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1. Comprehensive multiomics analysis reveals distinct differences between pediatric choroid plexus papilloma and carcinoma

Author

Yeonsong Choi, Seung Ah Choi, Eun Jung Koh, Ilsun Yun, Suhyun Park, Sungwon Jeon, Yeonkyung Kim, Sangbeen Park, Donggeon Woo, Ji Hoon Phi, Sung-Hye Park, Dong-Seok Kim, Se Hoon Kim, Jung Won Choi, Ji Won Lee, Tae-Young Jung, Jong Bhak, Semin Lee, and Seung-Ki Kim

Subjects
Choroid plexus tumor, Whole-genome sequencing, Whole-transcriptome sequencing, Methylation sequencing, Multiomics, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.

Published
2024
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2. Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications

Author

Joo Kyung Park, Hyoung-oh Jeong, Hyemin Kim, Jin Ho Choi, Eun Mi Lee, Seunghoon Kim, Jinho Jang, David Whee-Young Choi, Se-Hoon Lee, Kyoung Mee Kim, Kee-Taek Jang, Kwang Hyuck Lee, Kyu Taek Lee, Min Woo Lee, Jong Kyun Lee, and Semin Lee

Subjects
Pancreatic ductal adenocarcinoma, Liver metastasis, Single-cell RNA-sequencing, Intratumoral heterogeneity, Tumor microenvironment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. Methods We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. Results scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naï ve SELL hi regulatory T cells (Tregs) and activated TIGIT hi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. Conclusion We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

Published
2024
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3. Predicting preterm birth using machine learning techniques in oral microbiome

Author

You Mi Hong, Jaewoong Lee, Dong Hyu Cho, Jung Hun Jeon, Jihoon Kang, Min-Gul Kim, Semin Lee, and Jin Kyu Kim

Subjects
Medicine, Science
Abstract

Abstract Preterm birth prediction is essential for improving neonatal outcomes. While many machine learning techniques have been applied to predict preterm birth using health records, inflammatory markers, and vaginal microbiome data, the role of prenatal oral microbiome remains unclear. This study aimed to compare oral microbiome compositions between a preterm and a full-term birth group, identify oral microbiome associated with preterm birth, and develop a preterm birth prediction model using machine learning of oral microbiome compositions. Participants included singleton pregnant women admitted to Jeonbuk National University Hospital between 2019 and 2021. Subjects were divided into a preterm and a full-term birth group based on pregnancy outcomes. Oral microbiome samples were collected using mouthwash within 24 h before delivery and 16S ribosomal RNA sequencing was performed to analyze taxonomy. Differentially abundant taxa were identified using DESeq2. A random forest classifier was applied to predict preterm birth based on the oral microbiome. A total of 59 women participated in this study, with 30 in the preterm birth group and 29 in the full-term birth group. There was no significant difference in maternal clinical characteristics between the preterm and the full-birth group. Twenty-five differentially abundant taxa were identified, including 22 full-term birth-enriched taxa and 3 preterm birth-enriched taxa. The random forest classifier achieved high balanced accuracies (0.765 ± 0.071) using the 9 most important taxa. Our study identified 25 differentially abundant taxa that could differentiate preterm and full-term birth groups. A preterm birth prediction model was developed using machine learning of oral microbiome compositions in mouthwash samples. Findings of this study suggest the potential of using oral microbiome for predicting preterm birth. Further multi-center and larger studies are required to validate our results before clinical applications.

Published
2023
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4. Genomic characteristics of triple negative apocrine carcinoma: a comparison to triple negative breast cancer

Author

Ji-Yeon Kim, Sabin Park, Eun Yoon Cho, Jeong Eon Lee, Hae Hyun Jung, Byung Joo Chae, Seok Won Kim, Seok Jin Nam, Soo Youn Cho, Yeon Hee Park, Jin Seok Ahn, Semin Lee, and Young-Hyuck Im

Subjects
Medicine, Biochemistry, QD415-436
Abstract

Abstract Apocrine carcinoma is a rare breast cancer subtype. As such, the genomic characteristics of apocrine carcinoma with triple negative immunohistochemical results (TNAC), which has been treated as triple negative breast cancer (TNBC), have not been revealed. In this study, we evaluated the genomic characteristics of TNAC compared to TNBC with low Ki-67 (LK-TNBC). In the genetic analysis of 73 TNACs and 32 LK-TNBCs, the most frequently mutated driver gene in TNAC was TP53 (16/56, 28.6%), followed by PIK3CA (9/56, 16.1%), ZNF717 (8/56, 14.3%), and PIK3R1 (6/56, 10.71%). Mutational signature analysis showed enrichment of defective DNA mismatch repair (MMR)-related signatures (SBS6 and SBS21) and the SBS5 signature in TNAC, whereas an APOBEC activity-associated mutational signature (SBS13) was more prominent in LK-TNBC (Student’s t test, p

Published
2023
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5. A heterozygous mutation in UBE2H in a patient with developmental delay leads to an aberrant brain development in zebrafish

Author

Unbeom Shin, Yeonsong Choi, Hwa Soo Ko, Kyungjae Myung, Semin Lee, Chong Kun Cheon, and Yoonsung Lee

Subjects
UBE2H, Rare disease, Zebrafish, Transcriptomics, Brain, p53, Medicine, Genetics, QH426-470
Abstract

Abstract Background Ubiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin–proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants. Methods In our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis. Results Through trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos. Conclusion A de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.

Published
2023
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6. Single-cell RNA Sequencing Reveals Novel Cellular Factors for Response to Immunosuppressive Therapy in Aplastic Anemia

Author

Jinho Jang, Hongtae Kim, Sung-Soo Park, Miok Kim, Yong Ki Min, Hyoung-oh Jeong, Seunghoon Kim, Taejoo Hwang, David Whee-Young Choi, Hee-Je Kim, Sukgil Song, Dong Oh Kim, Semin Lee, Chang Hoon Lee, and Jong Wook Lee

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Aplastic anemia (AA) is a lethal hematological disorder; however, its pathogenesis is not fully understood. Although immunosuppressive therapy (IST) is a major treatment option for AA, one-third of patients do not respond to IST and its resistance mechanism remains elusive. To understand AA pathogenesis and IST resistance, we performed single-cell RNA sequencing (scRNA-seq) of bone marrow (BM) from healthy controls and patients with AA at diagnosis. We found that CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells were significantly depleted in AA, which suggests that the depletion of CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells might be one of the major mechanisms for AA pathogenesis related with BM-cell hypoplasia. More importantly, we observed the significant enrichment of CD8+ T cells and T cell–activating intercellular interactions in IST responders, indicating the association between the expansion and activation of T cells and the positive response of IST in AA. Taken together, our findings represent a valuable resource offering novel insights into the cellular heterogeneity in the BM of AA and reveal potential biomarkers for IST, building the foundation for future precision therapies in AA.

Published
2023
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7. Cellular plasticity and immune microenvironment of malignant pleural effusion are associated with EGFR-TKI resistance in non–small-cell lung carcinoma

Author

Hyoung-oh Jeong, Hayoon Lee, Hyemin Kim, Jinho Jang, Seunghoon Kim, Taejoo Hwang, David Whee-Young Choi, Hong Sook Kim, Naeun Lee, Yoo Mi Lee, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Semin Lee, and Se-Hoon Lee

Subjects
Cancer, immunology, omics, transcriptomics, Science
Abstract

Summary: Malignant pleural effusion (MPE) is a complication of lung cancer that can be used as an alternative method for tissue sampling because it is generally simple and minimally invasive. Our study evaluated the diagnostic potential of non–small-cell lung carcinoma (NSCLC)-associated MPE in terms of understanding tumor heterogeneity and identifying response factors for EGFR tyrosine kinase inhibitor (TKI) therapy. We performed a single-cell RNA sequencing analysis of 31,743 cells isolated from the MPEs of 9 patients with NSCLC (5 resistant and 4 sensitive to EGFR TKI) with EGFR mutations. Interestingly, lung epithelial precursor-like cells with upregulated GNB2L1 and CAV1 expression were enriched in the EGFR TKI-resistant group. Moreover, GZMK upregulated transitional effector T cells, and plasmacytoid dendritic cells were significantly enriched in the EGFR TKI-resistant patients. Our results suggest that cellular plasticity and immunosuppressive microenvironment in MPEs are potentially associated with the TKI response of patients with EGFR-mutated NSCLC.

Published
2022
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8. Sex-specific difference of in-hospital mortality from COVID-19 in South Korea

Author

Ae-Young Her, Youngjune Bhak, Eun Jung Jun, Song Lin Yuan, Scot Garg, Semin Lee, Jong Bhak, and Eun-Seok Shin

Subjects
Medicine, Science
Abstract

We sought to assess the impact of sex on in-hospital mortality of patients with COVID-19 infection in South Korea. The study recruited 5,628 prospective consecutive patients who were hospitalized in South Korea with COVID-19 infection, and enrolled in the Korea Centers for Disease Control and Prevention (KCDC) dataset between January 20, 2020, and April 30, 2020. The primary endpoint was in-hospital death from COVID-19. The cohort comprised of 3,308 women (59%) and 2,320 men (41%). In-hospital death was significantly lower in women than men (3.5% vs. 5.5%, hazard ratio (HR): 0.61; 95% confidence interval (CI): 0.47 to 0.79, p

Published
2022

9. Flightless-1 inhibits ER stress-induced apoptosis in colorectal cancer cells by regulating Ca2+ homeostasis

Author

Sun Sil Choi, Sang Kwon Lee, Joong Kwan Kim, Hye-Kyung Park, Eujin Lee, Jinho Jang, Yo Han Lee, Keon Woo Khim, Ji-Min Hyun, Hye-jin Eom, Semin Lee, Byuong Heon Kang, Young Chan Chae, Kyungjae Myung, Seung-Jae Myung, Chan Young Park, and Jang Hyun Choi

Subjects
Medicine, Biochemistry, QD415-436
Abstract

Cancer: Protein enhances survival of tumor cells under stress A cytoskeletal protein that helps tumors avoid cell death offers a promising new drug target for fighting cancer. A team led by Jang Hyun Choi and Sun Sil Choi of the Ulsan National Institute of Science and Technology, South Korea, detailed how a protein called Flightless I (FliI) that normally regulates the remodeling of structural filaments in the cell can, in colorectal cancer cells, serve as a tumor promoter through its action on calcium levels. Typically, cells respond to chronic stress by altering calcium signaling to promote their own death. In tumors, however, FliI maintains normal calcium levels to enhance cell survival even in the face of chemotherapy and other stressful stimuli. Suppressing FliI activity could thus help sensitize cancer cells to other stress- and death-inducing drug regimens.

Published
2020
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10. Global impact of somatic structural variation on the DNA methylome of human cancers

Author

Yiqun Zhang, Lixing Yang, Melanie Kucherlapati, Angela Hadjipanayis, Angeliki Pantazi, Christopher A. Bristow, Eunjung Alice Lee, Harshad S. Mahadeshwar, Jiabin Tang, Jianhua Zhang, Sahil Seth, Semin Lee, Xiaojia Ren, Xingzhi Song, Huandong Sun, Jonathan Seidman, Lovelace J. Luquette, Ruibin Xi, Lynda Chin, Alexei Protopopov, Peter J. Park, Raju Kucherlapati, and Chad J. Creighton

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored. Results By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration. Conclusion Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.

Published
2019
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11. Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer

Author

Miok Kim, Yong Ki Min, Jinho Jang, Hyejin Park, Semin Lee, and Chang Hoon Lee

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Although cancer immunotherapy is one of the most effective advanced-stage cancer therapies, no clinically approved cancer immunotherapies currently exist for colorectal cancer (CRC). Recently, programmed cell death protein 1 (PD-1) blockade has exhibited clinical benefits according to ongoing clinical trials. However, ongoing clinical trials for cancer immunotherapies are focused on PD-1 signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. In this study, we focused on revealing the distinct response mechanism for the potent CD73 ectoenzyme selective inhibitor AB680 as a promising drug candidate that functions by blocking tumorigenic ATP/adenosine signaling in comparison to current therapeutics that block PD-1 to assess the value of this drug as a novel immunotherapy for CRC.Methods To understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings.Results We initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay.Conclusions The intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.

Published
2021
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12. An enhanced genetic model of colorectal cancer progression history

Author

Lixing Yang, Su Wang, Jake June-Koo Lee, Semin Lee, Eunjung Lee, Eve Shinbrot, David A. Wheeler, Raju Kucherlapati, and Peter J. Park

Subjects
Tumor evolution, Tumor heterogeneity, Aneuploidy, Kataegis, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background The classical genetic model of colorectal cancer presents APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of genomic alterations, such as genomic rearrangements, are still unclear. Results Here, we perform comprehensive bioinformatic analysis to dissect the relative timing of somatic genetic alterations in 63 colorectal cancers with whole-genome sequencing data. Utilizing allele fractions of somatic single nucleotide variants as molecular clocks while accounting for the presence of copy number changes and structural alterations, we identify key events in the evolution of colorectal tumors. We find that driver point mutations, gene fusions, and arm-level copy losses typically arise early in tumorigenesis; different mechanisms act on distinct genomic regions to drive DNA copy changes; and chromothripsis—clustered rearrangements previously thought to occur as a single catastrophic event—is frequent and may occur multiple times independently in the same tumor through different mechanisms. Furthermore, our computational approach reveals that, in contrast to recent studies, selection is often present on subclones and that multiple evolutionary models can operate in a single tumor at different stages. Conclusion Combining these results, we present a refined tumor progression model which significantly expands our understanding of the tumorigenic process of human colorectal cancer.

Published
2019
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13. Deletions in CWH43 cause idiopathic normal pressure hydrocephalus

Author

Hong Wei Yang, Semin Lee, Dejun Yang, Huijun Dai, Yan Zhang, Lei Han, Sijun Zhao, Shuo Zhang, Yan Ma, Marciana F Johnson, Anna K Rattray, Tatyana A Johnson, George Wang, Shaokuan Zheng, Rona S Carroll, Peter J Park, and Mark D Johnson

Subjects
CWH43, GPI‐anchored protein, hydrocephalus, normal pressure hydrocephalus, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6‐fold and 2.7‐fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol‐anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol‐anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.

Published
2021
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14. Welfare Genome Project: A Participatory Korean Personal Genome Project With Free Health Check-Up and Genetic Report Followed by Counseling

Author

Yeonsu Jeon, Sungwon Jeon, Asta Blazyte, Yeo Jin Kim, Jasmin Junseo Lee, Youngjune Bhak, Yun Sung Cho, Yeshin Park, Eui-Kyu Noh, Andrea Manica, Jeremy S. Edwards, Dan Bolser, Sukyeon Kim, Yuji Lee, Changhan Yoon, Semin Lee, Byung Chul Kim, Neung Hwa Park, and Jong Bhak

Subjects
genomics, personal genome project, Korean genome project, population study, integrated healthcare, genetic report, Genetics, QH426-470
Abstract

The Welfare Genome Project (WGP) provided 1,000 healthy Korean volunteers with detailed genetic and health reports to test the social perception of integrating personal genetic and healthcare data at a large-scale. WGP was launched in 2016 in the Ulsan Metropolitan City as the first large-scale genome project with public participation in Korea. The project produced a set of genetic materials, genotype information, clinical data, and lifestyle survey answers from participants aged 20–96. As compensation, the participants received a free general health check-up on 110 clinical traits, accompanied by a genetic report of their genotypes followed by genetic counseling. In a follow-up survey, 91.0% of the participants indicated that their genetic reports motivated them to improve their health. Overall, WGP expanded not only the general awareness of genomics, DNA sequencing technologies, bioinformatics, and bioethics regulations among all the parties involved, but also the general public’s understanding of how genome projects can indirectly benefit their health and lifestyle management. WGP established a data construction framework for not only scientific research but also the welfare of participants. In the future, the WGP framework can help lay the groundwork for a new personalized healthcare system that is seamlessly integrated with existing public medical infrastructure.

Published
2021
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15. Polygenic risk score validation using Korean genomes of 265 early-onset acute myocardial infarction patients and 636 healthy controls.

Author

Youngjune Bhak, Yeonsu Jeon, Sungwon Jeon, Changhan Yoon, Min Kim, Asta Blazyte, Yeonkyung Kim, Younghui Kang, Changjae Kim, Sang Yeub Lee, Jang-Whan Bae, Weon Kim, Yeo Jin Kim, Jungae Shim, Nayeong Kim, Sung Chun, Byoung-Chul Kim, Byung Chul Kim, Semin Lee, Jong Bhak, and Eun-Seok Shin

Subjects
Medicine, Science
Abstract

BackgroundThe polygenic risk score (PRS) developed for coronary artery disease (CAD) is known to be effective for classifying patients with CAD and predicting subsequent events. However, the PRS was developed mainly based on the analysis of Caucasian genomes and has not been validated for East Asians. We aimed to evaluate the PRS in the genomes of Korean early-onset AMI patients (n = 265, age ≤50 years) following PCI and controls (n = 636) to examine whether the PRS improves risk prediction beyond conventional risk factors.ResultsThe odds ratio of the PRS was 1.83 (95% confidence interval [CI]: 1.69-1.99) for early-onset AMI patients compared with the controls. For the classification of patients, the area under the curve (AUC) for the combined model with the six conventional risk factors (diabetes mellitus, family history of CAD, hypertension, body mass index, hypercholesterolemia, and current smoking) and PRS was 0.92 (95% CI: 0.90-0.94) while that for the six conventional risk factors was 0.91 (95% CI: 0.85-0.93). Although the AUC for PRS alone was 0.65 (95% CI: 0.61-0.69), adding the PRS to the six conventional risk factors significantly improved the accuracy of the prediction model (P = 0.015). Patients with the upper 50% of PRS showed a higher frequency of repeat revascularization (hazard ratio = 2.19, 95% CI: 1.47-3.26) than the others.ConclusionsThe PRS using 265 early-onset AMI genomes showed improvement in the identification of patients in the Korean population and showed potential for genomic screening in early life to complement conventional risk prediction.

Published
2021
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16. Prediction of Chronic Periodontitis Severity Using Machine Learning Models Based On Salivary Bacterial Copy Number

Author

Eun-Hye Kim, Seunghoon Kim, Hyun-Joo Kim, Hyoung-oh Jeong, Jaewoong Lee, Jinho Jang, Ji-Young Joo, Yerang Shin, Jihoon Kang, Ae Kyung Park, Ju-Youn Lee, and Semin Lee

Subjects
chronic periodontitis, multiplex qPCR, machine learning, severity prediction, salivary bacterial copy number, slight periodontitis, Microbiology, QR1-502
Abstract

Periodontitis is a widespread chronic inflammatory disease caused by interactions between periodontal bacteria and homeostasis in the host. We aimed to investigate the performance and reliability of machine learning models in predicting the severity of chronic periodontitis. Mouthwash samples from 692 subjects (144 healthy controls and 548 generalized chronic periodontitis patients) were collected, the genomic DNA was isolated, and the copy numbers of nine pathogens were measured using multiplex qPCR. The nine pathogens are as follows: Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Treponema denticola (Td), Prevotella intermedia (Pi), Fusobacterium nucleatum (Fn), Campylobacter rectus (Cr), Aggregatibacter actinomycetemcomitans (Aa), Peptostreptococcus anaerobius (Pa), and Eikenella corrodens (Ec). By adding the species one by one in order of high accuracy to find the optimal combination of input features, we developed an algorithm that predicts the severity of periodontitis using four machine learning techniques. The accuracy was the highest when the models classified “healthy” and “moderate or severe” periodontitis (H vs. M-S, average accuracy of four models: 0.93, AUC = 0.96, sensitivity of 0.96, specificity of 0.81, and diagnostic odds ratio = 112.75). One or two red complex pathogens were used in three models to distinguish slight chronic periodontitis patients from healthy controls (average accuracy of 0.78, AUC = 0.82, sensitivity of 0.71, and specificity of 0.84, diagnostic odds ratio = 12.85). Although the overall accuracy was slightly reduced, the models showed reliability in predicting the severity of chronic periodontitis from 45 newly obtained samples. Our results suggest that a well-designed combination of salivary bacteria can be used as a biomarker for classifying between a periodontally healthy group and a chronic periodontitis group.

Published
2020
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17. A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases

Author

Yiqun Zhang, Lixing Yang, Melanie Kucherlapati, Fengju Chen, Angela Hadjipanayis, Angeliki Pantazi, Christopher A. Bristow, Eunjung A. Lee, Harshad S. Mahadeshwar, Jiabin Tang, Jianhua Zhang, Sahil Seth, Semin Lee, Xiaojia Ren, Xingzhi Song, Huandong Sun, Jonathan Seidman, Lovelace J. Luquette, Ruibin Xi, Lynda Chin, Alexei Protopopov, Wei Li, Peter J. Park, Raju Kucherlapati, and Chad J. Creighton

Subjects
Biology (General), QH301-705.5
Abstract

Summary: A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes—including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)—show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA. : Zhang et al. analyzed over 1,400 cancers by high- or low-pass whole-genome sequencing, focusing on patterns of structural variation. They saw a widespread impact of somatic structural variants on gene expression patterns, independent of copy-number alterations, involving key oncogenes and tumor suppressor genes. Keywords: cancer, structural variation, genomic rearrangement, whole genome sequencing, pan-cancer, TCGA

Published
2018
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18. Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer

Author

Minji Lim, Suhyun Park, Hyoung-Oh Jeong, Sung Hee Park, Sumit Kumar, Aelee Jang, Semin Lee, Dong Uk Kim, and Yoon-Kyoung Cho

Subjects
circulating tumor cells, circulating tumor cell clusters, pancreatic cancer, platelets, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (>3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159; overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.

Published
2021
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19. Microbiome of Saliva and Plaque in Children According to Age and Dental Caries Experience

Author

Eungyung Lee, Suhyun Park, Sunwoo Um, Seunghoon Kim, Jaewoong Lee, Jinho Jang, Hyoung-oh Jeong, Jonghyun Shin, Jihoon Kang, Semin Lee, and Taesung Jeong

Subjects
children, dental caries, microbiome, next-generation sequencing, Medicine (General), R5-920
Abstract

Dental caries are one of the chronic diseases caused by organic acids made from oral microbes. However, there was a lack of knowledge about the oral microbiome of Korean children. The aim of this study was to analyze the metagenome data of the oral microbiome obtained from Korean children and to discover bacteria highly related to dental caries with machine learning models. Saliva and plaque samples from 120 Korean children aged below 12 years were collected. Bacterial composition was identified using Illumina HiSeq sequencing based on the V3–V4 hypervariable region of the 16S rRNA gene. Ten major genera accounted for approximately 70% of the samples on average, including Streptococcus, Neisseria, Corynebacterium, and Fusobacterium. Differential abundant analyses revealed that Scardovia wiggsiae and Leptotrichia wadei were enriched in the caries samples, while Neisseria oralis was abundant in the non-caries samples of children aged below 6 years. The caries and non-caries samples of children aged 6–12 years were enriched in Streptococcus mutans and Corynebacterium durum, respectively. The machine learning models based on these differentially enriched taxa showed accuracies of up to 83%. These results confirmed significant alterations in the oral microbiome according to dental caries and age, and these differences can be used as diagnostic biomarkers.

Published
2021
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20. An ethnically relevant consensus Korean reference genome is a step towards personal reference genomes

Author

Yun Sung Cho, Hyunho Kim, Hak-Min Kim, Sungwoong Jho, JeHoon Jun, Yong Joo Lee, Kyun Shik Chae, Chang Geun Kim, Sangsoo Kim, Anders Eriksson, Jeremy S. Edwards, Semin Lee, Byung Chul Kim, Andrea Manica, Tae-Kwang Oh, George M. Church, and Jong Bhak

Subjects
Science
Abstract

The utility of a universal reference sequence for human genome comparisons is dependent on the ethnic origins of the individuals being sequenced. Here the authors report a Korean reference genome and consensus variome, and show that an ethnically-relevant reference can improve variant detection.

Published
2016
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21. Crystal structure of 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene

Author

Yi Ren, Semin Lee, Jeffery A. Bertke, and Jeffrey S. Moore

Subjects
crystal structure, tetrathiafulvalene, TTF, exTTF, Wittig–Horner reaction, Crystallography, QD901-999
Abstract

The crystal structure of the well-studied 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene molecule, C20H12S4, (I), also known as exTTF, is reported. The molecular structure of (I) consists of a dihydroanthracene moiety with two 1,3-dithiol-2-ylidene substituents. This is a saddle-shaped molecule, which interacts with a close neighbor through various π–π and C—H...π contacts to form a `dimer'. These `dimers' interact through a series of C—H...S and C—H...π contacts to construct a complex three-dimensional extended structure.

Published
2015
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22. Correction: Corrigendum: An ethnically relevant consensus Korean reference genome is a step towards personal reference genomes

Author

Yun Sung Cho, Hyunho Kim, Hak-Min Kim, Sungwoong Jho, JeHoon Jun, Yong Joo Lee, Kyun Shik Chae, Chang Geun Kim, Sangsoo Kim, Anders Eriksson, Jeremy S. Edwards, Semin Lee, Byung Chul Kim, Andrea Manica, Tae-Kwang Oh, George M. Church, and Jong Bhak

Subjects
Science
Abstract

Nature Communications 7: Article number: 13637 (2016): Published 24 November 2016; Updated 9 October 2017. The original version of this Article contained an error in the email address of the corresponding author George Church. The correct email is gchurch@genetics.med.harvard.edu. The error has beencorrected in the HTML and PDF versions of the Article.

Published
2017
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23. A role for mutations in AK9 and other genes affecting ependymal cells in idiopathic normal pressure hydrocephalus.

Author

Hong Wei Yang, Semin Lee, Berry, Bethany C., Dejun Yang, Shaokuan Zheng, Carroll, Rona S., Park, Peter J., and Johnson, Mark D.

Subjects
*HYDROCEPHALUS, *CHOROID plexus, *GENETIC mutation, *NEUROLOGICAL disorders, *HEPATITIS A virus cellular receptors
Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous CWH43 deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, and MYH13) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in AK9, which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated AK9 mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. AK9+/− mice displayed normal brain develop)ment and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Experimental systems for the analysis of mutational signatures: no ‘one-size-fits-all’ solution.

Author

Dmitri Ivanov, Taejoo Hwang, Lukasz Karol Sitko, Semin Lee, and Anton Gartner

Subjects
ETIOLOGY of cancer, DNA mismatch repair, DNA repair, CELL lines, MOLECULAR cloning, GENOMES
Abstract

Cells constantly accumulate mutations, which are caused by replication errors, as well as through the action of endogenous and exogenous DNA-damaging agents. Mutational patterns reflect the status of DNA repair machinery and the history of genotoxin exposure of a given cellular clone. Computationally derived mutational signatures can shed light on the origins of cancer. However, to understand the etiology of cancer signatures, they need to be compared with experimental signatures, which are obtained from the isogenic cell lines or organisms under controlled conditions. Experimental mutational patterns were instrumental in understanding the nature of signatures caused by mismatch repair and BRCA deficiencies. Here, we describe how different cell lines and model organisms were used in recent years to decipher mutational signatures observed in cancer genomes and provide examples of how data from different experimental systems complement and support each other. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Flightless-1 inhibits ER stress-induced apoptosis in colorectal cancer cells by regulating Ca2+ homeostasis

Author

Ji-Min Hyun, Eujin Lee, Seung-Jae Myung, Jinho Jang, Keon Woo Khim, Chan Young Park, Hye-Kyung Park, Byuong Heon Kang, Hye-Jin Eom, Young Chan Chae, Semin Lee, Sun Sil Choi, Kyungjae Myung, Jang Hyun Choi, Joong Kwan Kim, Yohan Lee, and Sang Kwon Lee

Subjects
Male, Programmed cell death, Thapsigargin, Cell Survival, Clinical Biochemistry, Immunoblotting, Apoptosis, QD415-436, Biochemistry, Article, chemistry.chemical_compound, Mice, Downregulation and upregulation, Cell Line, Tumor, Animals, Humans, Molecular Biology, Cancer, Chemistry, Endoplasmic reticulum, Microfilament Proteins, Tunicamycin, Endoplasmic Reticulum Stress, Xenograft Model Antitumor Assays, Cell biology, Unfolded protein response, Trans-Activators, Medicine, Molecular Medicine, Calcium, Colorectal Neoplasms, Intracellular
Abstract

The endoplasmic reticulum (ER) stress response is an adaptive mechanism that is activated upon disruption of ER homeostasis and protects the cells against certain harmful environmental stimuli. However, critical and prolonged cell stress triggers cell death. In this study, we demonstrate that Flightless-1 (FliI) regulates ER stress-induced apoptosis in colon cancer cells by modulating Ca2+ homeostasis. FliI was highly expressed in both colon cell lines and colorectal cancer mouse models. In a mouse xenograft model using CT26 mouse colorectal cancer cells, tumor formation was slowed due to elevated levels of apoptosis in FliI-knockdown (FliI-KD) cells. FliI-KD cells treated with ER stress inducers, thapsigargin (TG), and tunicamycin exhibited activation of the unfolded protein response (UPR) and induction of UPR-related gene expression, which eventually triggered apoptosis. FliI-KD increased the intracellular Ca2+ concentration, and this upregulation was caused by accelerated ER-to-cytosolic efflux of Ca2+. The increase in intracellular Ca2+ concentration was significantly blocked by dantrolene and tetracaine, inhibitors of ryanodine receptors (RyRs). Dantrolene inhibited TG-induced ER stress and decreased the rate of apoptosis in FliI-KD CT26 cells. Finally, we found that knockdown of FliI decreased the levels of sorcin and ER Ca2+ and that TG-induced ER stress was recovered by overexpression of sorcin in FliI-KD cells. Taken together, these results suggest that FliI regulates sorcin expression, which modulates Ca2+ homeostasis in the ER through RyRs. Our findings reveal a novel mechanism by which FliI influences Ca2+ homeostasis and cell survival during ER stress., Cancer: Protein enhances survival of tumor cells under stress A cytoskeletal protein that helps tumors avoid cell death offers a promising new drug target for fighting cancer. A team led by Jang Hyun Choi and Sun Sil Choi of the Ulsan National Institute of Science and Technology, South Korea, detailed how a protein called Flightless I (FliI) that normally regulates the remodeling of structural filaments in the cell can, in colorectal cancer cells, serve as a tumor promoter through its action on calcium levels. Typically, cells respond to chronic stress by altering calcium signaling to promote their own death. In tumors, however, FliI maintains normal calcium levels to enhance cell survival even in the face of chemotherapy and other stressful stimuli. Suppressing FliI activity could thus help sensitize cancer cells to other stress- and death-inducing drug regimens.

Published
2020

26. Depression and suicide risk prediction models using blood-derived multi-omics data

Author

Hae Woo Lee, Eun-Seok Shin, Yun Sung Cho, Semin Lee, Sungwon Jeon, Hak-Min Kim, Byung-Chul Kim, Youngjune Bhak, Jong Woo Paik, Asta Blazyte, Yeonsu Jeon, Hyoung Oh Jeong, Byung Joo Ham, Wooyoung Kang, Yumi Kim, Jong Bhak, Jeong-An Gim, Aram Kim, Juok Cho, and Seung Gu Park

Subjects
Adult, Male, 0301 basic medicine, MEDLINE, Suicide, Attempted, Models, Psychological, Predictive markers, Article, lcsh:RC321-571, Machine Learning, Epigenome, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Rating scale, medicine, Humans, Young adult, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Depression (differential diagnoses), Psychiatric Status Rating Scales, Depressive Disorder, Major, business.industry, Comparative genomics, Case-control study, Regression analysis, Middle Aged, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Major depressive disorder, Female, Transcriptome, business, 030217 neurology & neurosurgery, Predictive modelling, Clinical psychology
Abstract

More than 300 million people worldwide experience depression; annually, ~800,000 people die by suicide. Unfortunately, conventional interview-based diagnosis is insufficient to accurately predict a psychiatric status. We developed machine learning models to predict depression and suicide risk using blood methylome and transcriptome data from 56 suicide attempters (SAs), 39 patients with major depressive disorder (MDD), and 87 healthy controls. Our random forest classifiers showed accuracies of 92.6% in distinguishing SAs from MDD patients, 87.3% in distinguishing MDD patients from controls, and 86.7% in distinguishing SAs from controls. We also developed regression models for predicting psychiatric scales with R2 values of 0.961 and 0.943 for Hamilton Rating Scale for Depression–17 and Scale for Suicide Ideation, respectively. Multi-omics data were used to construct psychiatric status prediction models for improved mental health treatment.

Published
2019

27. Global impact of somatic structural variation on the DNA methylome of human cancers

Author

Alexei Protopopov, Xingzhi Song, Jiabin Tang, Lynda Chin, Christopher A. Bristow, Lixing Yang, Xiaojia Ren, Lovelace J. Luquette, Yiqun Zhang, Jonathan G. Seidman, Chad J. Creighton, Melanie H. Kucherlapati, Raju Kucherlapati, Eunjung Lee, Semin Lee, Huandong Sun, Ruibin Xi, Harshad S. Mahadeshwar, Jianhua Zhang, Angela Hadjipanayis, Angeliki Pantazi, Sahil Seth, and Peter J. Park

Subjects
Methyltransferase, lcsh:QH426-470, Genomic Structural Variation, Structural variation, Epigenome, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Humans, Gene, lcsh:QH301-705.5, 030304 developmental biology, Genetics, 0303 health sciences, biology, Research, Methylation, lcsh:Genetics, Histone, CpG site, lcsh:Biology (General), 030220 oncology & carcinogenesis, DNA methylation, biology.protein, CpG Islands
Abstract

Background Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored. Results By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration. Conclusion Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.

Published
2019

28. Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer

Author

Aelee Jang, Dong Uk Kim, Semin Lee, Sung Hee Park, Hyoung-oh Jeong, Yoon-Kyoung Cho, Minji Lim, Sumit Kumar, and Suhyun Park

Subjects
Cancer Research, business.industry, Mesenchymal stem cell, pancreatic cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, circulating tumor cells, medicine.disease, circulating tumor cell clusters, Article, Metastasis, Circulating tumor cell, Oncology, Pancreatic cancer, platelets, medicine, Cancer research, Clinical significance, Personalized medicine, business, Prospective cohort study, RC254-282, Whole blood
Abstract

Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (&gt, 3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159, overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.

Published
2021

29. An enhanced genetic model of colorectal cancer progression history

Author

Raju Kucherlapati, Peter J. Park, June Koo Lee, Semin Lee, Lixing Yang, Su Wang, Eunjung Lee, David A. Wheeler, and Eve Shinbrot

Subjects
Tumor heterogeneity, DNA Copy Number Variations, lcsh:QH426-470, Gene Dosage, Computational biology, Biology, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genetic model, medicine, Humans, Allele, lcsh:QH301-705.5, 030304 developmental biology, Chromothripsis, 0303 health sciences, Models, Genetic, Research, Point mutation, Kataegis, Aneuploidy, Human genetics, 3. Good health, lcsh:Genetics, Tumor evolution, lcsh:Biology (General), Tumor progression, Mutation, Disease Progression, KRAS, Colorectal Neoplasms, Carcinogenesis, 030217 neurology & neurosurgery
Abstract

Background The classical genetic model of colorectal cancer presents APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of genomic alterations, such as genomic rearrangements, are still unclear. Results Here, we perform comprehensive bioinformatic analysis to dissect the relative timing of somatic genetic alterations in 63 colorectal cancers with whole-genome sequencing data. Utilizing allele fractions of somatic single nucleotide variants as molecular clocks while accounting for the presence of copy number changes and structural alterations, we identify key events in the evolution of colorectal tumors. We find that driver point mutations, gene fusions, and arm-level copy losses typically arise early in tumorigenesis; different mechanisms act on distinct genomic regions to drive DNA copy changes; and chromothripsis—clustered rearrangements previously thought to occur as a single catastrophic event—is frequent and may occur multiple times independently in the same tumor through different mechanisms. Furthermore, our computational approach reveals that, in contrast to recent studies, selection is often present on subclones and that multiple evolutionary models can operate in a single tumor at different stages. Conclusion Combining these results, we present a refined tumor progression model which significantly expands our understanding of the tumorigenic process of human colorectal cancer. Electronic supplementary material The online version of this article (10.1186/s13059-019-1782-4) contains supplementary material, which is available to authorized users.

Published
2019

30. Deletions in CWH43 cause idiopathic normal pressure hydrocephalus

Author

Semin Lee, Tatyana A Johnson, Rona S. Carroll, Hong Wei Yang, George Wang, Yan Zhang, Marciana F Johnson, Anna Kathryn Rattray, Huijun Dai, Yan Ma, Lei Han, Sijun Zhao, Dejun Yang, Shaokuan Zheng, Mark D. Johnson, Shuo Zhang, and Peter J. Park

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, normal pressure hydrocephalus, Medicine (General), Ependymal Cell, Population, Neurological disorder, QH426-470, 03 medical and health sciences, 0302 clinical medicine, R5-920, Normal pressure hydrocephalus, medicine, Genetics, Cognitive decline, education, Exome sequencing, GPI‐anchored protein, education.field_of_study, business.industry, medicine.disease, CWH43, Hydrocephalus, 030104 developmental biology, Molecular Medicine, Choroid plexus, business, hydrocephalus, 030217 neurology & neurosurgery
Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6‐fold and 2.7‐fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol‐anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol‐anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.

Published
2021

31. Potential involvement of Drosophila flightless-1 in carbohydrate metabolism

Author

Min-Ji Kang, Jung-Eun Park, Su Jung Kim, Jinho Jang, Semin Lee, Hyun Ju Yoo, and Eun Ji Lee

Subjects
0301 basic medicine, fungi, Lipid metabolism, RNA sequencing, General Medicine, Articles, Pentose phosphate pathway, Carbohydrate metabolism, Biology, Biochemistry, Cell biology, Flightless-1, 03 medical and health sciences, Metabolic pathway, 030104 developmental biology, Metabolism, Lipogenesis, Gene expression, Metabolomics, Glycolysis, Molecular Biology, Gene
Abstract

A previous study of ours indicated that Drosophila flightless-1 controls lipid metabolism, and that there is an accumulation of triglycerides in flightless-1 (fliI)-mutant flies, where this mutation triggers metabolic stress and an obesity phenotype. Here, with the aim of characterizing the function of FliI in metabolism, we analyzed the levels of gene expression and metabolites in fliI-mutant flies. The levels of enzymes related to glycolysis, lipogenesis, and the pentose phosphate pathway increased in fliI mutants; this result is consistent with the levels of metabolites corresponding to a metabolic pathway. Moreover, high-throughput RNA sequencing revealed that Drosophila FliI regulates the expression of genes related to biological processes such as chromosome organization, carbohydrate metabolism, and immune reactions. These results showed that Drosophila FliI regulates the expression of metabolic genes, and that dysregulation of the transcription controlled by FliI gives rise to metabolic stress and problems in the development and physiology of Drosophila. [BMB Reports 2018; 51(9): 462-467].

Published
2018

32. KoVariome: Korean National Standard Reference Variome database of whole genomes with comprehensive SNV, indel, CNV, and SV analyses

Author

Kyudong Han, Hak-Min Kim, Hyunho Kim, Je Hoon Jun, Yun Sung Cho, Chang Geun Kim, Yumi Kim, Jung-Eun Kim, Jeremy S. Edwards, Semin Lee, Jong Bhak, Hye Jin Lee, In Song Koh, Kyun Shik Chae, Byungchul Kim, Jessica A. Weber, Sungwoong Jho, Ok Sung Chung, and Jinho Jang

Subjects
Male, 0301 basic medicine, DNA Copy Number Variations, Population, lcsh:Medicine, Genomics, Biology, computer.software_genre, Polymorphism, Single Nucleotide, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, Databases, Genetic, Republic of Korea, Genetic variation, Humans, Disease, Copy-number variation, education, Indel, lcsh:Science, Genetics, Whole genome sequencing, education.field_of_study, Multidisciplinary, Whole Genome Sequencing, Database, Genome, Human, lcsh:R, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Reference Standards, Personal Genome Project, Genetics, Population, 030104 developmental biology, Variome, 030220 oncology & carcinogenesis, Mutation, Female, lcsh:Q, computer
Abstract

High-coverage whole-genome sequencing data of a single ethnicity can provide a useful catalogue of population-specific genetic variations, and provides a critical resource that can be used to more accurately identify pathogenic genetic variants. We report a comprehensive analysis of the Korean population, and present the Korean National Standard Reference Variome (KoVariome). As a part of the Korean Personal Genome Project (KPGP), we constructed the KoVariome database using 5.5 terabases of whole genome sequence data from 50 healthy Korean individuals in order to characterize the benign ethnicity-relevant genetic variation present in the Korean population. In total, KoVariome includes 12.7M single-nucleotide variants (SNVs), 1.7M short insertions and deletions (indels), 4K structural variations (SVs), and 3.6K copy number variations (CNVs). Among them, 2.4M (19%) SNVs and 0.4M (24%) indels were identified as novel. We also discovered selective enrichment of 3.8M SNVs and 0.5M indels in Korean individuals, which were used to filter out 1,271 coding-SNVs not originally removed from the 1,000 Genomes Project when prioritizing disease-causing variants. KoVariome health records were used to identify novel disease-causing variants in the Korean population, demonstrating the value of high-quality ethnic variation databases for the accurate interpretation of individual genomes and the precise characterization of genetic variations.

Published
2018

33. Copy number analysis of whole-genome data using BIC-seq2 and its application to detection of cancer susceptibility variants

Author

Tae-Min Kim, Semin Lee, Peter J. Park, Ruibin Xi, and Yuchao Xia

Subjects
0301 basic medicine, Cancer genome sequencing, DNA Copy Number Variations, Sequence analysis, Receptor, ErbB-2, Copy number analysis, Computational biology, Biology, Genome, 03 medical and health sciences, Bayes' theorem, 0302 clinical medicine, Bayesian information criterion, Genetics, Humans, Copy-number variation, Nucleoplasmins, Base Composition, Genome, Human, Membrane Proteins, Bayes Theorem, Genomics, Sequence Analysis, DNA, Chromatin Assembly and Disassembly, Neoplasm Proteins, DNA-Binding Proteins, 030104 developmental biology, Cancer Genome Project, 030220 oncology & carcinogenesis, Carrier Proteins, Colorectal Neoplasms, Algorithms
Abstract

Whole-genome sequencing data allow detection of copy number variation (CNV) at high resolution. However, estimation based on read coverage along the genome suffers from bias due to GC content and other factors. Here, we develop an algorithm called BIC-seq2 that combines normalization of the data at the nucleotide level and Bayesian information criterion-based segmentation to detect both somatic and germline CNVs accurately. Analysis of simulation data showed that this method outperforms existing methods. We apply this algorithm to low coverage whole-genome sequencing data from peripheral blood of nearly a thousand patients across eleven cancer types in The Cancer Genome Atlas (TCGA) to identify cancer-predisposing CNV regions. We confirm known regions and discover new ones including those covering KMT2C, GOLPH3, ERBB2 and PLAG1. Analysis of colorectal cancer genomes in particular reveals novel recurrent CNVs including deletions at two chromatin-remodeling genes RERE and NPM2. This method will be useful to many researchers interested in profiling CNVs from whole-genome sequencing data.

Published
2016

34. Crystal structure of 9,10-bis­(1,3-di­thiol-2-yl­idene)-9,10-di­hydro­anthracene

Author

Semin Lee, Yi Ren, Jeffery A. Bertke, and Jeffrey S. Moore

Subjects
chemistry.chemical_classification, Anthracene, crystal structure, Crystallography, Stereochemistry, General Chemistry, Crystal structure, Condensed Matter Physics, Research Communications, chemistry.chemical_compound, tetra­thia­fulvalene, chemistry, tetrathiafulvalene, QD901-999, Close neighbor, Thiol, Moiety, General Materials Science, TTF, Tetrathiafulvalene, Wittig–Horner reaction, exTTF
Abstract

The title complex is composed of saddle-shaped mol­ecules which closely inter­act in a pairwise fashion through π–π and C—H⋯π contacts to form ‘dimers’. These ‘dimers’ further inter­act through C—H⋯S and C—H⋯π contacts to construct a complex three-dimensional extended structure., The crystal structure of the well-studied 9,10-bis­(1,3-di­thiol-2-yl­idene)-9,10-di­hydro­anthracene mol­ecule, C20H12S4, (I), also known as exTTF, is reported. The mol­ecular structure of (I) consists of a di­hydro­anthracene moiety with two 1,3-di­thiol-2-yl­idene substituents. This is a saddle-shaped mol­ecule, which inter­acts with a close neighbor through various π–π and C—H⋯π contacts to form a ‘dimer’. These ‘dimers’ inter­act through a series of C—H⋯S and C—H⋯π contacts to construct a complex three-dimensional extended structure.

Published
2015

35. Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data

Author

Daeun Ryu, Peter V. Kharchenko, Seok Jin Kim, Kihyun Kim, Semin Lee, Hae-Ock Lee, Catherine Xue, Woong-Yang Park, Jean Fan, Soohyun Lee, Peter J. Park, and Nikolaos Barkas

Subjects
0301 basic medicine, Transcription, Genetic, Method, RNA-Seq, Computational biology, Biology, Polymorphism, Single Nucleotide, Loss of heterozygosity, 03 medical and health sciences, Genetic Heterogeneity, Neoplasms, Genetic variation, Genetics, Humans, Epigenetics, Copy-number variation, Allele, Genetics (clinical), Alleles, Tumor microenvironment, Genetic heterogeneity, Computational Biology, High-Throughput Nucleotide Sequencing, 030104 developmental biology, Mutation, Single-Cell Analysis, Multiple Myeloma
Abstract

Characterization of intratumoral heterogeneity is critical to cancer therapy, as the presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss of heterozygosity in individual cells from single-cell RNA-sequencing data. By integrating allele and normalized expression information, HoneyBADGER is able to identify and infer the presence of subclone-specific alterations in individual cells and reconstruct the underlying subclonal architecture. By examining several tumor types, we show that HoneyBADGER is effective at identifying deletions, amplifications, and copy-neutral loss-of-heterozygosity events and is capable of robustly identifying subclonal focal alterations as small as 10 megabases. We further apply HoneyBADGER to analyze single cells from a progressive multiple myeloma patient to identify major genetic subclones that exhibit distinct transcriptional signatures relevant to cancer progression. Other prominent transcriptional subpopulations within these tumors did not line up with the genetic subclonal structure and were likely driven by alternative, nonclonal mechanisms. These results highlight the need for integrative analysis to understand the molecular and phenotypic heterogeneity in cancer.

Published
2018

36. MBRS-25. GENOMIC ANALYSES REVEALED RADIATION-INDUCED GLIOBLASTOMA IN A SUBSET OF RECURRENT MEDULLOBLASTOMAS

Author

Jong Bhak, Ae Kyung Park, Semin Lee, Hee Chul Park, In-Pyo Baek, Kim Byungchul, Kyun Won Shim, Ji Hoon Phi, Sung Hye Park, Ji Yeoun Lee, Dong Seok Kim, Chae-Yong Kim, Kyu-Chang Wang, Seung-Ki Kim, Eunhye Kim, and Se Hoon Kim

Subjects
Medulloblastoma, Cancer Research, business.industry, Radiation induced, medicine.disease, Second Primary Cancers, nervous system diseases, stomatognathic diseases, Abstracts, Oncology, Cancer research, Medicine, Neurology (clinical), business, Exome, neoplasms, Glioblastoma
Abstract

Despite advances in medulloblastoma treatment and research, recurrent medulloblastoma is still devastating. Additionally, misidentification of secondary malignancy due to histological ambiguity leads to misdiagnosis and eventual inappropriate treatment. Through deep-sequencing of RNA and whole-exome of recurrent tumors from 17 pediatric medulloblastomas, we found that 3 patients had radiation-induced glioblastoma rather than recurrent medulloblastomas. We also uncovered that PDGFRA is a putative driver in radiation-induced glioblastoma, which gives an insight into the possible application of PDGFRA-targeted therapy. The observation of frequent gain of 7q region containing EZH2 accompanied by its high expression both in primary and recurrent medulloblastomas provides a clue to new a therapeutic target to prevent recurrence.

Published
2018

37. Corrigendum: An ethnically relevant consensus Korean reference genome is a step towards personal reference genomes

Author

Hyunho Kim, Kyun Shik Chae, Sang Soo Kim, George M. Church, Jong Bhak, Jeremy S. Edwards, Andrea Manica, Anders Eriksson, Yun Sung Cho, Yong-Joo Lee, JeHoon Jun, Tae-Kwang Oh, Chang Geun Kim, Hak-Min Kim, Sungwoong Jho, Semin Lee, Byungchul Kim, Manica, Andrea [0000-0003-1895-450X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, History, Consensus, Science, MEDLINE, General Physics and Astronomy, Library science, Genomics, Bioinformatics, Genome, General Biochemistry, Genetics and Molecular Biology, 3105 Genetics, Article, 03 medical and health sciences, Email address, GEORGE (programming language), Asian People, Republic of Korea, Humans, Multidisciplinary, Genome, Human, Published Erratum, Chromosome Mapping, High-Throughput Nucleotide Sequencing, General Chemistry, Sequence Analysis, DNA, Corrigenda, 030104 developmental biology, Genome informatics, Reference genome, 31 Biological Sciences
Abstract

Human genomes are routinely compared against a universal reference. However, this strategy could miss population-specific and personal genomic variations, which may be detected more efficiently using an ethnically relevant or personal reference. Here we report a hybrid assembly of a Korean reference genome (KOREF) for constructing personal and ethnic references by combining sequencing and mapping methods. We also build its consensus variome reference, providing information on millions of variants from 40 additional ethnically homogeneous genomes from the Korean Personal Genome Project. We find that the ethnically relevant consensus reference can be beneficial for efficient variant detection. Systematic comparison of human assemblies shows the importance of assembly quality, suggesting the necessity of new technologies to comprehensively map ethnic and personal genomic structure variations. In the era of large-scale population genome projects, the leveraging of ethnicity-specific genome assemblies as well as the human reference genome will accelerate mapping all human genome diversity., The utility of a universal reference sequence for human genome comparisons is dependent on the ethnic origins of the individuals being sequenced. Here the authors report a Korean reference genome and consensus variome, and show that an ethnically-relevant reference can improve variant detection.

Published
2017

38. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, Humans, HRAS, Molecular Targeted Therapy, RNA, Neoplasm, Gene, neoplasms, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Oncogene, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Wnt signaling pathway, DNA, Neoplasm, Genomics, Oncogenes, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, FAT1, Signal Transduction, Transcription Factors
Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

39. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Author

A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A. Bristow, Katherine A. Hoadley, Lisa Iype, Matthew T. Chang, Andrew D. Cherniack, Christopher Benz, Gordon B. Mills, Roel G.W. Verhaak, Klaus G. Griewank, Ina Felau, Jean C. Zenklusen, Jeffrey E. Gershenwald, Lynn Schoenfield, Alexander J. Lazar, Mohamed H. Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M. Cebulla, Michelle D. Williams, Martine J. Jager, Sarah E. Coupland, Bita Esmaeli, Cyriac Kandoth, Scott E. Woodman, Adrian Ally, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Rameen Beroukhim, Inanc Birol, Tom Bodenheimer, Jay Bowen, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Kristian Cibulskis, Leslie Cope, Timothy Defreitas, John A. Demchok, Laurence Desjardins, Noreen Dhalla, Martin L. Ferguson, Scott Frazer, Stacey B. Gabriel, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Elizabeth A. Grimm, D. Neil Hayes, Apurva M. Hegde, David I. Heiman, Carmen Helsel, Shital Hobensack, Robert A. Holt, Alan P. Hoyle, Xin Hu, Carolyn M. Hutter, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Katayoon Kasaian, Jaegil Kim, Raju Kucherlapati, Eric Lander, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Pei Lin, Jia Liu, Wenbin Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, Harshad S. Mahadeshwar, Odette Mariani, Marco A. Marra, Michael Mayo, Sam Meier, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Bradley A. Murray, Rashi Naresh, Michael S. Noble, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Todd Pihl, Robert Pilarski, Alexei Protopopov, Amie Radenbaugh, Karan Rai, Nilsa C. Ramirez, Xiaojia Ren, Sheila M. Reynolds, Jeffrey Roach, Jason Roszik, Sara Sadeghi, Gordon Saksena, Xavier Sastre, Dirk Schadendorf, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Sahil Seth, Geetika Sethi, Margi Sheth, Yan Shi, Carol Shields, Ilya Shmulevich, Janae V. Simons, Arun D. Singh, Payal Sipahimalani, Tara Skelly, Heidi Sofia, Matthew G. Soloway, Xingzhi Song, Joshua Stuart, Qiang Sun, Huandong Sun, Angela Tam, Donghui Tan, Jiabin Tang, Roy Tarnuzzer, Barry S. Taylor, Nina Thiessen, Vesteinn Thorsson, Kane Tse, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, John N. Weinstein, Matthew D. Wilkerson, Lisa Wise, Tina Wong, Ye Wu, Liming Yang, Lixing Yang, Jiashan Zhang, Hailei Zhang, and Erik Zmuda

Subjects
0301 basic medicine, Uveal Neoplasms, Cancer Research, Medizin, Eukaryotic Initiation Factor-1, Uveal Neoplasm, medicine.disease_cause, 0302 clinical medicine, Monosomy, Medicine, Melanoma, Cancer, Genetics, BAP1, Mutation, molecular subtypes, Tumor, Serine-Arginine Splicing Factors, SF3B1, Prognosis, Gene Expression Regulation, Neoplastic, SRSF2, Oncology, 030220 oncology & carcinogenesis, EIF1AX, DNA methylation, RNA Splicing Factors, uveal melanoma, Ubiquitin Thiolesterase, DNA Copy Number Variations, Oncology and Carcinogenesis, TCGA Research Network, monosomy 3, GNA11, Biology, noncoding RNA, Article, 03 medical and health sciences, Rare Diseases, GNAQ, Biomarkers, Tumor, Humans, Oncology & Carcinogenesis, Eye Disease and Disorders of Vision, Neoplastic, business.industry, Tumor Suppressor Proteins, Human Genome, Neurosciences, Cell Biology, DNA Methylation, TCGA, medicine.disease, Phosphoproteins, 030104 developmental biology, Gene Expression Regulation, Cancer research, business, Biomarkers
Abstract

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Published
2017

40. The whale shark genome reveals how genomic and physiological properties scale with body size.

Author

Weber, Jessica A., Seung Gu Park, Luria, Victor, Sungwon Jeon, Hak-Min Kim, Yeonsu Jeon, Youngjune Bhak, Je Hun Jun, Sang Wha Kim, Won Hee Hong, Semin Lee, Yun Sung Cho, Karger, Amir, Cain, John W., Manica, Andrea, Soonok Kim, Jae-Hoon Kim, Edwards, Jeremy S., Jong Bhak, and Church, George M.

Subjects
WHALE shark, BODY size, GENOMES, COMPARATIVE genomics, ANIMALS
Abstract

The endangered whale shark (Rhincodon typus) is the largest fish on Earth and a long-lived member of the ancient Elasmobranchii clade. To characterize the relationship between genome features and biological traits, we sequenced and assembled the genome of the whale shark and compared its genomic and physiological features to those of 83 animals and yeast. We examined the scaling relationships between body size, temperature, metabolic rates, and genomic features and found both general correlations across the animal kingdom and features specific to the whale shark genome. Among animals, increased lifespan is positively correlated to body size and metabolic rate. Several genomic traits also significantly correlated with body size, including intron and gene length. Our large-scale comparative genomic analysis uncovered general features of metazoan genome architecture: Guanine and cytosine (GC) content and codon adaptation index are negatively correlated, and neural connectivity genes are longer than average genes in most genomes. Focusing on the whale shark genome, we identified multiple features that significantly correlate with lifespan. Among these were very long gene length, due to introns being highly enriched in repetitive elements such as CR1-like long interspersed nuclear elements, and considerably longer neural genes of several types, including connectivity, activity, and neurodegeneration genes. The whale shark genome also has the second slowest evolutionary rate observed in vertebrates to date. Our comparative genomics approach uncovered multiple genetic features associated with body size, metabolic rate, and lifespan and showed that the whale shark is a promising model for studies of neural architecture and lifespan. [ABSTRACT FROM AUTHOR]

Published
2020
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41. Ethnically relevant consensus Korean reference genome towards personal reference genomes

Author

Yun Sung Cho, Hyunho Kim, Hak-Min Kim, Sungwoong Jho, JeHoon Jun, Yong Joo Lee, Kyun Shik Chae, Chang Geun Kim, Sangsoo Kim, Anders Eriksson, Jeremy S. Edwards, Semin Lee, Byung Chul Kim, Andrea Manica, George M. Church, and Jong Bhak

Subjects
Genetics, education.field_of_study, Variome, Population, Human genome, Genomics, Computational biology, Genome project, Biology, education, Genome, Reference genome, Personal genomics
Abstract

Human genomes are routinely compared against a universal reference. However, this strategy could miss population-specific or personal genomic variations, which may be detected more efficiently using an ethnically-relevant and/or a personal reference. Here we report a hybrid assembly of Korean reference (KOREF) as a pilot case for constructing personal and ethnic references by combining sequencing and mapping methods. KOREF is also the first consensus variome reference, providing information on millions of variants from additional ethnically homogeneous personal genomes. We found that this ethnically-relevant consensus reference was beneficial for efficiently detecting variants. Systematic comparison of KOREF with previously established human assemblies showed the importance of assembly quality, suggesting the necessity of using new technologies to comprehensively map ethnic and personal genomic structure variations. In the era of large-scale population genome projects, the leveraging of ethnicity-specific genome assemblies as well as the human reference genome will accelerate mapping all human genome diversity.

Published
2016
Full Text
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42. The molecular taxonomy of primary prostate cancer

Author

Piotr A. Mieczkowski, Jianhua Zhang, Saianand Balu, Marc Ladanyi, Victor E. Reuter, Johanna Gardner, Junyuan Wu, Troy Shelton, Simone Chevalier, Marco A. Marra, Anuradha Gopalan, Roy Tarnuzzer, Pei Lin, Joel S. Parker, Umadevi Veluvolu, Lisle E. Mose, Rebecca Carlsen, Michel Carmel, Shalini S. Yadav, Joseph Paulauskis, Fadi Brimo, Sheila Reynolds, Scott Frazer, Natalya Dyakova, Christopher A. Bristow, Brian D. Robinson, Lucie Hamel, Yaron S.N. Butterfield, Yao Fu, Syed Haider, Christopher J. Logothetis, Michael Parfenov, Jeff Boyd, Katherine Tarvin, Kjong-Van Lehmann, Stuart R. Jefferys, Alan P. Hoyle, Arshi Arora, A. Gordon Robertson, Matti Annala, Thomas L. Bauer, Jianhua Luo, Rodolfo Borges Dos Reis, Louis Lacombe, Andrew Salner, Matti Nykter, Alexandre Doueik, Mei Huang, Alireza Moinzadeh, Joshua Armenia, Andre Kahles, Rehan Akbani, Todd Pihl, Gordon Saksena, Robert A. Holt, Felipe Amstalden Trevisan, Mario Berrios, Nina Thiessen, Ronglai Shen, Carrie Sougnez, Xiaojia Ren, Matthew G. Soloway, Lixing Yang, W. Marston Linehan, Chip Stewart, Angeliki Pantazi, Alain Bergeron, Andrea Sboner, Angela Hadjipanayis, Xingzhi Song, Carlos Gilberto Carlotti, Manaswi Gupta, Rashi Naresh, Yiling Lu, Hartmut Juhl, Mark Gerstein, Robert Leung, Sahil Seth, Teri A. Longacre, Ignaty Leshchiner, Chris Sander, Andrew Wei Xu, Anne Marie Mes-Masson, Patrick Teebagy, Julian M. Hess, Matthew Meyerson, Adrian Ally, Jiabin Tang, Ye Wu, Janae V. Simons, David Van Den Berg, Kenna R. Mills Shaw, Patricia Troncoso, Thomas Gribbin, Shannon J. McCall, Andrew K. Godwin, Daniel J. Weisenberger, Kimberly Rieger-Christ, Nilsa C. Ramirez, Peter J. Park, Margi Sheth, Mark E. Sherman, Eric S. Lander, Yunhu Wan, Lisa Iype, Robert Penny, J. Todd Auman, Ekta Khurana, Stephen J. Freedland, Jeffry Simko, Nils Weinhold, Bradley M. Broom, Angela Tam, Nikolaus Schultz, Erik Zmuda, Wei Zhang, Wenyi Wang, Jeffrey Roach, Christopher E. Barbieri, Alan H. Bryce, Qingguo Wang, Lawrence D. True, Christopher C. Benz, Mathieu Latour, Richard A. Moore, Michael Mayo, Yi Zhong, Tara M. Lichtenberg, Jacqueline E. Schein, Svitlana Tyekucheva, Ranabir Guin, Scott L. Carter, Michael Kerger, David Canes, Scott M. Lippman, Alexei Protopopov, Katayoon Kasaian, Peter A. Pinto, Peter S. Nelson, W. Kimryn Rathmell, David Mallery, Brett S. Carver, David I. Heiman, Juok Cho, Doug Voet, Thorsten Schlomm, Janet E. Cowan, Heidi J. Sofia, Peggy Yena, Matthew D. Wilkerson, Glenn Bubley, Tucker W. LeBien, Yan Shi, Lucas Lochovsky, Gordon B. Mills, Hailei Zhang, Andrea Holbrook, Christopher M. Hovens, Christina Yau, Jonathan G. Seidman, Samirkumar B. Amin, Corbin D. Jones, Andrew D. Cherniack, Lori Boice, Laxmi Lolla, Kristen M. Leraas, Denise Brooks, Francesca Demichelis, Maria Christina Tsourlakis, Katherine A. Hoadley, Charles Saller, Leigh B. Thorne, Julie M. Gastier-Foster, Jaegil Kim, Rameen Beroukhim, Peter R. Carroll, John A. Demchok, Christopher J. Kane, Jay Bowen, Massimo Loda, Richard Cartun, Ina Felau, Carl Morrison, Kerstin David, Eliezer M. Van Allen, Laura S. Schmidt, D. Neil Hayes, Adrian Bivol, Michael S. Lawrence, Raju Kucherlapati, Kelsey Zhu, Wen-Bin Liu, Matthew R. Cooperberg, Houtan Noushmehr, Daniel Crain, Luciano Neder, Lynda Chin, Barry S. Taylor, Jiashan Zhang, Bradley A. Murray, Ginette McKercher, Miruna Balasundaram, Chia Chin Wu, Peter T. Scardino, Suhn K. Rhie, Mark A. Rubin, Jean C. Zenklusen, Ronald Simon, Jaeil Ahn, Markus Graefen, Phillip H. Lai, Michael Ittmann, June M. Chan, Maria J. Merino, Andy Chu, Liming Yang, Charles M. Perou, Steven J.M. Jones, Gad Getz, Stacey Gabriel, Martin L. Ferguson, Jianjiong Gao, Payal Sipahimalani, Lisa Wise, Serghei Stepa, Arvind Rao, Bettina F. Drake, Antonia H. Holway, Armaz Mariamidze, Kiley Graim, Juliann Shih, Guido Sauter, Sarah Minner, Amanda Clarke, Harshad S. Mahadeshwar, Andrew J. Mungall, Alain Piché, Cathy D. Vocke, Sudha Chudamani, Yulia Newton, Davide Prandi, Roeland Verhaak, Ilya Shmulevich, Matthew T. Chang, Sara Sadeghi, Michael Button, Joshua M. Stuart, Anne Breggia, Kristian Cibulskis, Giovanni Ciriello, Paul C. Boutros, Yu Chen, Zhining Wang, Jerome Myers, Heidi Dvinge, Ashutosh Tewari, Scott Morris, Andrea Sorcini, Tara Skelly, Niall M. Corcoran, Michael S. Noble, Anthony J. Costello, Timothy C. Thompson, Eric Chuah, Carolyn M. Hutter, Robert K. Bradley, Fred Saad, John A. Libertino, Reanne Bowlby, John A. Stewart, Shiyun Ling, Gunnar Rätsch, George E. Sandusky, Alexis Sharp, Eric J. Burks, Thomas Zeng, Erin Curley, Charlie Sun, Rajiv Dhir, Yussanne Ma, Huihui Ye, Hui Shen, Nils Gehlenborg, Imelda Tenggara, Travis Sullivan, Tom Bodenheimer, Jia Liu, Christopher D. Andry, Adam Abeshouse, Daniela P. Tirapelli, John N. Weinstein, Kevin Lau, Francisco Sanchez-Vega, Armen Aprikian, Peter W. Laird, Noreen Dhalla, Candace Shelton, Joel Nelson, Bernard Têtu, Darlene Lee, Eleonora Scarlata, Mark Nelson, Steven E. Schumacher, Robert J. Klein, Mark Gerken, Donghui Tan, Semin Lee, John S. Witte, Shaowu Meng, Huandong Sun, Moiz S. Bootwalla, Scott A. Tomlins, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, and Voet, Douglas

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, DNA Repair, DNA repair, Urology, MEDLINE, Biology, SPOP, Bioinformatics, Molecular taxonomy, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Fusion gene, 03 medical and health sciences, Prostate cancer, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Gynecology, 0303 health sciences, Primary (chemistry), business.industry, Prostatic Neoplasms, medicine.disease, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, GENÉTICA, 030104 developmental biology, medicine.anatomical_structure, Receptors, Androgen, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Cancer research, ras Proteins, Gene Fusion, business, Signal Transduction
Abstract

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

Published
2015

43. Genomic Classification of Cutaneous Melanoma

Author

W. Kimryn Rathmell, Lauren E. Haydu, Nils Gehlenborg, David Mallery, Lynn M. Herbert, Hailei Zhang, Darlene Lee, Payal Sipahimalani, Richard A. Scolyer, Jonathan R. Stretch, Amanda Clarke, Sudha Chudamani, Dirk Schadendorf, Jeffrey Roach, Troy Shelton, Kerwin F. Shannon, Kadir C. Akdemir, Alexander J. Lazar, Lixing Yang, D. Murawa, Jingchun Zhu, Michael Mayo, Steven E. Schumacher, Marc Ladanyi, Yiling Lu, Levi A. Garraway, Andrew J. Spillane, Giandomenico Russo, Ian R. Watson, Matthew D. Wilkerson, Mei Huang, Chang Jiun Wu, Pedamallu Chandra Sekhar, Laura Brockway-Lunardi, Wiktoria Maria Suchorska, Michael A. Davies, John M. S. Bartlett, Benjamin Gross, Mark Gerken, Georgy Manikhas, William R. Jeck, Michael Dinikin, Sam Ng, Antje Sucker, Sharon K. Huang, Donghui Tan, Semin Lee, Da Yang, Yardena Samuels, Boris C. Bastian, Katherine A. Hoadley, Kenna R. Mills Shaw, Shaowu Meng, Kunal Rai, Sheila Fisher, Tom Bodenheimer, Robyn P. M. Saw, Joel S. Parker, Victoria Fulidou, Scot Waring, Vesteinn Thorsson, Jacqueline E. Schein, Heidi J. Sofia, Jia Liu, Eric S. Lander, Martin L. Miller, Scott E. Woodman, Yunhu Wan, Olga Voronina, Brenda Ayala, Moiz S. Bootwalla, Rileen Sinha, Yonathan Lissanu Deribe, Yussanne Ma, Gabriel Sica, Matthew Ibbs, Pam Bartlett, Arkadiusz Spychała, Sheila Reynolds, Nikolaus Schultz, Jianhua Zhang, Stephen B. Baylin, Saianand Balu, Jay Bowen, Eran Hodis, Olga Potapova, Lori Boice, Julie M. Gastier-Foster, Singer Ma, Victor G. Prieto, Steven J.M. Jones, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Ruibin Xi, Stergios J. Moschos, Lisa Iype, Robert Penny, Vonn Walter, Peter Hersey, Umadevi Veluvolu, Jiabin Tang, Mark A. Jensen, Aaron Chevalier, Nils Weinhold, Yaron S.N. Butterfield, S. Onur Sumer, Lisle E. Mose, Leslie Cope, Angela Tam, Carmelo Gaudioso, Giovanni Ciriello, Jaegil Kim, Noreen Dhalla, Candace Shelton, Andrzej Mackiewicz, Travis I. Zack, James G. Herman, Lisa Zimmer, Chia Chin Wu, Elena Pagani, Franklin W. Huang, Tanja Davidsen, Stuart R. Jefferys, Andy Chu, Harmanjatinder S. Sekhon, Richard A. Moore, Scott L. Carter, Ludmila Danilova, Peter W. Laird, Nicholas K. Hayward, Julien Baboud, A. Gordon Robertson, Scott Morris, Honorata Tatka, Gordon Saksena, Robert A. Holt, Angela Hadjipanayis, Jakub Brzezinski, Lihua Zou, Nilsa C. Ramirez, Witold Kycler, Yasin Senbabaoglu, Xingzhi Song, Barbara Tabak, Christopher C. Benz, Michael Dubina, Wei Zhang, Sophie Egea, Fedor Moiseenko, Marcus Bosenberg, Piotr A. Mieczkowski, Michael J. Quinn, Harindra Arachchi, Andrew J. Mungall, Lynn Cherney, Suresh Ramalingam, Christopher A. Bristow, Hojabr Kakavand, Chris Sander, Peiling Tsou, Anil Korkut, Alan P. Hoyle, Arshi Arora, Kenneth K. Lee, Netty Santoso, Raymond J. Cho, Ricardo Ramirez, Melissa Saul, Haiyan I. Li, Jeremy Parfitt, Valerie Jakrot, Tiffany L. Calderone, Jessica Frick, John N. Weinstein, Brady Bernard, John M. Kirkwood, Dave S.B. Hoon, Carolyn J. Shiau, Carmen Gomez-Fernandez, Michael Krauthammer, Carrie Sougnez, George E. Sandusky, Xiaojia Ren, Charles Schwallier, Carolyn M. Hutter, Radoslaw Łaźniak, Dmitry Belyaev, Richard F. Kefford, Jeffrey M. Trent, Ouida Liu, J. Stephen Ebrom, Yoon La Choi, Maciej Wiznerowicz, Ranabir Guin, Yan Shi, Ewa Leporowska, Zhenlin Ju, Charles Saller, Hyojin Kang, Jean C. Zenklusen, Tony Gutschner, Peter White, Luigi Nezi, Oxana Paklina, Harshad S. Mahadeshwar, Wiam Bshara, Roeland Verhaak, Kenneth Y. Tsai, Ilya Shmulevich, Kristian Cibulskis, Jonathan G. Seidman, Corbin D. Jones, Ayush T. Raman, D. Neil Hayes, Nandita Barnabas, Uma Rao, Jennifer Eschbacher, Timothy R. Fennell, Jeffrey E. Lee, Matthew Meyerson, Jeffrey E. Gershenwald, Elizabeth Buda, Xiaobei Zhao, Jason Roszik, M. Teresiak, Daniel DiCara, Pei Lin, Eliezer M. Van Allen, Scott Frazer, Genevieve M. Boland, Zhining Wang, Susan Hoppough, Konstanty Korski, Michael S. Noble, B. Arman Aksoy, Reanne Bowlby, Adeboye Osunkoya, Taofeek K. Owonikoko, Madhusmita Behera, Shiyun Ling, Erin Curley, Rajiv Dhir, Andrew Wei Xu, David I. Heiman, Samirkumar B. Amin, Andrew D. Cherniack, Brenna Matejka, Rameen Beroukhim, Michael S. Lawrence, Kelsey Zhu, Wen-Bin Liu, Stacey Gabriel, Martin L. Ferguson, Samantha Sharpe, Giannicola Genovese, Jay Engel, Johanna Gardner, Junyuan Wu, Marco A. Marra, Roy Tarnuzzer, John F. Thompson, Denise Brooks, Lawrence N. Kwong, Woong-Yang Park, Daniel J. Weisenberger, J. Todd Auman, Kristen M. Leraas, Margi Sheth, Riccardo Bono, John A. Demchok, Stefania D'Atri, Candace D. Carter, Miruna Balasundaram, Natalie Bir, Matthew G. Soloway, Angeliki Pantazi, Sahil Seth, Qixia A. Deng, Junehawk Lee, Dana Nicholson, Ye Wu, Keith T. Flaherty, Peter J. Park, Amie Radenbaugh, Benjamin Hanf, Katherine Tarvin, James S. Wilmott, Giancarlo Antonini Cappellini, Pawel Murawa, Maria Synott, Jonna Grimsby, Stephen Coons, Joachim Klode, Michael Button, Alyssa Janning, Alexei Protopopov, Florian L. Muller, Donald L. Morton, Joshua M. Stuart, Ina Felau, Cindy Sander, Ruth Halaban, John P. Miller, David Haussler, Monique Albert, Charles M. Perou, Timothy J. Triche, Yichao Sun, Aaron D. Black, Adrian Ally, Sousan Mehrabi, David Van Den Berg, Graham J. Mann, Erik Zmuda, Carl Morrison, Daniel Crain, Douglas Voet, Janae V. Simons, Norman E. Sharpless, Fadlo R. Khuri, Phillip H. Lai, Liming Yang, Anders Jacobsen, Keith A. Delman, Teresa R. Tabler, Gad Getz, Tara M. Lichtenberg, William Lee, Georgina V. Long, Nina Thiessen, Ronglai Shen, Francesca Passarelli, Bradley A. Ozenberger, Gordon B. Mills, Jessica Walton, Greg Eley, Leigh B. Thorne, Merrick I. Ross, Jared Malke, Barry S. Taylor, Juok Cho, William R. Burns, Michael Parfenov, Thomas Gribbin, Yuling Wang, Raju Kucherlapati, Lynda Chin, Bradley A. Murray, Lee Lichtenstein, Jianjiong Gao, and Lisa Wise

Subjects
Skin Neoplasms, Mutant, Medizin, Biology, General Biochemistry, Genetics and Molecular Biology, Subclass, Article, Transcriptome, chemistry.chemical_compound, Databases, Genetic, medicine, Humans, Gene, Melanoma, Genetics, Biochemistry, Genetics and Molecular Biology(all), Cancer, Binimetinib, medicine.disease, National Cancer Institute (U.S.), United States, 3. Good health, chemistry, Cutaneous melanoma, Mutation, Cancer research
Abstract

Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Published
2015

44. The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation

Author

Victor M. Bolanos-Garcia and Semin Lee

Subjects
Genome instability, Physiology, Protein complexes, chromosome segregation, protein-protein interactions, Review Article, Biology, lcsh:Physiology, spindle assembly checkpoint, Protein–protein interaction, protein-protein interaction, Chromosome segregation, Chromosome (genetic algorithm), Physiology (medical), cancer, Anaphase, Genetics, spindle assembly checkpoint (SAC), lcsh:QP1-981, Kinetochore, kinetochore-microtubules network, genome instability, Spindle apparatus, Cell biology, signal amplification, Spindle checkpoint, cell cycle regulation
Abstract

The control of chromosome segregation relies on the spindle assembly checkpoint (SAC), a complex regulatory system that ensures the high fidelity of chromosome segregation in higher organisms by delaying the onset of anaphase until each chromosome is properly bi-oriented on the mitotic spindle. Central to this process is the establishment of multiple yet specific protein-protein interactions in a narrow time-space window. Here we discuss the highly dynamic nature of multi-protein complexes that control chromosome segregation in which an intricate network of weak but cooperative interactions modulate signal amplification to ensure a proper SAC response. We also discuss the current structural understanding of the communication between the SAC and the kinetochore; how transient interactions can regulate the assembly and disassembly of the SAC as well as the challenges and opportunities for the definition and the manipulation of the flow of information in SAC signaling.

Published
2014
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45. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author

Caleb F. Davis, Christopher J. Ricketts, Min Wang, Lixing Yang, Andrew D. Cherniack, Hui Shen, Christian Buhay, Hyojin Kang, Sang Cheol Kim, Catherine C. Fahey, Kathryn E. Hacker, Gyan Bhanot, Dmitry A. Gordenin, Andy Chu, Preethi H. Gunaratne, Michael Biehl, Sahil Seth, Benny A. Kaipparettu, Christopher A. Bristow, Lawrence A. Donehower, Eric M. Wallen, Angela B. Smith, Satish K. Tickoo, Pheroze Tamboli, Victor Reuter, Laura S. Schmidt, James J. Hsieh, Toni K. Choueiri, A. Ari Hakimi, Lynda Chin, Matthew Meyerson, Raju Kucherlapati, Woong-Yang Park, A. Gordon Robertson, Peter W. Laird, Elizabeth P. Henske, David J. Kwiatkowski, Peter J. Park, Margaret Morgan, Brian Shuch, Donna Muzny, David A. Wheeler, W. Marston Linehan, Richard A. Gibbs, W. Kimryn Rathmell, Chad J. Creighton, Sabina Signoretti, Christopher Ricketts, Michael Seiler, Hsu Chao, Mike Dahdouli, Liu Xi, Nipun Kakkar, Jeffrey G. Reid, Brittany Downs, Jennifer Drummond, Donna Morton, Harsha Doddapaneni, Lora Lewis, Adam English, Qingchang Meng, Christie Kovar, Qiaoyan Wang, Walker Hale, Alicia Hawes, Divya Kalra, Kimberly Walker, Bradley A. Murray, Carrie Sougnez, Gordon Saksena, Scott L. Carter, Steven E. Schumacher, Barbara Tabak, Travis I. Zack, Gad Getz, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Inanc Birol, Denise Brooks, Yaron S.N. Butterfield, Eric Chuah, Amanda Clarke, Noreen Dhalla, Ranabir Guin, Robert A. Holt, Katayoon Kasaian, Darlene Lee, Haiyan I. Li, Emilia Lim, Yussanne Ma, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Steven J.M. Jones, Marco A. Marra, J. Todd Auman, Donghui Tan, Shaowu Meng, Corbin D. Jones, Katherine A. Hoadley, Piotr A. Mieczkowski, Lisle E. Mose, Stuart R. Jefferys, Jeffrey Roach, Umadevi Veluvolu, Matthew D. Wilkerson, Scot Waring, Elizabeth Buda, Junyuan Wu, Tom Bodenheimer, Alan P. Hoyle, Janae V. Simons, Mathew G. Soloway, Saianand Balu, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Daniel J. Weisenberger, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Stephen B. Baylin, Fengju Chen, Cristian Coarfa, Michael S. Noble, Daniel DiCara, Hailei Zhang, Juok Cho, David I. Heiman, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Petar Stojanov, Yingchun Liu, Lihua Zou, Jaegil Kim, Michael S. Lawrence, Alexei Protopopov, Xingzhi Song, Jianhua Zhang, Angeliki Pantazi, Angela Hadjipanayis, Eunjung Lee, Lovelace J. Luquette, Semin Lee, Michael Parfenov, Netty Santoso, Jonathan Seidman, Andrew W. Xu, Junehawk Lee, Steven A. Roberts, Leszek J. Klimczak, David Fargo, Martin Lang, Yoon-La Choi, June-Koo Lee, Wenyi Wang, Yu Fan, Jaeil Ahn, Rehan Akbani, John N. Weinstein, David Haussler, Singer Ma, Amie Radenbaugh, Jingchun Zhul, Tara M. Lichtenberg, Erik Zmuda, Aaron D. Black, Benjamin Hanf, Nilsa C. Ramirez, Lisa Wise, Jay Bowen, Kristen M. Leraas, Tracy M. Hall, Julie M. Gastier-Foster, William G. Kaelin, Leigh Thorne, Lori Boice, Mei Huang, Cathy Vocke, James Peterson, Robert Worrell, Maria Merino, Bogdan A. Czerniak, Kenneth D. Aldape, Christopher G. Wood, Paul T. Spellman, Michael B. Atkins, John Cheville, R. Houston Thompson, Mark A. Jensen, Todd Pihl, Yunhu Wan, Brenda Ayala, Julien Baboud, Sudhakar Velaga, Jessica Walton, Jia Liu, Sudha Chudamani, Ye Wu, Margi Sheth, Kenna R. Mills Shaw, John A. Demchok, Tanja Davidsen, Liming Yang, Zhining Wang, Roy W. Tarnuzzer, Jiashan Zhang, Greg Eley, Ina Felau, Jean Claude Zenklusen, Carolyn M. Hutter, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, and Intelligent Systems

Subjects
Mitochondrial DNA, Cancer Research, DNA Copy Number Variations, Somatic cell, Chromophobe Renal Cell Carcinoma, DNA Mutational Analysis, Molecular Sequence Data, Chromophobe cell, Biology, DNA, Mitochondrial, Article, Chromosome Breakpoints, Chromosomes, Human, Humans, Exome, Promoter Regions, Genetic, Carcinoma, Renal Cell, Telomerase, Genetics, Base Sequence, Genome, Human, Point mutation, Cell Biology, DNA Methylation, Kidney Neoplasms, Oncology, Kataegis, DNA methylation, Chromosome Deletion, Transcriptome
Abstract

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.

Published
2014

46. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, Katherine A., Yau, Christina, Wolf, Denise M., Cherniack, Andrew D., Tamborero, David, Sam, Ng, Leiserson, Max D. M., Niu, Beifang, Mclellan, Michael D., Uzunangelov, Vladislav, Zhang, Jiashan, Kandoth, Cyriac, Akbani, Rehan, Shen, Hui, Omberg, Larsson, Chu, Andy, Margolin, Adam A., Van'T Veer, Laura J., Lopez Bigas, Nuria, Laird, Peter W., Raphael, Benjamin J., Ding, Li, Robertson, A. Gordon, Byers, Lauren A., Mills, Gordon B., Weinstein, John N., Van Waes, Carter, Chen, Zhong, Collisson, Eric A., Benz, Christopher C, Perou, Charles M., Stuart, Joshua M., Rachel, Abbott, Scott, Abbott, Arman Aksoy, B., Kenneth, Aldape, Adrian, Ally, Samirku mar Amin, Dimitris, Anastassiou, Todd Auman, J., Baggerly, Keith A., Miruna, Balasundaram, Saianand, Balu, Baylin, Stephen B., Benz, Stephen C., Berman, Benjamin P., Brady, Bernard, Bhatt, Ami S., Inanc, Birol, Black, Aaron D., Tom, Bodenheimer, Bootwalla, Moiz S., Jay, Bowen, Ryan, Bressler, Bristow, Christopher A., Brooks, Angela N., Bradley, Broom, Elizabeth, Buda, Robert, Burton, Butterfield, Yaron S. N., Daniel, Carlin, Carter, Scott L., Casasent, Tod D., Kyle, Chang, Stephen, Chanock, Lynda, Chin, Dong Yeon Cho, Juok, Cho, Eric, Chuah, Chun, Hye Jung E., Kristian, Cibulskis, Giovanni, Ciriello, James Cle land, Melisssa, Cline, Brian, Craft, Creighton, Chad J., Ludmila, Danilova, Tanja, Davidsen, Caleb, Davis, Dees, Nathan D., Kim, Delehaunty, Demchok, John A., Noreen, Dhalla, Daniel, Dicara, Huyen, Dinh, Dobson, Jason R., Deepti, Dodda, Harshavardhan, Doddapaneni, Lawrence, Donehower, Dooling, David J., Gideon, Dresdner, Jennifer, Drummond, Andrea, Eakin, Mary, Edgerton, Eldred, Jim M., Greg, Eley, Kyle, Ellrott, Cheng, Fan, Suzanne, Fei, Ina, Felau, Scott, Frazer, Freeman, Samuel S., Jessica, Frick, Fronick, Catrina C., Ful ton, Lucinda L., Robert, Fulton, Gabriel, Stacey B., Jianjiong, Gao, Gastier Foster, Julie M., Nils, Gehlenborg, Myra, George, Gad, Getz, Richard, Gibbs, Mary, Goldman, Abel Gonzalez Perez, Benjamin, Gross, Ranabir, Guin, Preethi, Gunaratne, Angela, Hadjipanayis, Hamilton, Mark P., Hamilton, Stanley R., Leng, Han, Han, Yi, Harper, Hollie A., Psalm, Haseley, David, Haussler, Neil Hayes, D., Heiman, David I., Elena, Helman, Carmen, Helsel, Herbrich, Shelley M., Her man, James G., Toshinori, Hinoue, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Hoyle, Alan P., Lisa, Iype, Anders, Jacobsen, Jeffreys, Stuart R., Jensen, Mark A., Jones, Corbin D., Jones, Steven J. M., Zhenlin, Ju, Joonil, Jung, Andre, Kahles, Ari, Kahn, Joelle Kalicki Veizer, Divya, Kalra, Krishna Latha Kanchi, Kane, David W., Hoon, Kim, Jaegil, Kim, Theo, Knijnenburg, Koboldt, Daniel C., Christie, Kovar, Roger, Kramer, Richard, Kreisberg, Raju, Kucherlapati, Marc, Ladanyi, Lander, Eric S., Larson, David E., Lawrence, Michael S., Darlene, Lee, Eunjung, Lee, Semin, Lee, William, Lee, Kjong Van Lehmann, Kalle, Leinonen, Ler aas, Kristen M., Seth, Lerner, Levine, Douglas A., Lora, Lewis, Ley, Timothy J., Haiyan I., Li, Jun, Li, Wei, Li, Han, Liang, Lichtenberg, Tara M., Jake, Lin, Ling, Lin, Pei, Lin, Wen bin Liu, Yingchun, Liu, Yuexin, Liu, Lorenzi, Philip L., Charles, Lu, Yiling, Lu, Luquette, Love lace J., Singer, Ma, Magrini, Vincent J., Mahadeshwar, Harshad S., Mardis, Elaine R., Adam, Margolin, Marra, Marco A., Michael, Mayo, Cynthia, Mcallister, Mcguire, Sean E., Mcmichael, Joshua F., James, Melott, Shaowu, Meng, Matthew, Meyerson, Mieczkowski, Piotr A., Miller, Christopher A., Miller, Martin L., Michael, Miller, Moore, Richard A., Margaret, Morgan, Donna, Morton, Mose, Lisle E., Mungall, Andrew J., Donna, Muzny, Lam, Nguyen, Noble, Michael S., Houtan, Noushmehr, Michelle, O’Laughlin, Ojesina, Akinyemi I., Tai Hsien Ou Yang, Brad, Ozenberger, Angeliki, Pantazi, Michael, Parfenov, Park, Peter J., Parker, Joel S., Evan, Paull, Chandra Sekhar Pedamallu, Todd, Pihl, Craig, Pohl, David, Pot, Alexei, Protopopov, Teresa, Przytycka, Amie Raden baugh, Ramirez, Nilsa C., Ricardo, Ramirez, Gunnar Ra, ̈ tsch, Jeffrey, Reid, Xiao jia Ren, Boris, Reva, Reynolds, Sheila M., Rhie, Suhn K., Jeffrey, Roach, Hector, Rovira, Michael, Ryan, Gordon, Saksena, Sofie, Salama, Chris, Sander, Netty, Santoso, Schein, Jacqueline E., Heather, Schmidt, Nikolaus, Schultz, Schumacher, Steven E., Jonathan, Seidman, Yasin, Senbabaoglu, Sahil, Seth, Saman tha Sharpe, Ronglai, Shen, Margi, Sheth, Yan, Shi, Ilya, Shmulevich, Silva, Grace O., Simons, Janae V., Rileen, Sinha, Payal, Sipahimalani, Smith, Scott M., Sofia, Heidi J., Artem, Sokolov, Soloway, Mathew G., Xingzhi, Song, Carrie Soug nez, Paul, Spellman, Louis, Staudt, Chip, Stewart, Petar, Stojanov, Xiaoping, Su, Onur Sumer, S., Yichao, Sun, Teresa, Swatloski, Barbara, Tabak, Angela, Tam, Donghui, Tan, Jiabin, Tang, Roy, Tarnuzzer, Taylor, Barry S., Nina, Thiessen, Ves teinn Thorsson, Timothy Triche, J. r., Van Den Berg, David J., Vandin, Fabio, Varhol, Richard J., Vaske, Charles J., Umadevi, Veluvolu, Roeland, Verhaak, Doug, Voet, Jason, Walker, Wallis, John W., Peter, Waltman, Yunhu, Wan, Min, Wang, Wenyi, Wang, Zhining, Wang, Scot, Waring, Nils, Weinhold, Weisenberger, Daniel J., Wendl, Michael C., David, Wheeler, Wilkerson, Matthew D., Wilson, Richard K., Lisa, Wise, Andrew, Wong, Chang Jiun Wu, Chia Chin Wu, Hsin Ta Wu, Junyuan, Wu, Todd, Wylie, Liu, Xi, Ruibin, Xi, Zheng, Xia, Andrew W., Xu, Yang, Da, Liming, Yang, Lixing, Yang, Yang, Yang, Jun, Yao, Rong, Yao, Kai, Ye, Ko suke Yoshihara, Yuan, Yuan, Yung, Alfred K., Travis, Zack, Dong, Zeng, Jean Claude Zenklusen, Hailei, Zhang, Jianhua, Zhang, Nianxiang, Zhang, Qunyuan, Zhang, Wei, Zhang, Wei, Zhao, Siyuan, Zheng, Jing, Zhu, Erik, Zmuda, and Lihua, Zou

Subjects
Genetics and Molecular Biology (all), Cluster Analysis, Humans, Neoplasms, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Extramural, Biochemistry, Genetics and Molecular Biology(all), Cancer, Computational biology, Disease, Biology, medicine.disease, Bioinformatics, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 3. Good health, Molecular classification, TP63, CLUSTERS (ANÁLISE), medicine, Head and neck, Gene
Abstract

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

47. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Qunyuan Zhang, B. Arman Aksoy, Fabio Vandin, Eric A. Collisson, Larsson Omberg, S. Onur Sumer, John A. Demchok, Sven Nelander, Vladislav Uzunangelov, Michael C. Wendl, Roger Kramer, John W. Wallis, Brian Craft, Angeliki Pantazi, Leng Han, W. K. Alfred Yung, Brad Ozenberger, Philip L. Lorenzi, James G. Herman, Andy Chu, Sahil Seth, Richard A. Gibbs, Angela Hadjipanayis, Hector Rovira, Peter W. Laird, Inanc Birol, Richard K. Wilson, James Cleland, Peter J. Park, Jiashan Zhang, Payal Sipahimalani, Stanley R. Hamilton, Liming Yang, Seth Lerner, Amie Radenbaugh, Barry S. Taylor, Carrie Hirst, David Tamborero, Stephen B. Baylin, Gad Getz, Tanja Davidsen, Miruna Balasundaram, Cheng Fan, Yuan Yuan, Kristian Cibulskis, Yan Shi, Angela Tam, Divya Kalra, Chris Sander, Scott Abbott, Catrina Fronick, Margi Sheth, Chip Stewart, Angela N. Brooks, Noreen Dhalla, Lam Nguyen, Hui Shen, Travis I. Zack, Andrew J. Mungall, Artem Sokolov, Douglas A. Levine, Carrie Sougnez, Paul T. Spellman, Greg Eley, Deepti Dodda, Wenbin Liu, Michael B. Ryan, Liu Xi, Aaron D. Black, Rong Yao, Saianand Balu, Benjamin P. Berman, Raju Kucherlapati, James M. Melott, Xingzhi Song, Boris Reva, Huyen Dinh, David A. Pot, Michael D. McLellan, Kjong-Van Lehmann, Wenyi Wang, Petar Stojanov, Bradley McIntosh Broom, Timothy J. Ley, Da Yang, Mary Elizabeth Edgerton, Houtan Noushmehr, Mathew G. Soloway, Nina Thiessen, Zhenlin Ju, Mark D.M. Leiserson, Michael Parfenov, Laura van 't Veer, Scott L. Carter, Ludmila Danilova, Adrian Ally, Hailei Zhang, Ina Felau, Carmen Helsel, Kenneth Aldape, Teresia Kling, Charles Lu, Psalm Haseley, A. Gordon Robertson, Andrew Wei Xu, Jessica Frick, Benjamin Gross, Louis M. Staudt, Craig Pohl, Dimitris Anastassiou, Netty Santoso, Donna Muzny, Chad J. Creighton, Donghui Tan, Ryan Bressler, Andrew J. Wong, Barbara Tabak, Yasin Senbabaoglu, Daniel C. Koboldt, Darlene Lee, Doug Voet, Joonil Jung, Hollie A. Harper, Jianhua Zhang, Kyle Chang, Wei Zhao, Marc Ladanyi, Lisa Iype, Ricardo Ramirez, Ami S. Bhatt, Lisle E. Mose, Singer Ma, Abel Gonzalez-Perez, Jonathan G. Seidman, Kosuke Yoshihara, Denise M. Wolf, Corbin D. Jones, Patrik Johansson, Siyuan Zheng, André Kahles, Stacey Gabriel, John N. Weinstein, Han Liang, Samantha Sharpe, Steven E. Schumacher, Matthew Meyerson, D. Neil Hayes, David Haussler, Krishna L. Kanchi, Julie M. Gastier-Foster, Umadevi Veluvolu, Ari B. Kahn, Brady Bernard, Tod D. Casasent, Christopher A. Bristow, Akinyemi I. Ojesina, Sam Ng, Charles M. Perou, Moiz S. Bootwalla, Cyriac Kandoth, Lixing Yang, Joel S. Parker, Alan P. Hoyle, Timothy J. Triche, Dong Zeng, Sean E. McGuire, Christie Kovar, Kim D. Delehaunty, Juok Cho, Alexei Protopopov, Shaowu Meng, Ling Lin, Heather Schmidt, Nils Gehlenborg, Yuexin Liu, Elaine R. Mardis, Martin L. Miller, Jake Lin, Jason Walker, Lisa Wise, Suzanne S. Fei, Jacqueline E. Schein, Semin Lee, Christina Yau, Melisssa Cline, Tara M. Lichtenberg, David I. Heiman, Scot Waring, Richard A. Moore, Margaret B. Morgan, Robert S. Fulton, David E. Larson, Xiaoping Su, Kalle Leinonen, Samirkumar B. Amin, Joshua M. Stuart, J. Todd Auman, Rebecka Jörnsten, Rileen Sinha, Andrew D. Cherniack, Caleb F. Davis, Stephen J. Chanock, Nathan D. Dees, Adam Margolin, Haiyan I. Li, Yaron S.N. Butterfield, Daniel E. Carlin, Tai Hsien Ou Yang, Rameen Beroukhim, Vincent Magrini, Mark P. Hamilton, Grace O. Silva, Nils Weinhold, Harshad S. Mahadeshwar, Michael S. Lawrence, Eric Chuah, Jun Li, Wei Li, Robert A. Burton, Teresa M. Przytycka, Katherine A. Hoadley, Keith A. Baggerly, Sheila M. Reynolds, Daniel DiCara, Tom Bodenheimer, Charles J. Vaske, James M. Eldred, Richard Varhol, Mark A. Jensen, David W. Kane, Xiaojia Ren, Christopher A. Miller, Elizabeth Buda, Li Ding, Michael Mayo, Hsin-Ta Wu, Joelle Kalicki-Veizer, Shelley M. Herbrich, Eunjung Lee, Yingchun Liu, Joshua F. McMichael, Jennifer Drummond, Teresa Swatloski, Harshavardhan Doddapaneni, William Lee, Daniel J. Weisenberger, David A. Wheeler, Chia Chin Wu, Richard Kreisberg, Roeland Verhaak, Elena Helman, Piotr A. Mieczkowski, Mary Goldman, Ilya Shmulevich, Nikolaus Schultz, Min Wang, Lovelace J. Luquette, Marco A. Marra, Todd Pihl, Roy Tarnuzzer, Ronglai Shen, Donna Morton, Yichao Sun, Lawrence A. Donehower, Jun Yao, Theo A. Knijnenburg, Benjamin J. Raphael, Lora Lewis, Peter Waltman, Andrea Eakin, Martin Hirst, Jaegil Kim, Lihua Zou, Ranabir Guin, Yi Han, Scott M. Smith, Hoon Kim, Kristen M. Leraas, Heidi J. Sofia, Erik Zmuda, Matthew D. Wilkerson, Michelle O'Laughlin, Jianjiong Gao, Jeffrey G. Reid, Jing Zhu, Toshinori Hinoue, Gunnar Rätsch, Hye Jung E. Chun, Anders Jacobsen, Stephen C. Benz, Kenna R. Mills Shaw, Gordon B. Mills, Zhining Wang, Cynthia McAllister, Michael S. Noble, Christopher C. Benz, Rehan Akbani, Ruibin Xi, Nianxiang Zhang, Jay Bowen, Wei Zhang, Chandra Sekhar Pedamallu, Eric S. Lander, Yunhu Wan, David J. Dooling, Dong Yeon Cho, Preethi Gunaratne, Todd Wylie, Pei Lin, Chang-Jiun Wu, Jeffrey Roach, Scott Frazer, Samuel S. Freeman, Rachel Abbott, Zheng Xia, Lucinda Fulton, Kyle Ellrott, Nuria Lopez-Bigas, Yang Yang, Michael Miller, Nilsa C. Ramirez, Evan O. Paull, Janae V. Simons, Junyuan Wu, Lynda Chin, Gordon Saksena, Jiabin Tang, Vesteinn Thorsson, Robert A. Holt, Suhn K. Rhie, Steven J.M. Jones, Stuart R. Jeffreys, Giovanni Ciriello, Sofie R. Salama, Gideon Dresdner, Yiling Lu, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Genetics, medicine.medical_specialty, Genome, Gene Expression Profiling, Genomics, Computational biology, Biology, Humans, Neoplasms, Article, Analysis Project, Gene expression profiling, GENÉTICA MOLECULAR, Cancer genome, Genomic Profile, medicine, Medical genetics, Epigenetics
Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)

Published
2013

48. Comprehensive genomic characterization of squamous cell lung cancers

Author

Charles J. Vaske, Ying Du, Theodore C. Goldstein, Ping Yang, Yufeng Liu, Bryan Hernandez, Daniel R. Zerbino, Kenneth H. Buetow, Khurram Z. Khan, Semin Lee, Martin Peifer, Kristin G. Ardlie, James G. Herman, Sanja Dacic, Ashley Hill, Christopher Szeto, Jianjiong Gao, Singer Ma, Peng Chieh Chen, Carl F. Schaefer, David G. Beer, Kerstin David, Brent W. Zanke, Karen Mungall, Beverly Lee, Daniel DiCara, Kristen Rogers, Rui Jing, Christina Liquori, Carrie Sougnez, Ron Bose, Brian O'Connor, Piotr A. Mieczkowski, Scott L. Carter, Andy Chu, Peter W. Laird, David J. Kwiatkowski, R. Craig Cason, Marie Christine Aubry, Rileen Sinha, Dennis T. Maglinte, Chad J. Creighton, Howard H. Sussman, Jill M. Siegfried, Laura A.L. Dillon, Agnes Viale, Marco A. Marra, Stephen E. Schumacher, Dennis A. Wigle, Yongjun Zhao, Robert C. Onofrio, Heidi J. Sofia, Ranabir Guin, Lori Boice, Ling Li, Mark Backus, Pei Lin, Prachi Kothiyal, Jan F. Prins, Lauren Averett Byers, Haiyan I. Li, An He, Ka Ming Nip, Chang-Jiun Wu, Peter Dolina, James A. Robinson, Saianand Balu, Collisson E, Jinze Liu, Nicholas D. Socci, Erin Pleasance, Joan Pontius, Christina Yau, Eric E. Snyder, Shaowu Meng, Mei Huang, Aaron McKenna, Corbin D. Jones, Carl Morrison, Malcolm V. Brock, Chris Wakefield, Jared R. Slobodan, Ethan Cerami, Angela Tam, Jane Peterson, Michael D. Topal, Jacob M. Kaufman, Elena Helman, Richard T. Cheney, Dominik Stoll, Cristiane M. Ida, Dante Trusty, Peter S. Hammerman, Yevgeniy Antipin, D. Neil Hayes, Anders Jacobsen, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Peter Waltman, Chris Sander, Zhining Wang, Derek Y. Chiang, Elizabeth J. Thomson, Vonn Walter, JoEllen Weaver, Elena Nemirovich-Danchenko, Jacqueline E. Schein, Bradley M. Broom, Sandra C. Tomaszek, Peter A. Kigonya, Tod D. Casasent, Ari B. Kahn, Joanne Yi, Kyle Ellrott, John M. S. Bartlett, Payal Sipahimalani, William D. Travis, Douglas Voet, Sean P. Barletta, Elizabeth Chun, J. Todd Auman, Ludmila Danilova, Katherine A. Hoadley, Marcin Imielinski, Ramaswamy Govindan, David P. Carbone, Leigh B. Thorne, David A. Wheeler, Carrie Hirst, Barbara Tabak, Sugy Kodeeswaran, Ijeoma A. Azodo, James Stephen Marron, Michael S. Noble, Jianjua John Zhang, Paul K. Paik, Deepak Srinivasan, Boris Reva, B. Arman Aksoy, Kristian Cibulskis, Douglas B. Flieder, Fei Pan, Daniel J. Weisenberger, Ronglai Shen, Jinhua Zhang, Nils Weinhold, Harman Sekhon, David Van Den Berg, Mark S. Guyer, Robert Penny, Hartmut Juhl, Marc Danie Nazaire, Yiqun Zhang, Eric A. Collisson, Robin J.N. Coope, Tom Bodenheimer, Richard Thorp, Junyuan Wu, Matthew Meyerson, Nguyen Phi Hung, Jerome Myers, Artem Sokolov, Yidi J. Turman, Thomas Muley, Stephen B. Baylin, Anisha Gulabani, A. Gordon Robertson, Lynda Chin, Eric Chuah, Richard Varhol, Margi Sheth, Janae V. Simons, Nils Gehlenborg, Tanja Davidsen, Psalm Haseley, Miruna Balasundaram, Olga Potapova, Spring Yingchun Liu, W. Kimryn Rathmell, Bizhan Bandarchi-Chamkhaleh, Wendy Winckler, David Mallery, Nicholas J. Petrelli, Nicole Todaro, Alex E. Lash, James Shin, Travis Brown, Igor Jurisica, Benjamin Gross, Hailei Zhang, Nikolaus Schultz, Kenna R. Mills Shaw, Nam Pho, William Pao, Darlene Lee, Zhen Fan, Troy Shelton, Yan Shi, Shelley Alonso, Carmelo Gaudioso, Peter B. Illei, Stuart R. Jefferys, Maureen F. Zakowski, Marian Rutledge, Bruce E. Johnson, Andrew J. Mungall, Eric S. Lander, Matthew G. Soloway, Michael Mayo, Christopher G. Maher, John V. Heymach, Lihua Zou, Dominique L. Berton, Nina Thiessen, Gary K. Scott, Anna L. Chu, Richard A. Hajek, Ming-Sound Tsao, Liming Yang, Qianxing Mo, Nguyen Van Bang, Martin Hirst, John Eckman, Erin Curley, Rajiv Dhir, Gad Getz, Stanley Girshik, Xuan Van Le, Jeff Boyd, Roman K. Thomas, Konstantin V. Fedosenko, Juok Cho, Alexei Protopopov, Nguyen Viet Tien, Lixing Yang, Laetitia Borsu, Steven J.M. Jones, Matthew D. Wilkerson, Mark Sherman, Andrew Crenshaw, Doug Voet, Elizabeth Buda, Jennifer Brown, Yaron S.N. Butterfield, Rehan Akbani, Todd Pihl, Ruibin Xi, Nianxiang Zhang, Jessica Walton, Ricardo Ramirez, Lisle E. Mose, Leslie Cope, Greg Eley, Mark A. Jensen, John N. Weinstein, Li Ding, Li-Wei Chang, Matthew C. Nicholls, Peter J. Park, Bui Duc Phu, Christopher R. Cabanski, Bernard Kohl, Julien Baboud, Joseph Paulauskis, David Pot, Gordon Robertson, Jingchun Zhu, John A. Demchok, Eunjung Lee, Giovanni Ciriello, Mary Iacocca, Gordon Saksena, Jesse Walsh, Yupu Liang, William K. Funkhouser, Rashmi N. Sanbhadti, Sam Ng, Venkatraman E. Seshan, Valerie W. Rusch, Robert A. Holt, Robert Sfeir, Jung E. Hye-Chun, Kai Wang, Helga Thorvaldsdottir, Huy V. Nguyen, Christopher Wilks, Brian Craft, Donghui Tan, David Haussler, Charles M. Perou, Timothy J. Triche, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Stacey Gabriel, Martha Hatfield, Christine Czerwinski, Alan P. Hoyle, Marc Ladanyi, Joshua M. Stuart, Andrey Sivachenko, Jacqueline D. Palchik, Thomas Zeng, Inanc Birol, Rohini Raman, Ijeoma Azodo, Jianhua Zhang, Adam B. Olshen, Bradley A. Ozenberger, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Jill P. Mesirov, Petar Stojanov, Raju Kucherlapati, Richard Corbett, Farhad Kosari, Martin L. Ferguson, Natasha Rekhtman, Keith A. Baggerly, Scott Morris, Brenda Rabeno, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Lung Neoplasms, Squamous Differentiation, DNA Mutational Analysis, Adenocarcinoma of Lung, Biology, Adenocarcinoma, Article, Phosphatidylinositol 3-Kinases, Gefitinib, Mutation Rate, CDKN2A, Carcinoma, medicine, Humans, Molecular Targeted Therapy, Lung cancer, Multidisciplinary, Genome, Human, Gene Expression Profiling, Genes, p16, Genomics, medicine.disease, Genes, p53, Gene expression profiling, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Gene Deletion, medicine.drug, Necitumumab, Signal Transduction
Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers., National Institutes of Health (U.S.) (Grant U24 CA126561), National Institutes of Health (U.S.) (Grant U24 CA126551), National Institutes of Health (U.S.) (Grant U24 CA126554), National Institutes of Health (U.S.) (Grant U24 CA126543), National Institutes of Health (U.S.) (Grant U24 CA126546), National Institutes of Health (U.S.) (Grant U24 CA126563), National Institutes of Health (U.S.) (Grant U24 CA126544), National Institutes of Health (U.S.) (Grant U24 CA143845), National Institutes of Health (U.S.) (Grant U24 CA143858), National Institutes of Health (U.S.) (Grant U24 CA144025), National Institutes of Health (U.S.) (Grant U24 CA143882), National Institutes of Health (U.S.) (Grant U24 CA143866), National Institutes of Health (U.S.) (Grant U24 CA143867), National Institutes of Health (U.S.) (Grant U24 CA143848), National Institutes of Health (U.S.) (Grant U24 CA143840), National Institutes of Health (U.S.) (Grant U24 CA143835), National Institutes of Health (U.S.) (Grant U24 CA143799), National Institutes of Health (U.S.) (Grant U24 CA143883), National Institutes of Health (U.S.) (Grant U24 CA143843), National Institutes of Health (U.S.) (Grant U54 HG003067), National Institutes of Health (U.S.) (Grant U54 HG003079), National Institutes of Health (U.S.) (Grant U54 HG003273)

Published
2012

49. Ulla: a program for calculating environment-specific amino acid substitution tables

Author

Tom L. Blundell and Semin Lee

Subjects
Statistics and Probability, Theoretical computer science, Source code, Computer science, media_common.quotation_subject, Sequence alignment, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Protein sequencing, Protein structure, Amino acid residue, Databases, Protein, Molecular Biology, 030304 developmental biology, media_common, 0303 health sciences, Information retrieval, Sequence Homology, Amino Acid, Computational Biology, Proteins, Amino acid substitution, Structural Bioinformatics, Computer Science Applications, Computational Mathematics, Applications Note, Computational Theory and Mathematics, Amino Acid Substitution, Sequence Alignment, 030217 neurology & neurosurgery, Software
Abstract

Summary: Amino acid residues are under various kinds of local environmental restraints, which influence substitution patterns. Ulla,1 a program for calculating environment-specific substitution tables, reads protein sequence alignments and local environment annotations. The program produces a substitution table for every possible combination of environment features. Sparse data is handled using an entropy-based smoothing procedure to estimate robust substitution probabilities. Availability: The Ruby source code is available under a Creative Commons Attribution-Noncommercial License along with additional documentation from http://www-cryst.bioc.cam.ac.uk/ulla. Contact: semin@cryst.bioc.cam.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Published
2009
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