Institute of Innovative Cancer Research and Asan Institute for Life science

Seoul, South Korea

Institute of Innovative Cancer Research and Asan Institute for Life science

Seoul, South Korea
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Kim S.-K.,Korea Research Institute of Bioscience and Biotechnology | Kim S.-Y.,Korea Research Institute of Bioscience and Biotechnology | Kim J.-H.,Korea Research Institute of Bioscience and Biotechnology | Roh S.A.,University of Ulsan | And 7 more authors.
Molecular Oncology | Year: 2014

Colorectal cancer (CRC) patients frequently experience disease recurrence and distant metastasis. This study aimed to identify prognostic indicators, including individual responses to chemotherapy, in CRC patients. RNA-seq data was generated using 54 samples (normal colon, primary CRC, and liver metastases) from 18 CRC patients and genes associated with CRC aggressiveness were identified. A risk score based on these genes was developed and validated in four independent CRC patient cohorts (. n=1063). Diverse statistical methods were applied to validate the risk scoring system, including a generalized linear model likelihood ratio test, Kaplan-Meier curves, a log-rank test, and the Cox model. TREM1 and CTGF were identified as two activated regulators associated with CRC aggressiveness. A risk score based on 19 genes regulated by TREM1 or CTGF activation (TCA19) was a significant prognostic indicator. In multivariate and subset analyses based on pathological staging, TCA19 was an independent risk factor (HR=1.894, 95% CI=1.227-2.809, P=0.002). Subset stratification in stage III patients revealed that TCA19 had prognostic potential and identified patients who would benefit from adjuvant chemotherapy, regardless of age. The TCA19 predictor represents a novel diagnostic tool for identifying high-risk CRC patients and possibly predicting the response to adjuvant chemotherapy. © 2014 Federation of European Biochemical Societies.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research and Asan Institute for Life science | Ha Y.J.,University of Ulsan | Ha Y.J.,Institute of Innovative Cancer Research and Asan Institute for Life science | And 16 more authors.
British Journal of Cancer | Year: 2013

Background: Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy. Methods: A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway. Results: For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively. Conclusion: LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed. © 2013 Cancer Research UK. All rights reserved.

Yoon Y.S.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research and Asan Institute for Life science
World Journal of Gastroenterology | Year: 2014

The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culturebased chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyltetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC. © 2014 Baishideng Publishing Group Inc. All rights reserved.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research and Asan Institute for Life science | Kim S.Y.,Institute of Innovative Cancer Research and Asan Institute for Life science | Kim S.Y.,Korea Research Institute of Bioscience and Biotechnology | And 14 more authors.
Cancer Science | Year: 2010

Improved methods for predicting chemoresponsiveness involving the identification of polymorphic markers is highly desirable, considering narrow therapeutic index and frequent resistance to anti-cancer regimens. The genome-wide screening of chemosensitive single nucleotide polymorphisms (SNPs) was undertaken in association with in vitro chemosensitivity assays in 104 colorectal cancer patients for the initial screening step. Allele frequency, linkage disequilibrium, potential function, and Hardy-Weinberg equilibrium of the candidate SNPs were then determined for the identifying step. Finally, clinical association analysis in the other 260 evaluable patients or cell viability assays of transfected RKO cells was used to verify candidate SNPs for the validation step. In total, 12 SNPs to six regimens were initially chosen during the screening and identifying steps. In patients receiving fluoropyrimidine-based adjuvant chemotherapy, the substitution alleles of GPC5 rs553717 (AA) correlated significantly with tumor recurrence and shorter disease-free survival (P=0.019 and 0.023, respectively). Interestingly, RKO cells expressing mutant GPC5 showed enhanced cell death in response to 5-FU in cytotoxicity assays. Patients that were homozygous for the reference alleles SSTR4 rs2567608 (AA) and EPHA7 rs2278107 (TT) showed lower disease control rates in response to irinotecan and oxaliplatin regimens, respectively, than those with substitution alleles (P=0.022 and 0.014, respectively). Thus, we identified chemosensitive SNP markers using a novel three step process of genome-wide analysis consisting of in vitro screening, identification, and validation. The candidate chemosensitive SNP markers identified in our study, including those identified in vitro, can now be further verified in a large cohort study. © 2010 Japanese Cancer Association.

PubMed | University of Ulsan, Institute of Innovative Cancer Research and Asan Institute for Life science and Korea Research Institute of Bioscience and Biotechnology
Type: Journal Article | Journal: Oncotarget | Year: 2015

To characterize the mutation profiles of colorectal cancer (CRC) primary tumors (PTs) and liver metastases (CLMs), we performed both whole-exome and RNA sequencing. Ten significantly mutated genes, including BMI1, CARD11, and NRG1, were found in 34 CRCs with CLMs. We defined three mutation classes (Class 1 to 3) based on the absence or presence of mutations during liver metastasis. Most mutations were classified into Class 1 (shared between PTs and CLMs), suggesting the common clonal origin of PTs and CLMs. Class 1 was more strongly associated with the clinical characteristics of advanced cancer and was more frequently superimposed with chromosomal deletions in CLMs than Class 2 (PT-specific). The integration of exome and RNA sequencing revealed that variant-allele frequencies (VAFs) of mutations in the transcriptome tended to have stronger functional implications than those in the exome. For instance, VAFs of the TP53 and APC mutations in the transcriptome significantly correlated with the expression level of their target genes. Additionally, mutations with high functional impact were enriched with high VAFs in the CLM transcriptomes. We identified 11 mutation-associated splicing events in the CRC transcriptomes. Thus, the integration of the exome and the transcriptome may elucidate the underlying molecular events responsible for CLMs.

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