The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients / 부인종양

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and < or = median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

Estimation of Prognostic Marker Genes by Public Microarray Data in Patients with Ovarian Serous Cystadenocarcinoma

PURPOSE: Lymphatic invasion (LI) is regarded as a predictor of the aggressiveness of ovarian cancer (OC). However, LI is not always the major determinant of long-term patient survival. To establish proper diagnosis and treatment for OC, we analyzed differentially expressed genes (DEGs) for patients with serous epithelial OC, with or without LI, who did or did not survive for 5 years. MATERIALS AND METHODS: Gene expression data from 63 patients with OC and LI, and 35 patients with OC but without LI, were investigated using an Affymetrix Human Genome U133 Array and analyzed using The Cancer Genome Atlas (TCGA) database. Among these 98 patients, 16 survived for 5 years or more. DEGs were identified using the Bioconductor R package, and their functions were analyzed using the DAVID web tool. RESULTS: We found 55 significant DEGs (p<0.01) from the patients with LI and 20 highly significant DEGs (p<0.001) from those without it. Pathway analysis showed that DEGs associated with carbohydrate metabolism or with renal cell carcinoma pathways were enriched in the patients with and without LI, respectively. Using the top five prognostic marker genes, we generated survival scores that could be used to predict the 5-year survival of patients with OC without LI. CONCLUSION: The DEGs identified in this study could be used to elucidate the mechanism of tumor progression and to guide the prognosis and treatment of patients with serous OC but without LI.

Association of family risk and lifestyle/comorbidities in ovarian cancer patients / Associação de história familiar e estilo de vida a comorbidades em pacientes com câncer de ovário.

Summary Objectives: to analyze factors that might indicate familial predisposition for ovarian cancer in patients diagnosed with this disease. Methods: in a prospective single center cohort study at the Institute of Cancer of the State of São Paulo (ICESP), 51 women diagnosed with ovarian cancer were included. Familial predisposition for ovarian cancer was defined as having a higher than 10% chance of having a BRCA1/2 mutation according to the Manchester scoring system, a validated method to assess the likelihood of mutation detection. Each patient was interviewed with a standardized questionnaire on established risk factors for ovarian cancer and other factors that might influence the risk to develop ovarian cancer. Logistic regression analyses were performed to estimate the impact of the evaluated factors on the likelihood of mutation detection, by calculating odds ratios and 95% confidence intervals. Results: seventeen out of 51 patients had a family history of breast and/or ovarian cancer, four patients had a history of breast or endometrial cancer, 11 were diagnosed before the age of 50, and 12 presented a risk of familial predisposition to ovarian cancer higher than 10%. Patients with comorbidities, such as hypertension, diabetes, hormonal disorders, dyslipidemia and psychiatric conditions, presented a lower chance of having a familial predisposition for ovarian cancer (OR: 0.22; 95% CI: 0.06-0.88; p=0.03). Conclusion: in this study, having comorbidities was associated with a lower risk of having a familial predisposition for ovarian cancer. Other factors associated with the risk of ovarian cancer did not have an impact on this predisposition. .

Resumo Objetivos: analisar fatores que possam indicar uma predisposição familiar ao câncer de ovário em pacientes com este diagnóstico. Métodos: em estudo de coorte prospectiva realizado no Instituto do Câncer do Estado de São Paulo (ICESP), foram incluídas 51 mulheres diagnosticadas com câncer de ovário entre janeiro de 2009 e dezembro de 2011. Predisposição familiar para câncer de ovário foi definida como um risco maior de 10% de apresentar uma mutação em BRCA1/2, de acordo com o sistema de pontes de Manchester, um método validado para avaliar a probabilidade de detecção de mutação nesses genes. Cada paciente foi entrevistada com um questionário padronizado, abordando fatores de risco para câncer de ovário e outros fatores que pudessem influenciar o risco de desenvolver a doença. O impacto dos fatores avaliados na probabilidade de detecção da mutação foi avaliado com regressões logísticas. Resultados: dezessete das 51 pacientes referiram história familiar de câncer de mama e/ou ovário, quatro pacientes apresentavam antecedente pessoal de câncer de mama ou endométrio, 11 haviam sido diagnosticadas antes dos 50 anos e 12 apresentaram um risco maior que 10% de predisposição familiar a câncer de ovário. Pacientes com comorbidades como hipertensão, diabetes, disfunções hormonais, dislipidemia e distúrbios psiquiátricos apresentaram menor risco de predisposição familiar ao câncer de ovário (OR: 0.22; IC 95%: 0.06-0.88; p=0.03). Conclusão: neste estudo, apresentar alguma comorbidade foi associado a um menor risco de ter uma predisposição familiar ao câncer de ovário. Outros fatores associados ao risco de câncer de ovário não tiveram nenhum impacto sobre esta predisposição. .

Mutational Analysis of KRAS, BRAF, and TP53 Genes of Ovarian Serous Carcinomas in Korean Women

PURPOSE: To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas. MATERIALS AND METHODS: Patients with primary invasive serous carcinomas were classified according to the universal grading system. Grade 2 serous tumors were excluded. A total of 100 patients were included for clinical evaluation. Thirty-seven patients, including 20 with low-grade and 17 with high-grade carcinomas, were selected for mutational analysis. RESULTS: The low-grade carcinoma group was characterized by young age and premenopausal period compared with the high-grade carcinoma group, but there were no statistically significant differences in stage, metastasis of lymph node and residual disease. There were no statistically significant differences in survival rates, however, the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage (p = 0.064). Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group. KRAS and BRAF mutations were mutually exclusive, and both mutations were observed in 40% (8/20). The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009). CONCLUSION: Low-grade serous carcinoma shows mutation pattern different from that with high-grade carcinoma. As there were no significant differences in stage distribution and survival, especially in advanced stage, we suggest that more studies are needed to segregate these patients into distinct disease entities.

Different imprinting status of IGF-2 in epithelial ovarian tumors / 华中科技大学学报（医学）（英德文版）

To explore whether the imprinting status of IGF-2 in the malignant epithelial ovarian tumors is different from that in benign tumors, the target sequences (DNA and RNA) which contain a polymorphism site for ApaI restriction endonuclease digestion were amplified with PCR and RT-PCR methods. Then the PCR/RT-PCR products were digested by ApaI. The IGF-2 transcriptional pattern came out from the results of endonucleases digestion. Among the 36 cases of benign epithelial ovarian tumors, 20 were heterozygous for ApaI locus and all showed genomic imprinting. While in the malignant group, 22 were heterozygous for ApaI locus but six were found to lose imprinting. Significant differences existed between the two groups (P < 0.05). Loss of imprinting of IGF-2 may serve as a marker for differentiating the malignant ovarian cancers from the benign ones. In a new field of molecular genetics, our research provides an experimental basis for genetic diagnosis and treatment of the ovarian cancers.