Comprehensive profiling of DNA methylation in Korean patients with colorectal cancer

( Hyeran Shim ),( Kiwon Jang ),( Yeong Hak Bang ),( Hoang Bao Khanh Chu ),( Jisun Kang ),( Jin-young Lee ),( Sheehyun Cho ),( Hong Seok Lee ),( Jongbum Jeon ),( Taeyeon Hwang ),( Soobok Joe ),( Jinyeo 생화학분자생물학회 2024 BMB Reports Vol.57 No.2

Alterations in DNA methylation play an important pathophysiological role in the development and progression of colorectal cancer. We comprehensively profiled DNA methylation alterations in 165 Korean patients with colorectal cancer (CRC), and conducted an in-depth investigation of cancer-specific methylation patterns. Our analysis of the tumor samples revealed a significant presence of hypomethylated probes, primarily within the gene body regions; few hypermethylated sites were observed, which were mostly enriched in promoter-like and CpG island regions. The CpG Island Methylator Phenotype- High (CIMP-H) exhibited notable enrichment of microsatellite instability-high (MSI-H). Additionally, our findings indicated a significant correlation between methylation of the MLH1 gene and MSI-H status. Furthermore, we found that the CIMP-H had a higher tendency to affect the right-side of the colon tissues and was slightly more prevalent among older patients. Through our methylome profile analysis, we successfully verified the methylation patterns and clinical characteristics of Korean patients with CRC. This valuable dataset lays a strong foundation for exploring novel molecular insights and potential therapeutic targets for the treatment of CRC.

Comprehensive RNA-sequencing analysis of colorectal cancer in a Korean cohort

Jaeim Lee,Jong-Hwan Kim,Hoang Bao Khanh Chu,Seong-Taek Oh,Sung-Bum Kang,Sejoon Lee,Duck-Woo Kim,Heung-Kwon Oh,Ji-Hwan Park,Jisu Kim,Jisun Kang,Jin-Young Lee,Sheehyun Cho,Hyeran Shim,Hong Seok Lee,Seon Korean Society for Molecular and Cellular Biology 2024 Molecules and cells Vol.47 No.3

Considering the recent increase in the number of colorectal cancer (CRC) cases in South Korea, we aimed to clarify the molecular characteristics of CRC unique to the Korean population. To gain insights into the complexities of CRC and promote the exchange of critical data, RNA-sequencing analysis was performed to reveal the molecular mechanisms that drive the development and progression of CRC; this analysis is critical for developing effective treatment strategies. We performed RNA-sequencing analysis of CRC and adjacent normal tissue samples from 214 Korean participants (comprising a total of 381 including 169 normal and 212 tumor samples) to investigate differential gene expression between the groups. We identified 19,575 genes expressed in CRC and normal tissues, with 3,830 differentially expressed genes (DEGs) between the groups. Functional annotation analysis revealed that the upregulated DEGs were significantly enriched in pathways related to the cell cycle, DNA replication, and IL-17, whereas the downregulated DEGs were enriched in metabolic pathways. We also analyzed the relationship between clinical information and subtypes using the Consensus Molecular Subtype (CMS) classification. Furthermore, we compared groups clustered within our dataset to CMS groups and performed additional analysis of the methylation data between DEGs and CMS groups to provide comprehensive biological insights from various perspectives. Our study provides valuable insights into the molecular mechanisms underlying CRC in Korean patients and serves as a platform for identifying potential target genes for this disease. The raw data and processed results have been deposited in a public repository for further analysis and exploration.

ZNF204P is a stemness-associated oncogenic long non-coding RNA in hepatocellular carcinoma

( Ji-hyun Hwang ),( Jungwoo Lee ),( Won-young Choi ),( Min-jung Kim ),( Jiyeon Lee ),( Khanh Hoang Bao Chu ),( Lark Kyun Kim ),( Young-joon Kim ) 생화학분자생물학회 2022 BMB Reports Vol.55 No.6

Hepatocellular carcinoma is a major health burden, and though various treatments through much research are available, difficulties in early diagnosis and drug resistance to chemotherapy-based treatments render several ineffective. Cancer stem cell model has been used to explain formation of heterogeneous cell population within tumor mass, which is one of the underlying causes of high recurrence rate and acquired chemoresistance, highlighting the importance of CSC identification and understanding the molecular mechanisms of CSC drivers. Extracellular CSCmarkers such as CD133, CD90 and EpCAM have been used successfully in CSC isolation, but studies have indicated that increasingly complex combinations are required for accurate identification. Pseudogene-derived long non-coding RNAs are useful candidates as intracellular CSC markers - factors that regulate pluripotency and self-renewal - given their cancer-specific expression and versatile regulation across several levels. Here, we present the use of microarray data to identify stemness-associated factors in liver cancer, and selection of sole pseudogenederived lncRNA ZNF204P for experimental validation. ZNF204P knockdown impairs cell proliferation and migration/invasion. As the cytosolic ZNF204P shares miRNA binding sites with OCT4 and SOX2, well-known drivers of pluripotency and self-renewal, we propose that ZNF204P promotes tumorigenesis through the miRNA-145-5p/OCT4, SOX2 axis. [BMB Reports 2022; 55(6): 281-286]

Exploring the DNA methylome of Korean patients with colorectal cancer consolidates the clinical implications of cancer-associated methylation markers

( Sejoon Lee ),( Kil-yong Lee ),( Ji-hwan Park ),( Duck-woo Kim ),( Heung-kwon Oh ),( Seong-taek Oh ),( Jongbum Jeon ),( Dongyoon Lee ),( Soobok Joe ),( Hoang Bao Khanh Chu ),( Jisun Kang ),( Jin-youn 생화학분자생물학회 2024 BMB Reports Vol.57 No.3

Aberrant DNA methylation plays a critical role in the development and progression of colorectal cancer (CRC), which has high incidence and mortality rates in Korea. Various CRC-associated methylation markers for cancer diagnosis and prognosis have been developed; however, they have not been validated for Korean patients owing to the lack of comprehensive clinical and methylome data. Here, we obtained reliable methylation profiles for 228 tumor, 103 adjacent normal, and two unmatched normal colon tissues from Korean patients with CRC using an Illumina Infinium EPIC array; the data were corrected for biological and experiment biases. A comparative methylome analysis confirmed the previous findings that hypermethylated positions in the tumor were highly enriched in CpG island and promoter, 5’ untranslated, and first exon regions. However, hypomethylated positions were enriched in the open-sea regions considerably distant from CpG islands. After applying a CpG island methylator phenotype (CIMP) to the methylome data of tumor samples to stratify the CRC patients, we consolidated the previously established clinicopathological findings that the tumors with high CIMP signatures were significantly enriched in the right colon. The results showed a higher prevalence of microsatellite instability status and MLH1 methylation in tumors with high CMP signatures than in those with low or non-CIMP signatures. Therefore, our methylome analysis and dataset provide insights into applying CRC-associated methylation markers for Korean patients regarding cancer diagnosis and prognosis. [BMB Reports 2024; 57(3): 161-166]

Epigenetic insights into colorectal cancer: comprehensive genome-wide DNA methylation profiling of 294 patients in Korea

Soobok Joe,Jinyong Kim,Jinyoung Lee,Jongbum Jeon,Iksu Byeon,Sae-Won Han,Seung-Bum Ryoo,Kyu-Joo Park,Sang-Hyun Song,Sheehyun Cho,Hyeran Shim,Hoang Bao Khanh Chu,Jisun Kang,Hong Seok Lee,DongWoo Kim,You 생화학분자생물학회 2023 BMB Reports Vol.56 No.10

DNA methylation regulates gene expression and contributes totumorigenesis in the early stages of cancer. In colorectal cancer(CRC), CpG island methylator phenotype (CIMP) is recognizedas a distinct subset that is associated with specific molecularand clinical features. In this study, we investigated the genomewideDNA methylation patterns among patients with CRC. The methylation data of 1 unmatched normal, 142 adjacentnormal, and 294 tumor samples were analyzed. We identified40,003 differentially methylated positions with 6,933 (79.8%)hypermethylated and 16,145 (51.6%) hypomethylated probesin the genic region. Hypermethylated probes were predominantlyfound in promoter-like regions, CpG islands, and N shore sites;hypomethylated probes were enriched in open-sea regions. CRC tumors were categorized into three CIMP subgroups, with90 (30.6%) in the CIMP-high (CIMP-H), 115 (39.1%) in theCIMP-low (CIMP-L), and 89 (30.3%) in the non-CIMP group. The CIMP-H group was associated with microsatellite instabilityhightumors, hypermethylation of MLH1, older age, and rightsidedtumors. Our results showed that genome-wide methylationanalyses classified patients with CRC into three subgroupsaccording to CIMP levels, with clinical and molecular featuresconsistent with previous data.

Deciphering the DNA methylation landscape of colorectal cancer in a Korean cohort

Seok-Byung Lim,Soobok Joe,Hyo-Ju Kim,Jong Lyul Lee,In Ja Park,Yong Sik Yoon,Chan Wook Kim,Jong Hwan Kim,Sangok Kim,Jin-Young Lee,Hyeran Shim,Hoang Bao Khanh Chu,Sheehyun Cho,Jisun Kang,Si-Cho Kim,Hong 생화학분자생물학회 2023 BMB Reports Vol.56 No.10

Aberrant DNA methylation plays a pivotal role in the onsetand progression of colorectal cancer (CRC), a disease with highincidence and mortality rates in Korea. Several CRC-associateddiagnostic and prognostic methylation markers have been identified;however, due to a lack of comprehensive clinical andmethylome data, these markers have not been validated in theKorean population. Therefore, in this study, we aimed to obtainthe CRC methylation profile using 172 tumors and 128 adjacentnormal colon tissues of Korean patients with CRC. Based onthe comparative methylome analysis, we found that hypermethylatedpositions in the tumor were predominantly concentratedin CpG islands and promoter regions, whereas hypomethylatedpositions were largely found in the open-sea region,notably distant from the CpG islands. In addition, we stratifiedpatients by applying the CpG island methylator phenotype(CIMP) to the tumor methylome data. This stratification validatedprevious clinicopathological implications, as tumors with highCIMP signatures were significantly correlated with the proximalcolon, higher prevalence of microsatellite instability status, andMLH1 promoter methylation. In conclusion, our extensive methylomeanalysis and the accompanying dataset offers valuableinsights into the utilization of CRC-associated methylation markersin Korean patients, potentially improving CRC diagnosis andprognosis. Furthermore, this study serves as a solid foundationfor further investigations into personalized and ethnicity-specificCRC treatments.