Young-Joon Kim

Hyeran Shim, Hoang Bao Khanh Chu, Jiun Kim, Seohyeon Park, Subin Yoo, Jeongsil Kim-Ha & Young-Joon Kim. BMB Reports 2026;59:438-42. https://doi.org/10.5483/BMBRep.2025-0237

As a disease with a high mortality rate, colorectal cancer (CRC) highlights the importance of comprehending its molecular mechanisms to develop effective therapies. In this study, we conducted RNA sequencing (RNA-seq) analysis on 476 samples consisting of fresh-frozen CRC tissues and adjacent normal tissues obtained from Samsung Medical Center (SMC) in South Korea. By analyzing gene expression differences, we identified that upregulated genes in tumor samples were significantly associated with pathways related to the cell cycle, extracellular matrix (ECM)-receptor interaction, and DNA damage response (DDR). Conversely, genes exhibiting high expression in normal samples were primarily related to metabolic pathways. Tumor samples were found to be enriched in various DDR pathways, prompting an investigation into the enrichment of related genes. Additionally, the analysis focused on the Homologous recombination (HR) pathway, for which the Homologous recombination deficiency (HRD) score was calculated. Furthermore, we categorized colorectal tumor samples into four subgroups using in silico methods to identify the biological and clinical characteristics of each subgroup and compared our results with those of the widely used existing subgrouping methods. Majority of our fibroblast and immune enriched/fibroblast samples aligned with CMS4, characterized by stromal invasion and mesenchymal differentiation, whereas the immune enriched subtype aligned with CMS1, known for its immune-centric profile. To investigate the clinical implications, the composition of the tumor microenvironment (TME) by cell type was examined across four subgroups, along with an immunological analysis. In particular, the calculated HRD score and the expression levels of immune-related genes associated with CRC were analyzed to provide evidence for personalized therapeutic strategies for each subgroup. Our findings provide valuable insights into the molecular mechanisms underlying CRC in Korean patients, particularly in the SMC patient group, and offer opportunities for personalized therapeutic strategies.

Jinseon Yoo, Jong Lyul Lee, Hyeran Shim, Soobok Joe, Jong-Hwan Kim, Jongbum Jeon, Jisu Kim, Chan Wook Kim, Seok-Byung Lim, In Ja Park, Yong Sik Yoon, Hoang Bao Khanh Chu, Jisun Kang, Sheehyun Cho, Hong Seok Lee, Young-Joon Kim, Chang Sik Yu & Seon-Young Kim. BMB Reports 2026;59:273-82. https://doi.org/10.5483/BMBRep.2024-0183

Here we aimed to evaluate the feasibility of distinguishing colorectal microenvironments that support cancer cell growth from those that do not. We hypothesized that patients whose non-tumor-bearing tissue (NBT) obtained from the furthest margins of resected cancer specimens resembled the tumor had a poorer prognosis. Patients with colorectal cancer were divided into groups with tumor-supportive (TSM) or healthy microenvironments using bulk RNA sequencing data from 273 paired NBT and tumor samples. Patients in the TSM group exhibited significantly poorer 5-year recurrence-free survival and overall survival compared with those in the healthy microenvironment group. Pathway and 16S rRNA sequencing analyses revealed that NBT and tumors from the TSM group shared a microbiome composition, along with decreased pathway activity related to microvilli maintenance and flavonoid or vitamin metabolic processes. Single-cell RNA sequencing uncovered upregulated interactions between IL1B ^high neutrophils and OLFM4 ⁺ epithelial cells in NBTs from the TSM group, as well as organized microniches in TSM tumors, featuring interactions between EMP1 ^high epithelial cells, IL1B ^high neutrophils and GZMK ^high CD8 ⁺ T cells. Collectively, the colorectal microenvironment can serve as a prognostic biomarker to effectively predict cancer invasiveness and tumor-promoting inflammation. Maintaining a healthy colorectal mucosal microenvironment, potentially through dietary intervention, is crucial.

Colorectal cancer (CRC) has the second highest incidence rate among all cancers in Korea, with approximately 30% of patients with regional CRC experiencing recurrence. Understanding the genetic drivers of recurrence is essential for early detection and targeted treatment. Therefore, many studies have focused on genetic analysis using tumor-normal matched samples, as this approach provides more comprehensive insights. However, tumor-only samples are far more common in clinical practice because of the difficulty in obtaining normal tissues, making developing robust methods for analyzing tumor-only data a pressing need. This study aimed to investigate the genetic variations associated with CRC recurrence using tumor-only whole-exome sequencing data from 200 Korean patients with stage III CRC. By applying stringent filtering using public databases including Genome Aggregation Database (gnomAD), Exome Aggregation Consortium (ExAC), Single Nucleotide Polymorphism Database (dbSNP), 1000 Genomes Project (1000G), Korean Variant Archive 2 (KOVA2), and Korean Reference Genome Database (KRGDB), we identified 221 statistically significant mutations across 195 genes with distinct distributions between the recurrence and non-recurrence groups. Furthermore, statistical analysis of the clinical data revealed that the T-category, N-category, and preoperative carcinoembryonic antigen levels were correlated with CRC recurrence. Moreover, we identified nine networks through protein-protein interaction analysis and identified networks with high feature importance. We also developed a CRC recurrence prediction model using PyCaret, which achieved an area under the curve (AUC) of 0.77. Our findings highlight the importance of robust variant filtering in tumor-only sample analyses and provide insights into the genetic landscape of CRC recurrence in the Korean population.

Response to Editorial on “Exploring Methylation Signatures for High De Novo Recurrence Risk in Hepatocellular Carcinoma”

Background/Aims: Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.Methods: In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).Results: The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69–0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14–0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.Conclusions: Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.

Background: In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem; here, telomeres serve as a buffer against DNA loss. Thus, the activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. Methods: We compared neurofibroma (NF, benign) and malignant peripheral nerve sheath tumors (MPNSTs) occurring in the same patient with type 1 neurofibromatosis, where each NF–MPNST pair shared the same genetic background and differentiation lineage; this minimizes the genetic bias and contrasts only those changes that are related to malignant transformation. A total of 20 NF–MPNST pairs from 20 NF1 patients were analyzed. Whole-transcriptome sequencing (WTS) was conducted to profile the transcriptional relationship, and whole-genome sequencing (WGS) was performed to measure the telomere length. Results: We identified 22 differentially expressed genes (DEGs) during the malignant transformation of MPNSTs. Among them, NELL2 activated PAX7, which sequentially activated RAD52, the recombinase of RAD52-dependent alternative lengthening of telomeres (ALT). RAD52 elongated MPNSTs–telomeres (p = 0.017). Otherwise, neither NELL2 nor PAX7 affected telomere length (p = 0.647 and p = 0.354, respectively). RAD52 increased MPNSTs–telomeres length, independently of NELL2 and PAX7 in multiple analyses (p = 0.021). The group with increased telomere length during the malignant transformation showed inferior overall survival (OS) (HR = 3.809, p = 0.038) to the group without increased telomere length. Accordingly, the group with increased PAX7 showed inferior OS (HR = 4.896, p = 0.046) and metastasis-free survival (MFS) (HR = 9.129, p = 0.007) in comparison to the group without increased PAX7; the group with increased RAD52 showed inferior MFS (HR = 8.669, p = 0.011) in comparison to the group without increased RAD52. Conclusions: We suggest that the NELL2-PAX7 transcriptional cascade activates RAD52-dependent ALT to increase telomere length during the malignant transformation of MPNSTs, resulting in a poor prognosis.

Backgroud In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem and telomeres serve as a buffer against DNA loss. Cumulative telomere attrition leads to replicative senescence and the Hayflick limit. Thus, activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. We show that extracellular, but not intracellular, signals activate RAD52-dependent alternative lengthening of telomeres (ALT) during malignant transformation of malignant peripheral nerve sheath tumors (MPNSTs). Methods We compared neurofibroma (NF, benign) and MPNST occurring in the same patient with type-1 neurofibromatosis, where each NF-MPNST pair shares the same genetic background and differentiation lineage minimizing genetic bias and contrasts only changes related to malignant transformation. Results We found that the MEGF11 and the MEGF11-dependent ephrin signaling pathways (EFNA5-EPHPA6-PDZD9/PARD6B) activate the NELL2-PAX7 transcriptional cascade, which sequentially activates RAD52, the recombinase of RAD52-dependent ALT, resulting in telomere elongation, metastasis, and poor prognosis. In contrast, H2AFX, a DNA damage marker and intracellular signal, activates RAD51-dependent ALT to determine the MPNST grade. Conclusions We demonstrated the extracellular signals that activate RAD52-dependent ALT and distinguished the biological and clinical manifestations of RAD51 and RAD52-dependent ALT during malignant transformation of MPNSTs.

Jin-Young Lee, Won Park, Hyunjoong Kim, Hong Seok Lee, Tae-Wook Kang, Dong-Hun Shin, Kyung Su Kim, Yoon Kyeong Lee, Seon-Young Kim, Ji Hwan Park & Young-Joon Kim. BMB Reports -0001;0:. https://doi.org/10.5483/BMBRep.2023-0155