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Purpose Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.Materials and Methods We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.Results In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.Conclusion Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

Purpose The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. Materials and methods Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. Results The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). Conclusion Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea.

Purpose Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM(1,2,6), and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. Materials and methods We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. Results Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM(1,2,6), 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM(1,2,6) demonstrated higher specificity than the other models. Conclusion In the Korean population, overall predictive values of the three models (MMRPredict, PREMM(1,2,6), MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.

SNU (Seoul National University) cell lines have been established from Korean cancer patients since 1982. Of these 109 cell lines have been characterized and reported, i.e., 17 colorectal carcinoma, 12 hepatocellular carcinoma, 11 gastric carcinoma, 12 uterine cervical carcinoma, 17 B-lymphoblastoid cell lines derived from cancer patients, 5 ovarian carcinoma, 3 malignant mixed Mllerian tumor, 6 laryngeal squamous cell carcinoma, 7 renal cell carcinoma, 9 brain tumor, 6 biliary tract, and 4 pancreatic carcinoma cell lines. These SNU cell lines have been distributed to biomedical researchers domestic and worldwide through the KCLB (Korean Cell Line Bank), and have proven to be of value in various scientific research fields. The characteristics of these cell lines have been reported in over 180 international journals by our laboratory and by many other researchers from 1987. In this paper, the cellular and molecular characteristics of SNU human cancer cell lines are summarized according to their genetic and epigenetic alterations and functional analysis.