Spatial architectures of somatic mutations in normal prostate, benign prostatic hyperplasia and coexisting prostate cancer

Chae Jeesoo,Jung Seung-Hyun,Choi Eun Ji,Kim Jae Woong,Kim Na Yung,Moon Sung Won,Lee Ji Youl,Chung Yeun-Jun,Lee Sug Hyung 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-

This study aimed to identify somatic mutations in nontumor cells (NSMs) in normal prostate and benign prostatic hyperplasia (BPH) and to determine their relatedness to prostate cancer (PCA). From 22 PCA patients, two prostates were sampled for 3-dimensional mapping (50 normal, 46 BPH and 1 PCA samples), and 20 prostates were trio-sampled (two normal or BPH samples and one PCA sample) and analyzed by whole-genome sequencing. Normal and BPH tissues harbored several driver NSMs and copy number alterations (CNAs), including in FOXA1, but the variations exhibited low incidence, rare recurrence, and rare overlap with PCAs. CNAs, structural variants, and mutation signatures were similar between normal and BPH samples, while BPHs harbored a higher mutation burden, shorter telomere length, larger clone size, and more private NSMs than normal prostates. We identified peripheral-zonal dominance and right-side asymmetry in NSMs, but the asymmetry was heterogeneous between samples. In one normal prostate, private oncogenic RAS-signaling NSMs were detected, suggesting convergence in clonal maintenance. Early embryonic mutations exhibited two distinct distributions, characterized as layered and mixed patterns. Our study identified that the BPH genome differed from the normal prostate genome but was still closer to the normal genome than to the PCA genome, suggesting that BPH might be more related to aging or environmental stress than to tumorigenic processes.

Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16

( Jeesoo Chae ),( Weon Seo Park ),( Min Jung Kim ),( Se Song Jang ),( Dongwan Hong ),( Junsun Ryu ),( Chang Hwan Ryu ),( Ji-hyun Kim ),( Moon-kyung Choi ),( Kwan Ho Cho ),( Sung Ho Moon ),( Tak Yun ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.11

Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of 94.3× for WES and 35.3× for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC. [BMB Reports 2018; 51(11): 584-589]

영상처리 알고리즘 활용과 공유를 위한 효과적인 컴포넌트 구조에 관한 연구

어지수(Jeesoo Awe),조영탁(Youngtak Cho),채옥삼(Oksam Chae) 한국정보과학회 2005 한국정보과학회 학술발표논문집 Vol.32 No.1

전세계적으로 영상을 이용하는 분야는 급속도로 발전되고 확장되어 가고 있다. 이러한 시점에서 영상처리 기술의 중요성은 더욱더 강조 되고 있다. 하지만 영상처리 기술은 다른 기술들에 비하여 굉장히 특화되어 같은 기술이라도 사용 환경과 분야에 따라 각기 다른 형태와 다른 사용 방식을 요구하고 있다. 이러한 환경은 영상처리 기술들의 재사용성을 떨어뜨리고 기술 개발 비용의 증가를 가져 왔다. 본 논문에서는 이러한 문제점들 을 해결하고자 영상처리 기술을 활용하고 공유하기 위한 컴포넌트의 구조를 제안하고자 한다.

Nonsynonymous Variants in <i>PAX4</i> and <i>GLP1R</i> Are Associated With Type 2 Diabetes in an East Asian Population

Kwak, Soo Heon,Chae, Jeesoo,Lee, Seungbok,Choi, Sungkyoung,Koo, Bo Kyung,Yoon, Ji Won,Park, Jin-Ho,Cho, Belong,Moon, Min Kyong,Lim, Soo,Cho, Young Min,Moon, Sanghoon,Kim, Young Jin,Han, Sohee,Hwang, M American Diabetes Association 2018 Diabetes Vol.67 No.9

<P>We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 x 10(-16) and OR 0.84, P = 3.55 x 10(-8), respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 x 10(-4)). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA(1c) level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 x 10(-4)). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.</P>

A newly developed capture-based sequencing panel for genomic assay of lung cancer

Sun‑Wha Im,Jeesoo Chae,Se Song Jang,Jaeyong Choi,Jihui Yun,차수진,Nak‑Jung Kwon,Yoon Kyung Jeon,Yoohwa Hwang,Miso Kim,Tae Min Kim,Dong‑Wan Kim,Jong‑Il Kim,Young Tae Kim 한국유전학회 2020 Genes & Genomics Vol.42 No.7

Background The increase in genetic alterations targeted by specific chemotherapy in lung cancer has led to the need for universal use of more comprehensive genetic testing, which has highlighted the development of a lung cancer diagnostic panel using next-generation sequencing. Objective We developed a hybridization capture-based massively parallel sequencing assay named Friendly, Integrated, Research-based, Smart and Trustworthy (FIRST)-lung cancer panel (LCP), and evaluated its performance. Methods FIRST-LCP comprises 64 lung cancer-related genes to test for various kinds of genetic alterations including single nucleotide variations (SNVs), insertions and deletions (indels), copy number variations (CNVs), and structural variations. To assess the performance of FIRST-LCP, we compiled test sets using HapMap samples or tumor cell lines with disclosed genetic information, and also tested our clinical lung cancer samples whose genetic alterations were known by conventional methods. Results FIRST-LCP accomplished high sensitivity (99.4%) and specificity (100%) of the detection of SNVs. High precision was also achieved, with intra- or inter-run concordance rate of 0.99, respectively. FIRST-LCP detected indels and CNVs close to the expected allele frequency and magnitude, respectively. Tests with samples from lung cancer patients also identified all SNVs, indels and fusions. Conclusion Based on the current state of the art, continuous application of the panel design and analysis pipeline following up-to-date knowledge could ensure precision medicine for lung cancer patients.

영상처리 컴포넌트의 효과적인 재사용을 지원하는 공유환경의 설계

조영탁(Youngtak Cho),어지수(Jeesoo Awe),채옥삼(Oksam Chae) 한국정보과학회 2005 한국정보과학회 학술발표논문집 Vol.32 No.1

영상처리분야의 연구개발은 특정 분야에 특화된 알고리즘을 이용하고, 이러한 특수성으로 인해 유사한 기능을 반복적으로 구현하는 문제점을 안고 있다. 특히 연구개발결과물의 공유환경이 마련되어있지 않아 이러한 문제점을 더욱 가중시켜 연구개발비용의 증가를 유발하고 있다. 본 논문에서는 이러한 문제점을 해결하기 위해 영상처리용 통합개발환경과 연계된 P2P기반의 공유체계를 제안한다. 제안된 시스템은 많은 비용을 들여 연구개발한 영상처리 알고리즘이 사장되는 위험을 감소시키고 재활용 가능성을 높일 것으로 기대한다.

Unstable Genome and Transcriptome Dynamics during Tumor Metastasis Contribute to Therapeutic Heterogeneity in Colorectal Cancers

Cho, Sung-Yup,Chae, Jeesoo,Na, Deukchae,Kang, Wonyoung,Lee, Ahra,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Lee, Jieun,Sung, Chang Ohk,Chuang, Jeffrey H.,Lee, Charles,Lee, Won-Suk,Park, Hansoo,Kim, Jong-Il American Association for Cancer Research 2019 Clinical Cancer Research Vol.25 No.9

<P><B>Purpose:</B></P><P>Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on <I>in vivo</I> treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness.</P><P><B>Experimental Design:</B></P><P>We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and <I>in vivo</I> drug efficacy test on the corresponding PDX models.</P><P><B>Results:</B></P><P>Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.</P><P><B>Conclusions:</B></P><P>This study demonstrated <I>in vivo</I> therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.</P>

Alterations in the Rho pathway contribute to Epstein-Barr virus–induced lymphomagenesis in immunosuppressed environments

Cho, Sung-Yup,Sung, Chang Ohk,Chae, Jeesoo,Lee, Jieun,Na, Deukchae,Kang, Wonyoung,Kang, Jinjoo,Min, Seoyeon,Lee, Ahra,Kwak, Eunhye,Kim, Jooyoung,Choi, Boram,Kim, Hyunsoo,Chuang, Jeffrey H.,Pak, Hyo-Ky American Society of Hematology 2018 Blood Vol.131 No.17

<P>Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV1-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV1-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV1-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV1-DLBLs revealed enrichment ofmutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumorgrowth inEBV1-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.</P>

Association of HLA Genotype and Fulminant Type 1 Diabetes in Koreans

Kwak, Soo Heon,Kim, Yoon Ji,Chae, Jeesoo,Lee, Cue Hyunkyu,Han, Buhm,Kim, Jong-Il,Jung, Hye Seung,Cho, Young Min,Park, Kyong Soo Korea Genome Organization 2015 Genomics & informatics Vol.13 No.4

Fulminant type 1 diabetes (T1DM) is a distinct subtype of T1DM that is characterized by rapid onset hyperglycemia, ketoacidosis, absolute insulin deficiency, and near normal levels of glycated hemoglobin at initial presentation. Although it has been reported that class II human leukocyte antigen (HLA) genotype is associated with fulminant T1DM, the genetic predisposition is not fully understood. In this study we investigated the HLA genotype and haplotype in 11 Korean cases of fulminant T1DM using imputation of whole exome sequencing data and compared its frequencies with 413 participants of the Korean Reference Panel. The $HLA-DRB1^*04:05-HLA-DQB1^*04:01$ haplotype was significantly associated with increased risk of fulminant T1DM in Fisher's exact test (odds ratio [OR], 4.11; 95% confidence interval [CI], 1.56 to 10.86; p = 0.009). A histidine residue at $HLA-DR{\beta}1$ position 13 was marginally associated with increased risk of fulminant T1DM (OR, 2.45; 95% CI, 1.01 to 5.94; p = 0.054). Although we had limited statistical power, we provide evidence that HLA haplotype and amino acid change can be a genetic risk factor of fulminant T1DM in Koreans. Further large-scale research is required to confirm these findings.

Genomic alterations in <i>BCL2L1</i> and <i>DLC1</i> contribute to drug sensitivity in gastric cancer

Park, Hansoo,Cho, Sung-Yup,Kim, Hyerim,Na, Deukchae,Han, Jee Yun,Chae, Jeesoo,Park, Changho,Park, Ok-Kyoung,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Min, Jimin,Kwon, Jee Young,Suh, Yun-Suhk,Kong, Seong-H National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.40

<P><B>Significance</B></P><P>Gastric cancer (GC) is one of the major causes of cancer-related deaths worldwide, but targeted therapy for GC is limited. Here, we identified two druggable targets from genomic alteration profiling of 103 patients with GC from Asia and validated the target suitability using patient-derived GC xenograft models, which recapitulate the tumor biology observed in patients. Combination therapy of irinotecan (standard treatment) with a <I>BCL2L1</I> (<I>BCL2</I>-like 1)-targeted drug was effective in size reduction of GC tumors having amplification of the <I>BCL2L1</I> gene, and genomic mutations of deleted in liver cancer 1 (<I>DLC1</I>) were associated with increased sensitivity to a ROCK inhibitor. Therefore, our study strongly suggests that <I>BCL2L1</I> and <I>DLC1</I> can serve as targets for novel GC therapies.</P><P>Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [<I>APC</I>, <I>CTNNB1</I>, and <I>DLC1</I> (deleted in liver cancer 1)], ErbB signaling (<I>ERBB2</I>, <I>PIK3CA</I>, and <I>KRAS</I>), and p53 signaling/apoptosis [<I>TP53</I> and <I>BCL2L1</I> (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene <I>BCL2L1</I> was observed, and subsequently a <I>BCL2L1</I> inhibitor was shown to markedly decrease cell viability in <I>BCL2L1</I>-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in <I>DLC1</I> were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates <I>BCL2L1</I> and <I>DLC1</I> as potential druggable targets for specific subsets of GC cases.</P>