitaxel 175 mg/m2, for 90 min in hyperthermic phase (43–44°C). The survival rates were compared with 24 patients treated with conventional therapy (control group). Results The 8-year progression-free survival rates were 63.16% in the HIPEC-paclitaxel group and 29.17% in the control group (P = 0.027). The 8-year overall survival rates were 84.21% in the HIPEC-paclitaxel group and 25.00% in the control group (P = 0.0004). The time interval between initial treatment and HIPEC was statistically significant with respect to progression-free and overall survival in the HIPEC-paclitaxel group. Conclusion HIPEC with paclitaxel during 2nd-look laparotomy is feasible and relatively safe and showed a good effect on survival. In patients with epithelial ovarian cancer who have a complete pathologic response, HIPEC with paclitaxel should be considered as a consolidation treatment option. J. Surg. Oncol. 2010;101:149–155. © 2009 Wiley-Liss, Inc.

Biochemistry, College of Medicine,The Catholic University of Korea, Seoul, KoreaPark SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia-relatedgenes HIF1a and CUL2 in common human cancers. APMIS 2009; 117: 880–5.Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia-inducible factor 1a(HIF1a) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1a is upreg-ulated not only by hypoxia but also by genetic alterations in HIF1a-related genes, including VHL.Cullin 2 (CUL2) interacts with the trimeric VHL-elongin B-elongin C complex and plays an essentialrole in the ubiquitinated degradation of HIF1a. The aim of this study was to explore whether HIF1aand CUL2 genes are somatically mutated, and contribute to HIF1a activation in common human can-cers. For this, we have analyzed the coding region of oxygen-dependent degradation domain of HIF1ain 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias bya single-strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeatsequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability(MSI). We found one HIF1a mutation (p.Ala593Pro) in the hepatocellular carcinomas (1⁄47; 2.1%),but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2⁄41). Our data indicate thatsomatic mutation of HIF1a is rare in common cancers, and somatic mutation of CUL2 occurs in a frac-tion of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1a norCUL2 mutation may play a central role in HIF1a activation in gastric, colorectal, breast, lung andhepatocellular carcinomas, and acute leukemias.Key words: HIF1a; CUL2; hypoxia; mutation; cancer; microsatellite instability.Sug Hyung Lee, Department of Pathology, College of Medicine, The Catholic University of Korea,505 Banpo-dong, Socho-gu, Seoul 137 701, Korea. e-mail: suhulee@catholic.ac.kr*

Objective. To examine the relation between the plasma concentration of antioxidant micronutrients and endometrial cancer risk in Korean women. Design. Hospital-based case–control study. Setting. Seven tertiary medical institutes in Korea. Population. Incidence of 28 endometrial cancer cases were identified and 140 age-matched controls selected for the same period.Methods. Preoperative plasma concentrations of β-carotene, lycopene, zeaxanthin plus lutein, retinol, α-tocopherol, and γ-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. Conditional logistic regression was used to evaluate micronutrient effect after adjustment for body mass index (BMI), menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status.Main outcome measures. Effect of micronutrients on endometrial cancer risk.Results. The mean concentration of plasma β-carotene (p=0.001), lycopene (p=0.008), zeaxanthin plus lutein (p=0.031), retinol (p=0.048), and γ-tocopherol (p=0.0...

Objective. We investigated the relation between plasma carotenoids, retinol and tocopherol levels and ovarian cancer risk in Korean women. Design. Hospital-based case–control study. Setting. Six tertiary medical institutes in Korea. Population. Forty-five epithelial ovarian cancers and 135 age-matched controls. Methods. Preoperative plasma concentrations of β-carotene, lycopene, zeaxanthin plus lutein, retinol, α-tocopherol, and γ-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. Main outcome measures. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated by tertiles to evaluate the effect of micronutrients on endometrial cancer risk after adjustment for body mass (BMI) index, menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status. Results. Women in the highest tertile for β-carotene had 0.12-times the risk of ovarian cancer of in the lowest tertile (OR 0.12; 95%CI 0.04–0.36). Women with the highest tertiles of lycope...

Ovarian tumors are reported in 1 of every 200 pregnancies and may cause serious problems such as torsion, infarction, and obstruction of vaginal delivery. These tumors have typically been removed by elective surgery, preferably in the second trimester. Because abdominal surgery significantly stresses both the mother and fetus, this study was planned to determine the optimal management of ovarian tumors in 89 pregnant women with tumors requiring surgery. Surgery was emergent because of torsion of the tumor in 36 cases (group A) and elective in 53 cases (group B). The 2 groups were similar in maternal age, parity, and gestational age at the time of surgery. Emergency surgery was done in the first, second, and third trimesters in 22, 5, and 9 women, respectively. Elective surgery was done in the second trimester in two thirds of cases and in the first trimester in the others. Mean birth weights were similar for the 2 groups, but preterm births were significantly more frequent in group A (22% vs. 4%). There was no group difference in gestational age at preterm delivery. Tumors were of comparable size in the 2 groups, and there was no difference in their location. Most tumors were 6 to 10 cm in size. Nearly 10% of women in both groups had bilateral ovarian tumors. There were no perinatal deaths, and no difference was noted in rates of vaginal or cesarean delivery. Dermoid cyst was the most common histologic diagnosis, accounting for 36% of group A and 45% of group B cases. Two group A tumors but none of those in group B were malignant. In this series, the risk of adverse pregnancy outcomes was not greater when surgery was delayed until symptoms of ovarian tumor developed rather than being done electively. The authors favor a conservative approach to pregnant women who have an ovarian tumor.