Seon-Kyung Lee

BRCA1 and BRCA2 germline mutations in Korean ovarian cancer patients

PurposeTo evaluate the proportion of Korean ovarian cancer patients with a strong family history and the genetic status in such patients.Methods and patientsPedigree analysis and genetic counseling were performed on 337 ovarian cancer patients in the National Cancer Center Korea between January 2005 and June 2008. Patients with a strong family history were defined as (1) patients with double primary ovarian and breast cancer and (2) ovarian cancer patients with one or more first-degree relatives with breast or ovarian cancer. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by direct sequencing.ResultsSixteen percent (54/337) of patients had a strong family history. Of the 54 patients with a strong family history, 40 patients (74%) accepted the genetic test. Thirteen deleterious mutations (11 in BRCA1 and 2 in BRCA2) were identified (33%). Twenty-three of 283 patients (8%) without a strong family history underwent genetic testing and two deleterious mutations in BRCA1 were identified (9%). Eight of 15 mutations (53%) were novel, and c.1041delAGCinsT and c.2081insC in the BRCA1 gene were recurrent in two patients.ConclusionsThe proportion of Korean ovarian cancer patients with a strong family history was significant, and the prevalence of BRCA1 and BRCA2 mutations in such patients was high.

Pattern of lymph node metastasis and the optimal extent of pelvic lymphadenectomy in FIGO stage IB cervical cancer

Aim:  To evaluate the distribution pattern of lymph node metastasis and to determine the optimal extent of pelvic lymphadenectomy (LA) in FIGO stage IB cervical cancer.

Current status in the management of uterine corpus cancer in Korea

Uterine corpus cancer has increased in prevalence in Korean women over the last decade. Recently, elegant studies have been reported from many institutes. To improve treatment strategies, a review of our own data is warranted. This work will discuss the risks and prognostic factors for uterine corpus cancer, and the radiologic evaluation, prediction of lymph node metastasis, systematic lymphadenectomy, minimally invasive surgery, ovarian-saving surgery, fertility-sparing treatment, and adjuvant treatment in women with uterine cancer.

Comparison of adjuvant chemotherapy and radiation in patients with intermediate risk factors after radical surgery in FIGO stage IB–IIA cervical cancer

The aim of this study was to compare the outcome of chemotherapy or radiation as adjuvant therapy for patients with FIGO stage IB–IIA cervical cancer and surgically confirmed intermediate risk factors. Data were collected from patients with uterine cervical cancer FIGO stage IB–IIA who had adjuvant chemotherapy following radical hysterectomy with pelvic lymph node dissection (RHLND, cases) or adjuvant radiotherapy following RHLND (controls). The study groups consisted of 38 cases and 42 controls. Adjuvant treatment was given to the patients with a combination of intermediate risk factors including deep stromal invasion (>50%), lymphvascular space invasion, large tumor size (3–6 cm), or close vaginal resection margin (<1 cm). Comparison of the cases with the controls revealed no significant differences in variables studied including median age (P= 0.18), stage distribution (P= 0.30), histologic subtype (P= 0.93), pathologic tumor size (P= 0.46), depth of the stromal invasion (P= 0.29), lymphvascular space invasion (P= 0.50), and close vaginal resection margin (P= 0.62). The difference in disease-free survival rates was not significant (P= 0.68). However, the overall survival analysis was incomplete due to the limited number of events available at the end of the study period. The findings of this study suggest that adjuvant chemotherapy in patients with FIGO stage IB–IIA uterine cervical cancer and surgically confirmed intermediate risk factors may be effective.

Frequent inactivation of hSRBC in ovarian cancers by promoter CpG island hypermethylation.

Objective. To explore the implication of human SRBC gene [serum deprivation response factor‐related gene product that binds to the c‐kinase (hSRBC)] abnormality in ovarian tumorigenesis. Design. Retrospective study. Setting. Medical center. Sample. Twenty‐two epithelial ovarian cancer and six normal ovary tissues. Measures. Mutation and altered expression of hSRBC gene. Methods. hSRBC expression was characterized by polymerase chain reaction (PCR) analysis. Promoter CG dinucleotide (CpG) site methylation was determined using methylation specific PCR and bisulfite sequencing. Results. Expression of hSRBC transcript was easily detectable in all normal tissues we examined, but 50% (two of four) of cancer cell lines and 41% (nine of 22) of primary carcinomas exhibited undetectable or substantially decreased expression. While genomic deletion or somatic mutations of the gene was not identified, its expression was reactivated in tumor cells by 5‐aza‐2′‐deoxycytidine treatment, suggesting epigenetic inactivation of the gene in tumors. Promoter methylation was detected in all nine tumors with low expression but in only one of 13 (7.7%) tumors with normal expression. Bisulfite DNA sequencing analysis of 23 CpG sites within the promoter region revealed that the CpG sites are highly methylated in low‐expressing tumors. In addition, promoter CpG sites methylation status showed a tight association with gene expression level. Conclusion. Our data demonstrate that epigenetic inactivation of hSRBC due to aberrant promoter hypermethylation is a common event and might be implicated in human ovarian tumorigenesis.

Expression and mutational analysis of TGF-β/Smads signaling in human cervical cancers

OBJECTIVE To define the molecular basis of TGF-beta1 function in cervical carcinogenesis, we explored the expression and mutational status of TGF-beta1, TGF-beta1 receptors, and Smads, the regulators of the TGF-beta1 signaling pathway, in human cervical cancers. METHODS Expression of TGF-beta1, TGF-beta1 receptors, and Smads transcripts were determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR), and sequence alteration was analyzed using RT-PCR-single-strand conformation polymorphism (SSCP) analysis. Genomic levels of TGF-beta1, TGF-beta1 receptors and Smads was also measured by quantitative genomic PCR. RESULTS Abnormal overexpression of TGF-beta1 and abnormal reduction of type II TGF-beta1 receptor were identified in 36% (18 of 50) and 20% (10 of 50) of cervical cancer tissues, respectively. 22% (11 of 50) in Smad2 and 14% (7 of 50) in Smad4 revealed tumor specific mRNA reduction less than a half of normal means. In addition, no evidence for sequence alterations of the gene was found by RT-PCR-SSCP analysis. CONCLUSION Our study demonstrates that disruption of TGF-beta/Smad signaling pathway exist in human cervical cancer, suggesting that abnormal expressions of the member of TGF-beta/Smad signaling pathway might contribute to the malignant progression of human cervical tumors via suppressing the tumor suppression function of TGF-beta1 1s tumor suppression function.

Correlation between FDG uptake by PET/CT and the expressions of glucose transporter type 1 and hexokinase II in cervical cancer.

Background The aim of this study was to explore the association between 2-deoxy-2-F18-fluoro-D-glucose uptake and the expressions of glucose transporter type 1 (GLUT-1) and hexokinase II (HK-II) in the lymph nodes of patients with cervical cancer. Methods This prospective study included 20 women with International Federation of Gynecology and Obstetrics stage IB to stage IIA cervical cancer who underwent positron emission tomography (PET)–computed tomography (CT) (PET/CT) before surgical treatment. In 333 dissected lymph nodes (LNs) obtained, we examined the size, tumor involvement, and expressions of GLUT-1 and HK-II. These characteristics were compared with PET/CT and pathological findings. Results Pathological analysis found that 21% (70) of the 333 surgically dissected LNs were metastatic. Positron emission tomography/CT detected metastasis with 22.8% sensitivity and 98.5% specificity. The levels of GLUT-1 and HK-II expression in false-positive LNs were higher than those in pathologically confirmed negative nodes (P = 0.015 and P = 0.001, respectively). In metastatic LNs, PET/CT-positive nodes were significantly different from PET/CT-negative nodes in mean size (P = 0.043), tumor involvement (P = 0.008), and proportion of GLUT-1–positive tumor cells (P = 0.042). Conclusions Our results indicate that overexpression of GLUT-1 and HK-II may be related to 2-deoxy-2-F18-fluoro-D-glucose uptake in false-positive tissues on PET/CT. In metastatic lymph nodes, the ability of PET/CT to detect cancer may depend on tumor involvement, lymph node size, and GLUT-1 expression.

Genetic Polymorphism of PRKCDBP is Associated with an Increased Risk of Endometrial Cancer

PRKCDBP is a putative tumor suppressor located at 11p15.4, where frequent genomic loss has been observed in human cancers. We explored the possible association between an intra-exonic single nucleotide polymorphism (SNP), rs1051992, that results in a Leu to Pro substitution, and risk for endometrial carcinogenesis. We assessed the genotype of rs1051992 in endometrial cancer tissues from 147 patients and normal endometrial tissue from 191 healthy individuals by restriction endonuclease PvuII-based genotyping. Allele frequencies in the cancer specimens were compared with those in the healthy controls. We also evaluated the association between polymorphisms at this locus and histopathological features of endometrial cancer.

Neoadjuvant chemotherapy in bulky stage IB-IIA cervical cancer: results of a quick course with vincristine, bleomycin, and cisplatin.

We retrospectively analyzed 51 consecutive patients with bulky International Federation of Gynecology and Obstetrics stage IB-IIA cervical cancer who were treated with vincristine (1 mg/m2), bleomycin (25 mg/m2; days 1-3), and cisplatin (50 mg/m2) every 10 days between 1995 and 2005 to assess the efficacy and the safety of a quick course of neoadjuvant chemotherapy. A clinical response occurred in 37 patients (72.5%), including 7 patients (13.7%) with a complete response and 30 patients (58.8%) with a partial response; 13 patients (25.5%) had a stable disease, and 1 patient (2.0%) had a progressive disease. Among the 50 patients who were surgically explored, 42 patients had a radical hysterectomy with pelvic and para-aortic lymphadenectomy; radical surgery was aborted in 8 patients because of paracervical and para-aortic lymph node involvement. Hematologic toxicity was the most common adverse event with anemia occurring most frequently, followed by leukopenia. Importantly, pulmonary toxicity occurred in 7 patients, 2 of whom died of complications from pulmonary fibrosis 1 and 3 months after radical surgery. With a median follow-up of 53 months (range, 2-129 months), the estimated 2- and 5-year survival rates were 74.9% and 61.3%, respectively. In conclusion, the survival benefit of a quick course of neoadjuvant chemotherapy consisting of vincristine, bleomycin, and cisplatin may be uncertain despite the significant clinical response in bulky International Federation of Gynecology and Obstetrics stage IB2-IIA cervical cancer. Special care is required to monitor bleomycin-induced pulmonary toxicity.

Pulmonary toxicity after a quick course of combinatorial vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy in cervical cancer.

Pulmonary toxicity is one of the most serious adverse effects associated with a quick course of vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy (NAC-VBP). The aim of this study was to evaluate pulmonary toxicity related to a quick course NAC-VBP. A total of consecutive 61 patients, who underwent at most 3 cycles of NAC-VBP every 10 days in the International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIB cervical cancer from 1995 to 2007, were retrospectively analyzed. Of the 61 study subjects, 7 (11.5%) were identified to have pulmonary toxicity and 2 (3.3%) died of pulmonary fibrosis progression despite aggressive treatment and the use of a multidisciplinary approach. No factor predisposing pulmonary toxicity was identified. Initial symptoms were non-specific, but bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis were characteristic findings by high-resolution computed tomography of the chest. The benefit of steroid therapy was uncertain and was associated with steroid-induced diabetes mellitus requiring insulin therapy in two patients. Fatal pulmonary toxicity is a major concern of a quick course NAC-VBP. In conclusion, these patients require special monitoring for bleomycin-induced pulmonary toxicity.