116 results on '"Gu Kong"'
Search Results
2. Data from NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression
- Author
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Gu Kong, Jeong-Yeon Lee, Young-Ha Oh, Kyueng-Whan Min, Ho Lee, Taekwon Son, Hyung-Yong Kim, Jin Park, Hyung-Jun Choi, Young-Un Park, Hee Woon An, Hee-Joo Choi, Mi Kyung Park, and Ga-Young Jeong
- Abstract
Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial–mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3–NOTCH signaling regulatory axis in aggressive breast cancer.Significance:This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.
- Published
- 2023
3. Supplementary Tables 1 - 15 from Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
- Author
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Se Jin Jang, Daehyun Baek, Gu Kong, Eunsil Yu, Charles Lee, Eunho Yang, Hye Yoon Jang, Wang-rim Jung, Jong-eun Lee, Sun Young Lee, Farhan Haq, Deokhoon Kim, Joon Seon Song, Ji-Young Lee, Yong-Hee Kim, Sang-We Kim, Eun Kyung Choi, Sung-Min Chun, Chang-min Choi, Sung-Min Ahn, Sukjun Kim, Jongkyu Kim, Chang Ohk Sung, Hyeong Ryul Kim, and Seongmin Choi
- Abstract
Supplementary Tables 1 - 15. Supp. Table 1. Sequenced reads per tumor and normal sample. Supp. Table 2. Comparison of significantly mutated genes detected using various MuTect thresholds. Supp. Table 3. Comparison of the number and rate of substitutions between never-smokers and smokers. Supp. Table 4. Comparison of various methods used to compute the background mutation rate. Supp. Table 5. Significantly mutated genes detected in our discovery cohort. Supp. Table 6. Comparison of significantly mutated genes and previously reported cancer driver genes. Supp. Table 7. Thirteen significantly altered CNV regions detected in our discovery cohort. Supp. Table 8. Druggable target candidates in the 22 significantly mutated genes and the 60 genes in the significantly altered CNV regions detected in the discovery cohort. Supp. Table 9. Pathways significantly enriched in the 22 significantly mutated genes and the 60 genes included in the significantly altered CNV regions that were detected in the discovery cohort. Supp. Table 10. Cox multivariable regression analysis for RB pathway alterations. Supp. Table 11. Cox univariable regression analysis of RB pathway alterations. Supp. Table 12. Comparison of mutations detected using whole-exome sequencing and Sequenom in selected genes. Supp. Table 13. Prevalence of known driver candidates when using two different MuTect parameters. Supp. Table 14. Number of patients included in the overall, tumor, node, and metastasis stage categories. Supp. Table 15. List of potential cancer driver genes with somatic substitutions or small indels determined in previous studies.
- Published
- 2023
4. Supplementary Table 1 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
- Author
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
Substitution signature exposures estimated in 640 breast cancer WGS and the ovarian sample (AOCS-166).
- Published
- 2023
5. Data from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
- Author
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
- Published
- 2023
6. Supplementary Table 3 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
Mutations in MMR genes
- Published
- 2023
7. Supplementary Table 4 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
- Author
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
Detection of MMR deficient breast cancers in whole exome sequencing data (WES)
- Published
- 2023
8. Supplementary Data from NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression
- Author
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Gu Kong, Jeong-Yeon Lee, Young-Ha Oh, Kyueng-Whan Min, Ho Lee, Taekwon Son, Hyung-Yong Kim, Jin Park, Hyung-Jun Choi, Young-Un Park, Hee Woon An, Hee-Joo Choi, Mi Kyung Park, and Ga-Young Jeong
- Abstract
Supplementary Data
- Published
- 2023
9. Supplementary Methods, Supplementary Figure Legends, and Supplementary Table Legends from Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
- Author
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Se Jin Jang, Daehyun Baek, Gu Kong, Eunsil Yu, Charles Lee, Eunho Yang, Hye Yoon Jang, Wang-rim Jung, Jong-eun Lee, Sun Young Lee, Farhan Haq, Deokhoon Kim, Joon Seon Song, Ji-Young Lee, Yong-Hee Kim, Sang-We Kim, Eun Kyung Choi, Sung-Min Chun, Chang-min Choi, Sung-Min Ahn, Sukjun Kim, Jongkyu Kim, Chang Ohk Sung, Hyeong Ryul Kim, and Seongmin Choi
- Abstract
Supplementary Methods, Supplementary Figure Legends, and Supplementary Table Legends.
- Published
- 2023
10. Supplementary Table 2 from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
- Author
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
Details of 11 MMR deficient breast cancers.
- Published
- 2023
11. Supplementary Figures 1 - 9 from Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
- Author
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Se Jin Jang, Daehyun Baek, Gu Kong, Eunsil Yu, Charles Lee, Eunho Yang, Hye Yoon Jang, Wang-rim Jung, Jong-eun Lee, Sun Young Lee, Farhan Haq, Deokhoon Kim, Joon Seon Song, Ji-Young Lee, Yong-Hee Kim, Sang-We Kim, Eun Kyung Choi, Sung-Min Chun, Chang-min Choi, Sung-Min Ahn, Sukjun Kim, Jongkyu Kim, Chang Ohk Sung, Hyeong Ryul Kim, and Seongmin Choi
- Abstract
Supplementary Figures 1 - 9. Supp. Figure 1. Comparison of mutation rates between never-smokers and smokers. Supp. Figure 2. Druggable gene candidates. Supp. Figure 3. Prevalence of somatic mutations and the CNVs of the genes in the RB pathway. Supp. Figure 4. Association between RB pathway alterations and poor prognosis in early-stage LA patients who were not treated with adjuvant chemotherapy. Supp. Figure 5. Disease-free survival curve of randomly resampled early-stage LA patients included in the discovery cohort. Supp. Figure 6. Global landscape of significantly mutated genes and significantly altered CNV regions. Supp. Figure 7. Comparison of read depths for EGFR, KRAS, and BRAF. Supp. Figure 8. Mapped read depths of exome-captured regions of KEAP1 and STK11. Supp. Figure 9. Mutation rates between smokers and never-smokers.
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- 2023
12. Supplementary Information from Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
- Author
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Serena Nik-Zainal, Michael R. Stratton, Gu Kong, Jorunn E. Eyfjord, Alastair Thompson, Anne-Lise Børresen-Dale, Andrea L. Richardson, Alain Viari, Xueqing Zou, Dominik Glodzik, Hege Russnes, Elin Borgen, Se Jin Jang, Colin A. Purdie, Sandro Morganella, and Helen Davies
- Abstract
This file contains the following Supplementary figures and Supplementary Material and Methods: Supplementary Figure 1: Contribution of base substitution signatures and indels in 640 breast cancer WGS. Supplementary Figure 2: Whole genome plots for 11 MMR deficient breast cancers Supplementary Figure 3: Genome plots for the two samples with germline PMS2 mutations. Supplementary Figure 4: Scatter plot demonstrating the relationship between total number of substitutions associated with the three MMR signatures 6, 20, and 26 and number of indels. Supplementary Materials and Methods 1. Mutational signatures background 2. Detection of MMR deficient cancers in other data sets 2.1 Detection of a genomic profile characteristic of PMS2 deficient tumours in Ovarian cancer. 2.2 Detection of MMR deficient breast cancers in WES
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- 2023
13. Data from Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
- Author
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Se Jin Jang, Daehyun Baek, Gu Kong, Eunsil Yu, Charles Lee, Eunho Yang, Hye Yoon Jang, Wang-rim Jung, Jong-eun Lee, Sun Young Lee, Farhan Haq, Deokhoon Kim, Joon Seon Song, Ji-Young Lee, Yong-Hee Kim, Sang-We Kim, Eun Kyung Choi, Sung-Min Chun, Chang-min Choi, Sung-Min Ahn, Sukjun Kim, Jongkyu Kim, Chang Ohk Sung, Hyeong Ryul Kim, and Seongmin Choi
- Abstract
Purpose: To better understand the complete genomic architecture of lung adenocarcinoma.Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes.Results: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma.Conclusions: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. Clin Cancer Res; 21(11); 2613–23. ©2014 AACR.See related commentary by Collisson, p. 2418
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- 2023
14. Data from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
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Powel H. Brown, Karen Johnson, William W. Lamph, Reid Bissonnette, Susan G. Hilsenbeck, Syed Mohsin, Sunita Pal, Ivan Uray, Yuxin Li, David DeNardo, Gu Kong, and Hee-Tae Kim
- Abstract
Retinoids have been found to be promising chemopreventive agents that play an important role in regulating cell growth, differentiation, and apoptosis. The action of retinoids is mediated by retinoid receptors (retinoic acid receptors and retinoid X receptors), which are nuclear transcription factors that, when bound to retinoids, regulate gene expression. LGD1069 is a highly selective RXR agonist that has reduced toxicity compared with retinoids. Our previous studies have shown that RXR-selective ligands (or “rexinoids”), including LGD1069, can inhibit the growth of normal and malignant breast cells and can suppress the development of breast cancer in transgenic mice. For the current study, we attempted to identify biomarkers of the chemopreventive effect of the RXR-selective retinoid LGD1069. In these experiments, we used Affymetrix microarrays to identify target genes that were modulated by LGD1069 in normal human breast cells. Affymetrix and dChip analysis identified more than 100 genes that were up-regulated or down-regulated by LGD1069 treatment. We then tested 16 of these genes in validation experiments using quantitative reverse transcription-PCR and Western blotting of independently prepared samples, and found that 15 of 16 genes were modulated in a similar manner in these validation experiments as in the microarray experiments. Genes found to be regulated include known retinoid-regulated genes, growth regulatory genes, transcription factors, and differentiation markers. We then showed that the expression of several of these rexinoid-regulated biomarkers is modulated in vivo in mammary glands from mice treated with LGD1069. These critical growth-regulating proteins will be promising targets of future agents for the prevention and treatment of breast cancer. (Cancer Res 2006; 66(24): 12009-18)
- Published
- 2023
15. Supplementary Diagrams 1-2 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
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Powel H. Brown, Karen Johnson, William W. Lamph, Reid Bissonnette, Susan G. Hilsenbeck, Syed Mohsin, Sunita Pal, Ivan Uray, Yuxin Li, David DeNardo, Gu Kong, and Hee-Tae Kim
- Abstract
Supplementary Diagrams 1-2 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
- Published
- 2023
16. Supplementary Figures 3-5 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
- Author
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Powel H. Brown, Karen Johnson, William W. Lamph, Reid Bissonnette, Susan G. Hilsenbeck, Syed Mohsin, Sunita Pal, Ivan Uray, Yuxin Li, David DeNardo, Gu Kong, and Hee-Tae Kim
- Abstract
Supplementary Figures 3-5 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
- Published
- 2023
17. Supplementary Tables 1-4, Figures 1-2 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
- Author
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Powel H. Brown, Karen Johnson, William W. Lamph, Reid Bissonnette, Susan G. Hilsenbeck, Syed Mohsin, Sunita Pal, Ivan Uray, Yuxin Li, David DeNardo, Gu Kong, and Hee-Tae Kim
- Abstract
Supplementary Tables 1-4, Figures 1-2 from Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays
- Published
- 2023
18. 『The Petit Bourgeois』 thesis—Minor Citizen as a Symptom
- Author
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Jong-gu Kong
- Subjects
media_common.quotation_subject ,Petite bourgeoisie ,General Medicine ,Minor (academic) ,Art ,Humanities ,media_common - Published
- 2021
19. CTTN Overexpression Confers Cancer Stem Cell-like Properties and Trastuzumab Resistance via DKK-1/WNT Signaling in HER2 Positive Breast Cancer
- Author
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So-Jeong Moon, Hyung-Jun Choi, Young-Hyeon Kye, Ga-Young Jeong, Hyung-Yong Kim, Jae-Kyung Myung, and Gu Kong
- Subjects
cancer stem cells ,Cancer Research ,trastuzumab resistance ,Oncology ,CTTN ,HER2 positive breast cancer - Abstract
Background: Despite the therapeutic success of trastuzumab, HER2 positive (HER2+) breast cancer patients continue to face significant difficulties due to innate or acquired drug resistance. In this study we explored the potential role of CTTN in inducing trastuzumab resistance of HER2+ breast cancers. Methods: Genetic changes of CTTN and survival of HER2+ breast cancer patients were analyzed in multiple breast cancer patient cohorts (METABRIC, TCGA, Kaplan-Meier (KM) plotter, and Hanyang University cohort). The effect of CTTN on cancer stem cell activity was assessed using the tumorsphere formation, ALDEFLUOR assay, and by in vivo xenograft experiments. CTTN-induced trastuzumab resistance was assessed by the sulforhodamine B (SRB) assay, colony formation assays, and in vivo xenograft model. RNA-seq analysis was used to clarify the mechanism of trastuzumab resistance conferred by CTTN. Results: Survival analysis indicated that CTTN overexpression is related to a poor prognosis in HER2+ breast cancers (OS, p = 0.05 in the Hanyang University cohort; OS, p = 0.0014 in KM plotter; OS, p = 0.008 and DFS, p = 0.010 in METABRIC). CTTN overexpression-induced cancer stem cell-like characteristics in experiments of tumorsphere formation, ALDEFLUOR assays, and in vivo limiting dilution assays. CTTN overexpression resulted in trastuzumab resistance in SRB, colony formation assays, and in vivo xenograft models. Mechanistically, the mRNA and protein levels of DKK-1, a Wnt antagonist, were downregulated by CTTN. Treatment of the β-catenin/TCF inhibitor reversed CTTN-induced cancer stem cell-like properties in vitro. Combination treatment with trastuzumab and β-catenin/TCF inhibitor overcame trastuzumab resistance conferred by CTTN overexpression in in vitro colony formation assays. Conclusions: CTTN activates DKK-1/Wnt/β-catenin signaling to induce trastuzumab resistance. We propose that CTTN is a novel biomarker indicating a poor prognosis and a possible therapeutic target for overcoming trastuzumab resistance.
- Published
- 2023
20. NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression
- Author
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Taekwon Son, Hyung Jun Choi, Kyueng-Whan Min, Hee Joo Choi, Jin Park, Young Ha Oh, Young Un Park, Hee Woon An, Gu Kong, Ho Lee, Hyung-Yong Kim, Mi Kyung Park, Jeong-Yeon Lee, and Ga Young Jeong
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Notch signaling pathway ,Apoptosis ,Breast Neoplasms ,Mice, SCID ,Biology ,Epigenesis, Genetic ,Metastasis ,Malignant transformation ,Histones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Cell Movement ,Mice, Inbred NOD ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Epigenetics ,Receptor, Notch1 ,Cell Proliferation ,EZH2 ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,DNA Methylation ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Metastatic breast cancer ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Histone methyltransferase ,Cancer research ,Female - Abstract
Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial–mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3–NOTCH signaling regulatory axis in aggressive breast cancer. Significance: This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.
- Published
- 2021
21. Cancer Target Gene Screening: a web application for breast cancer target gene screening using multi-omics data analysis
- Author
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Gu Kong, Jeong-Yeon Lee, Hee Joo Choi, and Hyung-Yong Kim
- Subjects
Proteomics ,0301 basic medicine ,Candidate gene ,DNA Copy Number Variations ,Druggability ,Breast Neoplasms ,Computational biology ,Disease ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,Humans ,Genetic Testing ,Molecular Biology ,Survival analysis ,Epigenomics ,Internet ,Gene Expression Profiling ,Cancer ,Genomics ,medicine.disease ,Survival Analysis ,030104 developmental biology ,030220 oncology & carcinogenesis ,DNA methylation ,Female ,Transcriptome ,Information Systems - Abstract
Breast cancer comprises several molecular subtypes with distinct clinical features and treatment responses, and a substantial portion of each subtype remains incurable. A comprehensive analysis of multi-omics data and clinical profiles is required in order to better understand the biological complexity of this cancer type and to identify new prognostic and therapeutic markers. Thus, there arises a need for useful analytical tools to assist in the investigation and clinical management of the disease. We developed Cancer Target Gene Screening (CTGS), a web application that provides rapid and user-friendly analysis of multi-omics data sets from a large number of primary breast tumors. It allows the investigation of genomic and epigenomic aberrations, evaluation of transcriptomic profiles and performance of survival analyses and of bivariate correlations between layers of omics data. Notably, the genome-wide screening function of CTGS prioritizes candidate genes of clinical and biological significance among genes with copy number alteration, DNA methylation and dysregulated expression by the integrative analysis of different types of omics data in customized subgroups of breast cancer patients. These features may help in the identification of druggable cancer driver genes in a specific subtype or the clinical condition of human breast cancer. CTGS is available at http://ctgs.biohackers.net.
- Published
- 2019
22. Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer
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Jeong-Yeon Lee, Taekwon Son, Hyeong Seok Joo, Hee Woon An, Sora Jin, Kyueng-Whan Min, Young Ha Oh, Hee Joo Choi, Gu Kong, Hyung-Yong Kim, Wan Seop Kim, Ga Young Jeong, Seung Eun Lee, and Mi Kyung Park
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Breast Neoplasms ,Mice, SCID ,ADAM17 Protein ,ADAM10 Protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,Trastuzumab ,Cell Line, Tumor ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Polycomb Repressive Complex 1 ,business.industry ,Gene Amplification ,medicine.disease ,Xenograft Model Antitumor Assays ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Anti her2 ,business ,medicine.drug - Abstract
Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided.MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P.001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213).MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.
- Published
- 2018
23. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer
- Author
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Kyueng-Whan Min, Hyeong-Seok Joo, Hee-Young Won, Hee Joo Choi, Taekwon Son, Hyung-Yong Kim, Young Ha Oh, Jeong-Yeon Lee, and Gu Kong
- Subjects
0301 basic medicine ,Cancer Research ,Receptor, ErbB-2 ,Estrogen receptor ,Kaplan-Meier Estimate ,Mice, SCID ,Drug resistance ,Receptor tyrosine kinase ,Receptor, IGF Type 1 ,Cohort Studies ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Mice, Inbred NOD ,skin and connective tissue diseases ,Phosphoinositide-3 Kinase Inhibitors ,biology ,Carcinoma, Ductal, Breast ,Nuclear Proteins ,Neoplasm Proteins ,Nuclear Receptor Interacting Protein 1 ,Tumor Burden ,Receptors, Estrogen ,Oncology ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Neoplastic Stem Cells ,Heterografts ,Colorimetry ,Female ,medicine.drug ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Breast Neoplasms ,Disease-Free Survival ,03 medical and health sciences ,Cyclin D1 ,Breast cancer ,ErbB ,Internal medicine ,medicine ,Animals ,Humans ,Adaptor Proteins, Signal Transducing ,Insulin-like growth factor 1 receptor ,Analysis of Variance ,business.industry ,medicine.disease ,Tamoxifen ,030104 developmental biology ,Endocrinology ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Carrier Proteins ,Retinoblastoma-Binding Protein 2 ,business - Abstract
Background Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Methods Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. Results RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). Conclusions RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.
- Published
- 2017
24. Gene-based comparative analysis of tools for estimating copy number alterations using whole-exome sequencing data
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Hyung-Yong Kim, Jeong-Yeon Lee, Jin-Woo Choi, and Gu Kong
- Subjects
0301 basic medicine ,DNA Copy Number Variations ,Concordance ,Sequencing data ,CNA estimation ,Single-nucleotide polymorphism ,Biology ,Sensitivity and Specificity ,03 medical and health sciences ,Breast cancer ,copy number ,Neoplasms ,Cancer genome ,Exome Sequencing ,medicine ,Humans ,Gene ,Exome sequencing ,Genetics ,Computational Biology ,Sequence Analysis, DNA ,medicine.disease ,030104 developmental biology ,Oncology ,NGS ,WES ,Databases, Nucleic Acid ,cancer CNV ,Algorithms ,Software ,Human cancer ,Research Paper ,Genome-Wide Association Study - Abstract
// Hyung-Yong Kim 1 , Jin-Woo Choi 1 , Jeong-Yeon Lee 2 , Gu Kong 1, 2 1 Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea 2 Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Republic of Korea Correspondence to: Gu Kong, email: gkong@hanyang.ac.kr Keywords: cancer CNV, CNA estimation, WES, NGS, copy number Received: April 10, 2016 Accepted: February 20, 2017 Published: March 06, 2017 ABSTRACT Accurate detection of copy number alterations (CNAs) using next-generation sequencing technology is essential for the development and application of more precise medical treatments for human cancer. Here, we evaluated seven CNA estimation tools (ExomeCNV, CoNIFER, VarScan2, CODEX, ngCGH, saasCNV, and falcon) using whole-exome sequencing data from 419 breast cancer tumor-normal sample pairs from The Cancer Genome Atlas. Estimations generated using each tool were converted into gene-based copy numbers; concordance for gains and losses and the sensitivity and specificity of each tool were compared to validated copy numbers from a single nucleotide polymorphism reference array. The concordance and sensitivity of the tumor-normal pair methods for estimating CNAs (saasCNV, ExomeCNV, and VarScan2) were better than those of the tumor batch methods (CoNIFER and CODEX). SaasCNV had the highest gain and loss concordances (65.0%), sensitivity (69.4%), and specificity (89.1%) for estimating copy number gains or losses. These findings indicate that improved CNA detection algorithms are needed to more accurately interpret whole-exome sequencing results in human cancer.
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- 2017
25. Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences
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Sandrine Boyault, Laura Van't Veer, Serge Dronov, Alain Viari, David C. Wedge, Xavier Pivot, Jos Jonkers, Dominik Glodzik, Se Jin Jang, Sandro Morganella, Hee Jin Lee, Marcel Smid, Serena Nik-Zainal, Hyung-Yong Kim, Steven Van Laere, Iris Pauporté, Ludmil B. Alexandrov, Gilles Romieu, Sancha Martin, Sarah O’Meara, Sunil R. Lakhani, Lucy R. Yates, Åke Borg, Michael R. Stratton, Ewan Birney, Miriam Ragle Aure, Young Seok Ju, Olafur A. Stefansson, Andrea L. Richardson, Helen Davies, Carlos Caldas, Andrew Menzies, Gerrit K. J. Hooijer, Luc Dirix, Anne Lise Børresen-Dale, Gilles Thomas, Moritz Gerstung, Gu Kong, Naoto T. Ueno, Andrew Tutt, Anita Langerød, Kamna Ramakrishnan, Paul N. Span, Jorunn E. Eyfjord, Johan Staaf, Rebecca Shepherd, Lucy Stebbings, David Jones, Jeong-Yeon Lee, Markus Ringnér, Jane E. Brock, Annegien Broeks, Peter T. Simpson, Stian Knappskog, Manasa Ramakrishna, Gert Van den Eynden, P. Andrew Futreal, Ole Christian Lingjærde, Hendrik G. Stunnenberg, Isabelle Treilleux, Xueqing Zou, Savitri Krishnamurthy, Tari A. King, Sung-Min Ahn, Inigo Martincorena, John A. Foekens, Christine Desmedt, John W.M. Martens, Marc J. van de Vijver, Alastair M Thompson, Anieta M. Sieuwerts, Germán Fg Rodríguez-González, Aquila Fatima, Ville Mustonen, Peter J. Campbell, Keiran Raine, Stefania Tommasi, Anne Vincent-Salomon, Yang Li, Colin A. Purdie, Peter B. Vermeulen, Arie B. Brinkman, Adam Butler, Jon W. Teague, Peter Van Loo, Stuart McLaren, Christos Sotiriou, and Benita Kiat Tee Bk Tan
- Subjects
0301 basic medicine ,Multidisciplinary ,Somatic cell ,Published Erratum ,Section (typography) ,MEDLINE ,Médecine pathologie humaine ,Computational biology ,Sciences bio-médicales et agricoles ,Biology ,medicine.disease ,Genome ,Article ,Cancérologie ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,medicine ,Sentence - Abstract
In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected., SCOPUS: er.j, info:eu-repo/semantics/published
- Published
- 2019
26. Roles and epigenetic regulation of epithelial–mesenchymal transition and its transcription factors in cancer initiation and progression
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Jeong-Yeon Lee and Gu Kong
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0301 basic medicine ,Epithelial-Mesenchymal Transition ,Epigenetic regulation of neurogenesis ,Carcinogenesis ,Epigenesis, Genetic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Neoplasms ,Animals ,Humans ,Gene silencing ,Cancer epigenetics ,Epigenetics ,Epithelial–mesenchymal transition ,Molecular Biology ,Pharmacology ,Genetics ,biology ,fungi ,Cell Biology ,Chromatin ,Cell biology ,030104 developmental biology ,Histone ,embryonic structures ,DNA methylation ,Disease Progression ,biology.protein ,Molecular Medicine ,Transcription Factors - Abstract
The epithelial-mesenchymal transition (EMT) is a crucial developmental process by which epithelial cells undergo a mesenchymal phenotypic change. During EMT, epigenetic mechanisms including DNA methylation and histone modifications are involved in the regulation of EMT-related genes. The epigenetic gene silencing of the epithelial marker E-cadherin has been well characterized. In particular, three major transcriptional repressors of E-cadherin, Snail, ZEB, and Twist families, also known as EMT-inducing transcription factors (EMT-TFs), play a crucial role in this process by cooperating with multiple epigenetic modifiers. Furthermore, recent studies have identified the novel epigenetic modifiers that control the expression of EMT-TFs, and these modifiers have emerged as critical regulators of cancer development and as novel therapeutic targets for human cancer. In this review, the diverse functions of EMT-TFs in cancer progression, the cooperative mechanisms of EMT-TFs with epigenetic modifiers, and epigenetic regulatory roles for the expression of EMT-TFs will be discussed.
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- 2016
27. <scp>UTX</scp> inhibits <scp>EMT</scp> ‐induced breast <scp>CSC</scp> properties by epigenetic repression of <scp>EMT</scp> genes in cooperation with <scp>LSD</scp> 1 and <scp>HDAC</scp> 1
- Author
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Ji-Hye Park, Chang-Hoon Lee, Mi-Kyung Park, Hyeong Seok Joo, Hee Joo Choi, Gu Kong, Jeong-Yeon Lee, and Hee Young Won
- Subjects
Repressor ,Biology ,Biochemistry ,HDAC1 ,Histone ,Epigenetic Repression ,embryonic structures ,Genetics ,Cancer research ,biology.protein ,DNMT1 ,Demethylase ,Epithelial–mesenchymal transition ,Molecular Biology ,Transcription factor - Abstract
The histone H3K27 demethylase, UTX, is a known component of the H3K4 methyltransferase MLL complex, but its functional association with H3K4 methylation in human cancers remains largely unknown. Here we demonstrate that UTX loss induces epithelial-mesenchymal transition (EMT)-mediated breast cancer stem cell (CSC) properties by increasing the expression of the SNAIL, ZEB1 and ZEB2 EMT transcription factors (EMT-TFs) and of the transcriptional repressor CDH1. UTX facilitates the epigenetic silencing of EMT-TFs by inducing competition between MLL4 and the H3K4 demethylase LSD1. EMT-TF promoters are occupied by c-Myc and MLL4, and UTX recognizes these proteins, interrupting their transcriptional activation function. UTX decreases H3K4me2 and H3 acetylation at these promoters by forming a transcriptional repressive complex with LSD1, HDAC1 and DNMT1. Taken together, our findings indicate that UTX is a prominent tumour suppressor that functions as a negative regulator of EMT-induced CSC-like properties by epigenetically repressing EMT-TFs.
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- 2015
28. Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
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Joon Seon Song, Eunsil Yu, Chang-Min Choi, Chang Ohk Sung, Hyeong Ryul Kim, Farhan Haq, Charles Lee, Jiyoung Lee, Seongmin Choi, Yong-Hee Kim, Wang-rim Jung, Hye Yoon Jang, Jong Eun Lee, Jongkyu Kim, Se Jin Jang, Daehyun Baek, Gu Kong, Sang-We Kim, Eun Kyung Choi, Sung-Min Ahn, Eunho Yang, Sung-Min Chun, Sukjun Kim, Sun Young Lee, and Deokhoon Kim
- Subjects
Male ,Cancer Research ,Lung Neoplasms ,DNA Copy Number Variations ,Adenocarcinoma of Lung ,Genomics ,Adenocarcinoma ,Biology ,Bioinformatics ,medicine.disease_cause ,Retinoblastoma Protein ,Genome ,Disease-Free Survival ,Adjuvant therapy ,medicine ,Humans ,Cyclin D1 ,Copy-number variation ,Stage (cooking) ,Exome sequencing ,Aged ,Neoplasm Staging ,Mutation ,Genome, Human ,Middle Aged ,Prognosis ,medicine.disease ,Oncology ,Female - Abstract
Purpose: To better understand the complete genomic architecture of lung adenocarcinoma. Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. Results: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma. Conclusions: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. Clin Cancer Res; 21(11); 2613–23. ©2014 AACR. See related commentary by Collisson, p. 2418
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- 2015
29. MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence
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Jong Kyu Woo, Jin Woo Choi, Dong-Hui Shin, Ji-Hye Park, Hye-Yeon Kim, Seung Hyun Oh, Sehwan Kim, Hyung-Yong Kim, Kiseok Jang, Taekwon Son, Hee-Young Won, Gu Kong, Young Ha Oh, Hee Joo Choi, Kijong Yi, Jeong-Yeon Lee, and Ju-Hee Kang
- Subjects
Receptor, ErbB-2 ,Aminopyridines ,Estrogen receptor ,Triple Negative Breast Neoplasms ,Kaplan-Meier Estimate ,Mice ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,RNA, Neoplasm ,Progesterone ,Polycomb Repressive Complex 1 ,Carcinoma, Ductal, Breast ,General Medicine ,Neoplasm Proteins ,Cysteine Endopeptidases ,Hormone receptor ,Female ,Receptors, Progesterone ,Research Article ,medicine.drug ,Proteasome Endopeptidase Complex ,medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,Antineoplastic Agents, Hormonal ,Sp1 Transcription Factor ,Morpholines ,Breast Neoplasms ,Biology ,Breast cancer ,Downregulation and upregulation ,Internal medicine ,Endopeptidases ,Progesterone receptor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,RNA, Messenger ,neoplasms ,Proportional Hazards Models ,Estrogen Receptor alpha ,Sumoylation ,Estrogens ,medicine.disease ,carbohydrates (lipids) ,Tamoxifen ,Endocrinology ,Drug Resistance, Neoplasm ,Cancer research ,Tumor Suppressor Protein p53 ,Protein Processing, Post-Translational ,Estrogen receptor alpha ,Neoplasm Transplantation - Abstract
The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.
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- 2015
30. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
- Author
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Anieta M. Sieuwerts, Gu Kong, Christos Sotiriou, Sandrine Boyault, John W.M. Martens, Sunil R. Lakhani, Steven Van Laere, Peter J. Campbell, Andrew Tutt, Keiran Raine, Michael R. Stratton, Peter T. Simpson, Sancha Martin, Paul N. Span, Ewan Birney, Jorunn E. Eyfjord, Sandro Morganella, Lucy R. Yates, Marc J. van de Vijver, Alain Viari, Johan Staaf, Hendrik G. Stunnenberg, Anne Vincent-Salomon, Manasa Ramakrishna, Xueqing Zou, Dominik Glodzik, Tari A Ta King, Andrea L. Richardson, Serena Nik-Zainal, Anne Lise Børresen-Dale, Åke Borg, Alastair M Thompson, Helen Davies, The Wellcome Trust Sanger Institute [Cambridge], Guy's and St Thomas' Hospital [London], Lund University [Lund], AstraZeneca, Centre Léon Bérard [Lyon], Department of Medical Oncology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre for Clinical Research [Brisbane], University of Queensland [Brisbane], Memorial Sloane Kettering Cancer Center [New York], University of Iceland [Reykjavik], Hanyang University, Department of Molecular Biology [Nijmegen], Radboud University Medical Center [Nijmegen], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Oslo (UiO), Oslo University Hospital [Oslo], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Breakthrough Breast Cancer Centre, London Institute of Cancer, The University of Texas M.D. Anderson Cancer Center [Houston], HistoGeneX, Brigham and Women's Hospital [Boston], Dana-Farber Cancer Institute [Boston], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Pathology, CCA - Cancer biology and immunology, Medical Oncology, Sieuwerts, Anieta M [0000-0003-1341-5400], Raine, Keiran [0000-0002-5634-1539], Martens, John WM [0000-0002-3428-3366], Tutt, Andrew [0000-0001-8715-2901], and Apollo - University of Cambridge Repository
- Subjects
Male ,0301 basic medicine ,endocrine system diseases ,Somatic cell ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Breast Neoplasms ,Poly(ADP-ribose) Polymerase Inhibitors ,Poly (ADP-Ribose) Polymerase Inhibitor ,Article ,General Biochemistry, Genetics and Molecular Biology ,Germline ,Breast Neoplasms, Male ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,Cancer genomics ,Humans ,skin and connective tissue diseases ,Biology ,Molecular Biology ,Polymerase ,BRCA2 Protein ,Ovarian Neoplasms ,Genetics ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,Models, Genetic ,biology ,BRCA1 Protein ,Area under the curve ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,3. Good health ,Pancreatic Neoplasms ,Chemistry ,Logistic Models ,030104 developmental biology ,Area Under Curve ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Cancer research ,Female ,Human medicine - Abstract
International audience; Approximately 1–5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (~1–5%) who could have selective therapeutic sensitivity to PARP inhibition.
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- 2017
31. CBX7 inhibits breast tumorigenicity through DKK‐1‐mediated suppression of the Wnt/β‐catenin pathway
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Gu Kong, Ji-Hye Park, Hey-Yon Kim, Hee-Young Won, and Jeong-Yeon Lee
- Subjects
Cell ,Population ,Gene Expression ,Breast Neoplasms ,Mice, SCID ,Models, Biological ,Biochemistry ,Epigenesis, Genetic ,Mice ,Breast cancer ,Mice, Inbred NOD ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,education ,Wnt Signaling Pathway ,Molecular Biology ,Cyclin-Dependent Kinase Inhibitor p16 ,Tumor Stem Cell Assay ,beta Catenin ,Polycomb Repressive Complex 1 ,education.field_of_study ,biology ,Chemistry ,Tumor Suppressor Proteins ,CD44 ,Wnt signaling pathway ,medicine.disease ,HEK293 Cells ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Catenin ,Cancer cell ,biology.protein ,Cancer research ,Heterografts ,Intercellular Signaling Peptides and Proteins ,Female ,Stem cell ,TCF Transcription Factors ,Biotechnology - Abstract
Polycomb protein chromobox homolog 7 (CBX7) is involved in several biologic processes including stem cell regulation and cancer development, but its roles in breast cancer remain unknown. Here, we demonstrate that CBX7 negatively regulates breast tumor initiation. CD44(+)/CD24(-)/ESA(+) breast stem-like cells showed diminished CBX7 expression. Furthermore, small hairpin RNA-mediated CBX7 knockdown in breast epithelial and cancer cells increased the CD44(+)/CD24(-)/ESA(+) cell population and reinforced in vitro self-renewal and in vivo tumor-initiating ability. Similarly, CBX7 overexpression repressed these effects. We also found that CBX7 inhibits the Wnt/β-catenin/T cell factor pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist. In particular, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of the DKK-1 promoter. Furthermore, pharmacologic inhibition of DKK-1 in CBX7-overexpressing cells showed recovery of Wnt signaling and consequent rescue of the CD44(+)/CD24(-)/ESA(+) cell population. Taken together, these findings indicate that CBX7-mediated epigenetic induction of DKK-1 is crucial for the inhibition of breast tumorigenicity, suggesting that CBX7 could be a potential tumor suppressor in human breast cancer.
- Published
- 2014
32. Genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification
- Author
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Wang Rim Jung, Mao Mao, Seung-Mo Hong, Sung-Min Ahn, Sung-Min Chun, Daehyun Baek, Hyun Jeung Choi, Sunyoung Lee, Gu Kong, Chang Ohk Sung, Farhan Haq, Han Chu Lee, Seongmin Choi, Young-Joo Lee, Wing-Kin Sung, Deokhoon Kim, Sukjun Kim, Jong Eun Lee, Jongkyu Kim, Eunho Yang, Nikki P. Lee, Charles Lee, Se Jin Jang, Jessica Zucman-Rossi, Hye Yoon Jang, Adnan Ahmad Ansari, Ju Hyun Shim, Shin Hwang, and Eunsil Yu
- Subjects
medicine.medical_specialty ,Cirrhosis ,Hepatology ,Copy number analysis ,Biology ,medicine.disease ,Resectable Hepatocellular Carcinoma ,CDKN2A ,Hepatocellular carcinoma ,Internal medicine ,medicine ,Carcinoma ,Cancer research ,Exome sequencing - Abstract
Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). Conclusion: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients. (Hepatology 2014;60:1971–1981)
- Published
- 2014
33. LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis
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H. S. Joo, Gu Kong, H. J. Choi, M. K. Park, K. P. Kim, Tae Jin Lee, J. H. Park, Carlo Croce, H. Y. Won, B. Han, J. Y. Lee, and D. H. Shin
- Subjects
0301 basic medicine ,Cancer Research ,animal structures ,Transcription, Genetic ,Breast Neoplasms ,Mice, SCID ,Protein degradation ,Methylation Site ,Transfection ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ubiquitin ,Mice, Inbred NOD ,Cell Line, Tumor ,Genetics ,Protein methylation ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Molecular Biology ,Histone Demethylases ,biology ,Neovascularization, Pathologic ,Methylation ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,Mi-2/NuRD complex ,Cell biology ,Vascular endothelial growth factor ,030104 developmental biology ,HEK293 Cells ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Demethylase ,Heterografts ,Female - Abstract
Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.
- Published
- 2016
34. Discovery of Urinary Biomarkers in Patients with Breast Cancer Based on Metabolomics
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Gu Kong, Seok Jin Nam, Jeongae Lee, Han Min Woo, and Bong Chul Chung
- Subjects
Oncology ,medicine.medical_specialty ,Chemistry ,Urinary system ,Pattern analysis ,Urine ,Urinary biomarkers ,medicine.disease ,Metabolomics ,Breast cancer ,Internal medicine ,medicine ,Biomarker (medicine) ,In patient - Abstract
A metabolomics study was conducted to identify urinary biomarkers for breast cancer, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), analyzed by principal components analy-sis (PCA) as well as a partial least squares-discriminant analysis (PLS-DA) for a metabolic pattern analysis. To find potentialbiomarkers, urine samples were collected from before- and after-mastectomy of breast cancer patients and healthy controls.Androgens, corticoids, estrogens, nucleosides, and polyols were quantitatively measured and urinary metabolic profiles wereconstructed through PCA and PLS-DA. The possible biomarkers were discriminated from quantified targeted metabolites with ametabolic pattern analysis and subsequent screening. We identified two biomarkers for breast cancer in urine, β-cortol and 5-methyl-2-deoxycytidine, which were categorized at significant levels in a student t-test (p-value < 0.05). The concentrations ofthese metabolites in breast cancer patients significantly increased relative to those of controls and patients after mastectomy.Biomarkers identified in this study were highly related to metabolites causing oxidative DNA damage in the endogenous metab-olism. These biomarkers are not only useful for diagnostics and patient stratification but can be mapped on a biochemical chartto identify the corresponding enzyme for target identification via metabolomics.Key words: Metabolomics, Breast Cancer, Biomarker, PLS-DA, Urine
- Published
- 2013
35. The topography of mutational processes in breast cancer genomes
- Author
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Peter J. Campbell, Serena Nik-Zainal, Gilles Thomas, Steven Van Laere, Michael R. Stratton, Hyung-Yong Kim, Hendrik G. Stunnenberg, Christos Sotiriou, Sancha Martin, Andrea L. Richardson, Anieta M. Sieuwerts, Adam Butler, Anne Lise Børresen-Dale, Paul N. Span, Jorunn E. Eyfjord, Julian E. Sale, Alastair M Thompson, Sandro Morganella, John W.M. Martens, Ludmil B. Alexandrov, Åke Borg, Gu Kong, Arie B. Brinkman, Helen Davies, Johan Staaf, Cristina Rada, Ewan Birney, Xueqing Zou, Sunil R. Lakhani, Marc J. van de Vijver, Dominik Glodzik, Manasa Ramakrishna, P. Andrew Futreal, Medical Oncology, CCA -Cancer Center Amsterdam, Pathology, Span, Paul N [0000-0002-1930-6638], Lakhani, Sunil R [0000-0003-1879-2555], Rada, Cristina [0000-0003-4898-5550], and Apollo - University of Cambridge Repository
- Subjects
DNA Replication ,0301 basic medicine ,DNA Repair ,Transcription, Genetic ,DNA repair ,DNA damage ,Science ,General Physics and Astronomy ,Breast Neoplasms ,Biology ,Genome ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Germline mutation ,SDG 3 - Good Health and Well-being ,Humans ,Indel ,Molecular Biology ,Apolipoproteins B ,Genetics ,Multidisciplinary ,Genome, Human ,DNA replication ,Médecine pathologie humaine ,Sequence Analysis, DNA ,General Chemistry ,Sciences bio-médicales et agricoles ,Chromatin ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Cancérologie ,030104 developmental biology ,Mutagenesis ,Mutation ,MCF-7 Cells ,Female ,Human genome ,Human medicine ,DNA Damage - Abstract
Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2016
36. Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- Author
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John W.M. Martens, Sandrine Boyault, David Jones, Stefania Tommasi, Jeong-Yeon Lee, Germán Fg Rodríguez-González, Inigo Martincorena, Sung-Min Ahn, Alastair M Thompson, Manasa Ramakrishna, Gilles Thomas, Helen Davies, Savitri Krishnamurthy, Stian Knappskog, Steven Van Laere, Lucy Stebbings, Andrea L. Richardson, Andrew Tutt, Anne Lise Børresen-Dale, Olafur Oa Stefansson, Sunil R. Lakhani, Michiel M. Smid, Gerrit Gk Hooijer, Young Seok Ju, Tari Ta King, Rebecca Shepherd, Luc Dirix, Xavier Pivot, Adam Butler, Aquila Fatima, Peter Pt Simpson, Serena Nik-Zainal, Sancha Martin, Hyung-Yong Kim, Hendrik G. Stunnenberg, Jos Jonkers, Michael R. Stratton, Jon W. Teague, Se Jin Jang, Sandro Morganella, Ville Mustonen, Moritz Gerstung, Gu Kong, Carlos Caldas, Anne Vincent-Salomon, Anieta M. Sieuwerts, Lucy R. Yates, Sarah O’Meara, Peter B. Vermeulen, Dominik Glodzik, Peter Van Loo, Naoto T. Ueno, Arie B. Brinkman, Stuart McLaren, Yang Li, Marc J. van de Vijver, Laura Van't Veer, P. Andrew Futreal, Markus Ringnér, Christos Sotiriou, Ewan Birney, Kamna Ramakrishnan, Miriam Ragle Aure, Johan Staaf, Jane E. Brock, Benita Kiat Tee Bk Tan, Alain Viari, Xueqing Zou, Anita Langerød, David C. Wedge, Hee Jin Lee, Christine Desmedt, Gilles Romieu, Paul N. Span, Jorunn E. Eyfjord, Annegien Broeks, Isabelle Treilleux, Åke Borg, Colin Ca Purdie, Ole Christian Lingjærde, Gert Van den Eynden, John A. Foekens, Serge Dronov, Andrew Menzies, Peter J. Campbell, Iris Pauporté, Ludmil B. Alexandrov, Keiran Raine, The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboud university [Nijmegen], Oslo University Hospital Radiumhospitalet, University of Oslo (UiO), Gachon University Hospital, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brigham and Women's Hospital [Boston], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Algemeen Ziekenhuis St Augustinus Oncology, Dana-Farber Cancer Institute [Boston], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Ulsan, NASA Johnson Space Center (JSC), NASA, University of Stuttgart, Esso UK Ltd, Department of Exploration, Esso UK Ltd, Department of Computer Science & Engineering [Riverside] (CSE), University of California [Riverside] (UCR), University of California-University of California, Department of Geriatric Medicine [Singapore] (Alexandra Hospital), Institut national du cancer [Boulogne] (INCA), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], Canary Institute for Cancer Research (ICIC), Department of Biochemistry and Physiology, Faculty of Health Sciences, University of Las Palmas de Gran Canaria (ULPGC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Medical Oncology [Rotterdam], Cancer Genomics Centre, University of Queensland [Brisbane], University of Iceland [Reykjavik], Beckman Research Institute [Duarte, CA], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), European Central Bank (ECB), European Central Bank, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Tumor Biology, Institut Curie [Paris], University of Cambridge [UK] (CAM), Division of Diagnostic Oncology, Netherlands Cancer Institute, Agendia BV, Breakthrough Breast Cancer Centre, London Institute of Cancer, University of Bergen (UiB), National Cancer Centre Singapore (NCCS), National Cancer Centre Singapore, Division of Molecular Biology, National Institutes of Natural Sciences, The Graduate University for Advanced Studies, Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Radiation Oncology 874, Radboud University Medical Center [Nijmegen], Department of Laboratory Medicine, Department Medical Oncology, Department of Pathology, Ospedale 'Mater Salutis', Goddard Earth Sciences and Technology and Research (GESTAR), NASA-Universities Space Research Association (USRA), Department of Molecular Biology [Nijmegen], Department of Organismic and Evolutionary Biology [Cambridge] (OEB), Harvard University [Cambridge], Department of Computing [London], Biomedical Image Analysis Group [London] (BioMedIA), Imperial College London-Imperial College London, Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Sagot, Marie-France, Radboud University [Nijmegen], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nik-Zainal, Serena [0000-0001-5054-1727], Zou, Xueqing [0000-0003-1143-1028], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Medical Oncology, Harvard University, Fondation Synergie Lyon Cancer [Lyon], CCA -Cancer Center Amsterdam, Pathology, Erasmus University Medical Center [Rotterdam], University of Oslo ( UiO ), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Netherlands Cancer Institute ( NKI ), Institut Jules Bordet, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ), NASA Johnson Space Center ( JSC ), Department of Computer Science & Engineering [Riverside] ( CSE ), University of California [Riverside] ( UCR ), Institut national du cancer [Boulogne] ( INCA ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Department of Medical Oncology, Erasmus Medical Center Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, University of Las Palmas de Gran Canaria ( ULPGC ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Erasmus MC, Beckman Research Institute, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Antwerp ( UA ), European Central Bank ( ECB ), U 830, Institut National de la Santé et de la Recherche Médicale, Institut Curie, University of Cambridge [UK] ( CAM ), University of Bergen ( UIB ), National Cancer Centre Singapore ( NCCS ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Goddard Earth Sciences and Technology and Research ( GESTAR ), NASA-Universities Space Research Association ( USRA ), Department of Organismic and Evolutionary Biology ( OEB ), and Biomedical Image Analysis Group [London] ( BioMedIA )
- Subjects
0301 basic medicine ,DNA Replication ,Male ,Mutation rate ,DNA repair ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Genome ,Cohort Studies ,03 medical and health sciences ,Germline mutation ,SDG 3 - Good Health and Well-being ,Mutation Rate ,medicine ,Humans ,Gene ,Molecular Biology ,Genetics ,Mutation ,Multidisciplinary ,[ SDV ] Life Sciences [q-bio] ,Genome, Human ,Recombinational DNA Repair ,DNA, Neoplasm ,Genomics ,Oncogenes ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Mutagenesis ,Human genome ,Female ,Engineering sciences. Technology - Abstract
Item does not contain fulltext We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
- Published
- 2016
37. The effect of raw vegetable and fruit intake on thyroid cancer risk among women: a case–control study in South Korea
- Author
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Sukyoung Jung, Kirang Kim, Gu Kong, Mi Kyung Kim, and Kyung Tae
- Subjects
Adult ,Citrus ,medicine.medical_specialty ,Inverse Association ,Thyroid Gland ,Medicine (miscellaneous) ,Gastroenterology ,Young Adult ,Risk Factors ,Surveys and Questionnaires ,Internal medicine ,Republic of Korea ,Vegetables ,medicine ,Humans ,Thyroid Neoplasms ,Thyroid Nodule ,Risk factor ,Thyroid cancer ,Aged ,Ultrasonography ,Academic Medical Centers ,Nutrition and Dietetics ,business.industry ,Thyroid ,Case-control study ,Cancer ,Raw vegetables ,Diospyros ,Middle Aged ,medicine.disease ,Diet ,Logistic Models ,Endocrinology ,medicine.anatomical_structure ,Case-Control Studies ,Fruit ,Female ,business - Abstract
Thyroid cancer is the most common cancer among Korean women. However, there are few data on dietary factors related to thyroid cancer risk. The objective of the present study was to evaluate the association between raw vegetables and fruits intake and thyroid cancer in a case–control study. We included 111 histologically confirmed malignant thyroid cancer cases and 115 benign cases. Controls who did not have nodules in thyroid ultrasonography were matched to cases by age ( ± 2 years). Food and nutrient intakes were estimated using a quantitative FFQ with 121 items. Conditional logistic regression analysis was used to obtain OR and corresponding 95 % CI. The intake of total vegetables was not associated with malignant thyroid cancer, but inversely associated with benign cases. High raw vegetable intake was inversely associated with thyroid cancer risk both in malignant and benign cases (P for trend = 0·01 in both malignant and benign cases). Among fruits, persimmon intake had an inverse association with thyroid cancer risk in both malignant and benign cases (P for trend = 0·06 in malignant cases; P for trend = 0·01 in benign cases) and tangerine intake had an inverse association in malignant cases (P for trend = 0·03). The frequency of consumption of raw vegetables and persimmon also had a consistent inverse association in both malignant and benign cases. These results suggest that high consumption of raw vegetables, persimmons and tangerines may decrease thyroid cancer risk and help prevent early-stage thyroid cancer.
- Published
- 2012
38. The in vitro and in vivo anti-tumor effect of KO-202125, a sauristolactam derivative, as a novel epidermal growth factor receptor inhibitor in human breast cancer
- Author
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Jeong-Yeon Lee, Sung-Dae Cho, Hyun-Jun Kim, Mi-Yun Oh, Gu Kong, Seung Hyun Oh, Ji-Hye Park, Young Ki Min, Tingting Oian, and Dong Hui Shin
- Subjects
Cancer Research ,Estrogen receptor ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Isoindoles ,Pharmacology ,Biology ,Mice ,chemistry.chemical_compound ,Gefitinib ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Growth factor receptor inhibitor ,Epidermal growth factor receptor ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,EGFR inhibitors ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Xenograft Model Antitumor Assays ,ErbB Receptors ,Wnt Proteins ,Receptors, Estrogen ,Oncology ,chemistry ,biology.protein ,Female ,Growth inhibition ,Proto-Oncogene Proteins c-akt ,A431 cells ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction ,medicine.drug - Abstract
Epidermal growth factor receptor (EGFR) is one of the most promising targets for cancer therapy. Here, we show the in vitro and in vivo anticancer effects and associated mechanisms of KO-202125, one of the synthesized aristolactam analogs, as a novel EGFR inhibitor, in EGFR-overexpressing cancer cell lines. KO-202125 showed more effective growth inhibition and apoptosis induction than gefitinib, a representative EGFR inhibitor, in various EGFR-overexpressing human cancers including estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Epidermal growth factor receptor phosphorylation at Tyr1068 was reduced and, consequently, the association of EGFR with p85 was decreased by KO-202125 treatment in MDA-MB-231 cell lines. This led to inactivation of the PI3K/Akt pathway, and consequently suppression of activation of the Wnt pathway and enhancement of the nuclear import of p27Kip1. KO-202125 treatment in nude mice injected with MDA-MB-231 cells showed inhibition of tumor growth without toxicity. Collectively, our results showed the possibility of KO-202125 as an effective therapy agent of EGFR-overexpressing cancer cells through reduced EGFR activity and downregulation of the Akt pathway.
- Published
- 2011
39. Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex
- Author
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Gu Kong, J. Y. Lee, J. H. Park, Hyuck Kim, and Qian T
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Inhibitor of Differentiation Protein 1 ,Cancer Research ,Ubiquitin-Protein Ligases ,Blotting, Western ,Gene Expression ,Polycomb-Group Proteins ,Transfection ,Epigenesis, Genetic ,Histones ,Ubiquitin ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Genetics ,Transcriptional regulation ,Polycomb-group proteins ,Humans ,Gene silencing ,Epigenetics ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Polycomb Repressive Complex 1 ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Ubiquitination ,Nuclear Proteins ,Geminin ,Ubiquitin ligase ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,biology.protein ,Cancer research ,Signal Transduction - Abstract
The helix-loop-helix inhibitor of differentiation and DNA binding (Id1) is well known as an oncogene in various tumors. Although it has been reported that Id1 promotes several oncogenic processes, it is still unclear whether Id1 functions through epigenetic transcriptional regulation. In this study, we examined the effect of Id1 on polycomb group (PcG) proteins, which are crucial epigenetic gene silencers, and found that Id1 regulated the expression of Mel-18 and Bmi-1, both of which belong to polycomb repressive complex 1. We also confirmed that Id1 induced Mel-18 downregulation, which was mediated by the Akt pathway, and consequently upregulated the transcription of its target gene, c-Myc. Using a promoter-reporter, we demonstrated that Id1 regulated Bmi-1 transcription through c-Myc binding to its E-box in the promoter. Finally, we examined the activity of E3 ligase RING1b, whose catalytic activity is increased by binding with the RING finger protein Bmi-1, and found that Id1 overexpression enhanced RING1b E3 ligase activity leading to accumulation of H2A ubiquitination and ubiquitin/proteasome-mediated degradation of geminin. Taken together, our study provided a novel link between Id1 and PcG proteins and suggested that Id1 may contribute to tumor development through PcG-mediated epigenetic regulation.
- Published
- 2010
40. A case–control study on seaweed consumption and the risk of breast cancer
- Author
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Mi Kyung Kim, Yoon Jung Yang, Seok Jin Nam, and Gu Kong
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Adult ,medicine.medical_specialty ,Food intake ,Medicine (miscellaneous) ,Breast Neoplasms ,Diet Surveys ,Breast cancer ,Risk Factors ,Internal medicine ,Odds Ratio ,medicine ,Humans ,Risk factor ,Aged ,Korea ,Nutrition and Dietetics ,Obstetrics ,business.industry ,Confounding ,Case-control study ,Cancer ,Middle Aged ,Seaweed ,medicine.disease ,Diet ,Menopause ,Endocrinology ,Food ,Case-Control Studies ,Female ,Breast disease ,business - Abstract
Gim (Porphyra sp.) and miyeok (Undaria pinnatifida) are the seaweeds most consumed by Koreans. We investigated the association between the intake of gim and miyeok and the risk of breast cancer in a case–control study. Cases were 362 women aged 30–65 years old, who were histologically confirmed to have breast cancer. Controls visiting the same hospital were matched to cases according to their age (sd 2 years) and menopausal status. Food intake was estimated by the quantitative FFQ with 121 items, including gim and miyeok. Conditional logistic regression analysis was used to obtain the OR and corresponding 95 % CI. The average intake and consumption frequency of gim in cases were lower than in controls. The daily intake of gim was inversely associated with the risk of breast cancer (5th v. 1st quintile, OR, 0·48; 95 % CI, 0·27, 0·86; P for trend, 0·026) after adjustment for potential confounders. After stratification analysis was performed according to menopausal status, premenopausal women (5th v. 1st quintile, OR, 0·44; 95 % CI, 0·24, 0·80; P for trend, 0·007) and postmenopausal women (5th v. 1st quintile, OR, 0·32; 95 % CI, 0·13, 0·80; P for trend, 0·06) showed similar inverse associations between gim intake and the risk of breast cancer after an adjustment for potential confounders except dietary factors. Miyeok consumption did not have any significant associations with breast cancer. These results suggest that high intake of gim may decrease the risk of breast cancer.
- Published
- 2009
41. Quantitative analysis of urinary phospholipids found in patients with breast cancer by nanoflow liquid chromatography–tandem mass spectrometry: II. Negative ion mode analysis of four phospholipid classes
- Author
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Gu Kong, Myeong Hee Moon, and Hye Kyeong Min
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Spectrometry, Mass, Electrospray Ionization ,Electrospray ,Phospholipid ,Phosphatidic Acids ,Breast Neoplasms ,Phosphatidylserines ,Urine ,Phosphatidylinositols ,Mass spectrometry ,Sensitivity and Specificity ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Breast cancer ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,Phosphatidylcholine ,medicine ,Humans ,Phospholipids ,Chromatography ,Chemistry ,Phosphatidylglycerols ,Phosphatidic acid ,Middle Aged ,medicine.disease ,Female ,Chromatography, Liquid - Abstract
Analysis was performed on four different categories of phospholipids (phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidic acid (PA)) from urine in patients with breast cancer. This quantitative analysis was conducted using nanoflow liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS-MS). This study shows the profiling of the phospholipids (PLs) that can be identified by the negative ion mode of MS. A previous study (Kim et al. Anal. Bioanal. Chem. 393:1649, 21) focused on only two PL classes: phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) and were identified by positive ion mode. PLs were extracted by lyophilization of 1 mL of urine from both healthy normal females and breast cancer patients before and after surgery. Separation of PLs was performed by nLC followed by structural identification of PLs using data-dependent collision-induced dissociation. A total of 34 urinary PL molecules (12 PSs, 12 PIs, four PGs, and six PAs) were quantitatively examined. Among the four PL categories examined in this study, most PL classes showed an increase in the total amounts in the cancer patients, yet PIs exhibited some decreases. The present study suggests that the lipid composition found in the urine of breast cancer patients can be utilized for the possible development of disease markers, when the analysis is performed with negative ion mode of nLC-ESI-MS-MS.
- Published
- 2009
42. Sulforaphane enhances caspase-dependent apoptosis through inhibition of cyclooxygenase-2 expression in human oral squamous carcinoma cells and nude mouse xenograft model
- Author
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In-Sun Choi, Kyung-Suk Moon, Sung-Dae Cho, Nam-Pyo Cho, Ji-Youn Jung, Gu Kong, Kyeong-Hee Choi, Yunjo Soh, Hyeong-Jin Kim, Hye-Suk Han, Seoung Hwan Choi, and Dae-Ho Leem
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Cell ,Mice, Nude ,Apoptosis ,Mice ,chemistry.chemical_compound ,Nude mouse ,Isothiocyanates ,Republic of Korea ,medicine ,Animals ,Anticarcinogenic Agents ,Humans ,Cyclooxygenase 2 Inhibitors ,biology ,business.industry ,biology.organism_classification ,In vitro ,Squamous carcinoma ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Epidermoid carcinoma ,chemistry ,Caspases ,Sulfoxides ,Carcinoma, Squamous Cell ,Cancer research ,biology.protein ,Mouth Neoplasms ,Cyclooxygenase ,Oral Surgery ,business ,Thiocyanates ,Sulforaphane - Abstract
In this study, we found that oral squamous cell carcinomas (OSCCs) in Korean patients have a high level of COX-2 expression when compared with normal mucosa. Sulforaphane (SFN), rich in cruciferous vegetables, has been reported to display anti-cancer activity against many cancers. However, the effect and molecular mechanism of SFN in the proliferation of OSCC still remains unclear. To elucidate this mechanism, we investigated the anti-proliferative effect of SFN on KB and YD-10B cells and demonstrated that SFN significantly induced caspase-dependent apoptosis. Also, we observed that SFN inhibited COX-2 but not COX-1. In addition, bcl-2 protein, one of downstream targets of COX-2, was down-regulated by SFN. Furthermore, SFN also inhibited tumor growth in KB cell xenografts. These results show that SFN can act as a potent anti-oral cancer compound by inhibiting COX-2 activity.
- Published
- 2009
43. Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition
- Author
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Qian T, Cheorl Ho Kim, Hyuck Kim, Seong Ho Jang, Gu Kong, J. Y. Lee, Kang Mb, and Yoon-Shin Kim
- Subjects
Inhibitor of Differentiation Protein 1 ,Cancer Research ,Tumor suppressor gene ,Breast Neoplasms ,Biology ,Models, Biological ,Transactivation ,Cell Line, Tumor ,Genetics ,Humans ,Tensin ,PTEN ,Enzyme Inhibitors ,Phosphorylation ,Promoter Regions, Genetic ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,PTEN Phosphohydrolase ,Wnt signaling pathway ,Gene Expression Regulation, Neoplastic ,Wnt Proteins ,Cancer research ,biology.protein ,TCF Transcription Factors ,Proto-Oncogene Proteins c-akt ,Cyclin-Dependent Kinase Inhibitor p27 ,Subcellular Fractions - Abstract
Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3beta phosphorylation at Ser9, stabilization and nuclear localization of beta-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27(Kip1) phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.
- Published
- 2008
44. Gene expression profiles of murine fatty liver induced by the administration of methotrexate
- Author
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Mingoo Kim, Byung-Hoon Lee, Heekyoung Chung, Ju Han Kim, Il Hong, Mi-Ock Lee, Kyung-Sun Kang, Min-Ho Lee, Hyung Lae Kim, Byung Il Yoon, and Gu Kong
- Subjects
Male ,Ratón ,medicine.drug_class ,Administration, Oral ,Gene Expression ,Biology ,Pharmacology ,Toxicology ,Toxicogenetics ,Antimetabolite ,Mice ,chemistry.chemical_compound ,Gene expression ,medicine ,Animals ,RNA, Messenger ,Enzyme Inhibitors ,Oligonucleotide Array Sequence Analysis ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Fatty liver ,Lipid Metabolism ,medicine.disease ,Fatty Liver ,Disease Models, Animal ,Methotrexate ,chemistry ,Antifolate ,Immunology ,Toxicogenomics ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Methotrexate (MTX) is used to treat a variety of chronic inflammatory and neoplastic diseases. However, it can induce hepatotoxicity such as microvesicular steatosis and necrosis. To explore the mechanisms of MTX-induced hepatic steatosis, we used microarray analysis to profile the gene expression patterns of mouse liver after MTX treatment. MTX was administered orally as a single dose of 10mg/kg (low dose) or 100 mg/kg (high dose) to ICR mice, and the livers were obtained 6 h, 24 h, and 72 h after treatment. Serum alanine aminotransferase, aspartate aminotransferase and triacylglycerol levels were not significantly altered in the experimental animals. Signs of steatosis were observed at 24 h after administration of high dose of MTX. From microarray data analysis, 908 genes were selected as MTX-responsive genes (P0.05, two-way ANOVA; cutoffor =1.5-fold). Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are response to unfolded proteins, phosphate metabolism, and cellular lipid metabolism. Functional categorization of these genes identified 28 genes involved in lipid metabolism that was interconnected with the biological pathways of biosynthesis, catabolism, and transport of lipids and fatty acids. Taken together, these data provide a better understanding of the molecular mechanisms of MTX-induced steatogenic hepatotoxicity, and useful information for predicting hepatotoxicity through pattern recognition.
- Published
- 2008
45. Mel-18 Negatively Regulates INK4a/ARF-Independent Cell Cycle Progression via Akt Inactivation in Breast Cancer
- Author
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Kiseok Jang, Hyun-Jun Kim, Mi-Yun Oh, Gu Kong, Dong-Hui Shin, Yong-Seok Kim, and Jeong-Yeon Lee
- Subjects
Cancer Research ,Blotting, Western ,Down-Regulation ,Fluorescent Antibody Technique ,Breast Neoplasms ,Cyclin D1 ,Cancer stem cell ,Cyclin-dependent kinase ,Cell Line, Tumor ,hemic and lymphatic diseases ,Tumor Suppressor Protein p14ARF ,Humans ,Phosphorylation ,neoplasms ,Protein kinase B ,Cyclin-Dependent Kinase Inhibitor p16 ,Polycomb Repressive Complex 1 ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Kinase ,Akt/PKB signaling pathway ,Cell Cycle ,Cyclin-dependent kinase 2 ,Cell biology ,Carcinoma, Ductal ,DNA-Binding Proteins ,Repressor Proteins ,carbohydrates (lipids) ,Oncology ,biology.protein ,Proto-Oncogene Proteins c-akt - Abstract
Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G1 arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G1-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27Kip1 phosphorylation at Thr157, but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser473 was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27Kip1 was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3β phosphorylation, β-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18→Akt→G1 phase regulators. [Cancer Res 2008;68(11):4201–9]
- Published
- 2008
46. Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell linesin vitroand in nude mice xenografts
- Author
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Hyun-Jun Kim, Kiseok Jang, Young-mi Jung, Jeong-Yeon Lee, Dong-Hui Shin, Mi-Yun Oh, Kun Ho Son, Su Jin Jeon, Gu Kong, and Heekyoung Chung
- Subjects
Cancer Research ,medicine.medical_specialty ,Programmed cell death ,Receptor, ErbB-2 ,Mice, Nude ,Estrogen receptor ,Apoptosis ,Breast Neoplasms ,Biology ,Mice ,chemistry.chemical_compound ,Wogonin ,Cyclin D1 ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Protein kinase B ,Cell Proliferation ,Mice, Inbred BALB C ,Cell growth ,Akt/PKB signaling pathway ,Estrogen Receptor alpha ,Xenograft Model Antitumor Assays ,Endocrinology ,Oncology ,chemistry ,Caspases ,Flavanones ,Cancer cell ,Cancer research ,Female ,Drugs, Chinese Herbal ,Signal Transduction - Abstract
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Wnt signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types.
- Published
- 2008
47. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice
- Author
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Mingoo Kim, Hu-Quan Yin, Kyung-Sun Kang, Byung Il Yoon, Mi-Ock Lee, Hyung Lae Kim, Gu Kong, Byung-Hoon Lee, and Ju Han Kim
- Subjects
Male ,Administration, Oral ,Gene Expression ,Biology ,Toxicology ,Mice ,chemistry.chemical_compound ,Gene expression ,medicine ,Animals ,Fatty acid synthesis ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,Ethanol ,Gene Expression Profiling ,Fatty Acids ,Fatty liver ,Fatty acid ,Lipid Metabolism ,medicine.disease ,Molecular biology ,Sterol regulatory element-binding protein ,Disease Models, Animal ,Fatty acid synthase ,Liver ,chemistry ,Biochemistry ,biology.protein ,Steatosis ,Steatohepatitis ,Fatty Liver, Alcoholic - Abstract
Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayedor=2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.
- Published
- 2007
48. Gene expression profiles of murine fatty liver induced by the administration of valproic acid
- Author
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Kyung-Sun Kang, Byung-Il Yoon, Il Hong, Mi-Ock Lee, Hyung Lae Kim, Mingoo Kim, Byunghoon Lee, Gu Kong, Minho Lee, Heekyoung Chung, and Ju-Han Kim
- Subjects
Male ,medicine.medical_specialty ,Microvesicular Steatosis ,Biology ,Toxicology ,Mice ,Internal medicine ,medicine ,Animals ,Oligonucleotide Array Sequence Analysis ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred ICR ,Valproic Acid ,Catabolism ,Gene Expression Profiling ,Fatty Acids ,Fatty liver ,Fatty acid ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,Fatty Liver ,Gene expression profiling ,Endocrinology ,Liver ,chemistry ,Anticonvulsants ,Steroids ,lipids (amino acids, peptides, and proteins) ,Steatosis ,Signal Transduction ,medicine.drug - Abstract
Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.
- Published
- 2007
49. DOT1L: a new therapeutic target for aggressive breast cancer
- Author
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Jeong-Yeon Lee and Gu Kong
- Subjects
Transcriptional Activation ,Methyltransferase ,Epithelial-Mesenchymal Transition ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Methylation ,Chromosome Section ,Histones ,Mice ,breast cancer ,hemic and lymphatic diseases ,Histone methylation ,medicine ,Animals ,Humans ,histone methylation ,Leukemia ,EMT ,DOT1L ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,Cell cycle ,medicine.disease ,Fusion protein ,Histone ,Oncology ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Benzimidazoles ,Female ,Editorial: Chromosome - Abstract
Disruptor of telomeric silencing-1 like (DOT1L) is a histone-modifying enzyme that specifically catalyzes the mono-, di-, and tri-methylation of histone H3 on lysine-79 (H3K79). DOTlL-mediated H3K79 methylation is associated with active transcription, and it has been implicated in many biological processes including DNA damage response, cell cycle, and embryonic cell development [1]. Furthermore, accumulating studies have shown the emerging role of DOT1L and H3K79 methylation in the initiation and maintenance of mixed lineage leukemia (MLL)-rearranged leukemia. During leukemogenesis, MLL fusion proteins such as AF9, AF10, and ENL recruit DOT1L to their target gene loci to elevate H3K79 methylation levels, thus increasing the aberrant expression of genes that contribute to leukemic transformation of hematopoietic progenitors [2]. Thus, DOT1L has been suggested to be a promising molecular target for MLL-rearranged leukemia. Indeed, selective DOT1L inhibitors exhibit remarkable anti-tumor effects in these cells, and EPZ-5676, the most advanced DOT1L inhibitor, is currently in clinical trials for adult and pediatric patients with MLL-rearranged leukemia [2]. While the oncogenic potential of DOT1L in leukemia has been well described, there is little evidence for the role of DOT1L in solid tumors.
- Published
- 2015
50. Comprehensive genomic profiles of small cell lung cancer
- Author
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Lucia Anna Muscarella, Yong-Hee Kim, Ilona Dahmen, Marc Bos, Luka Ozretić, Dedeepya Vaka, Frauke Leenders, John K. Field, Montserrat Sanchez-Cespedes, Matthew D. Wilkerson, Gavin M. Wright, Sung-Min Chun, Viktor Achter, Lukas C. Heukamp, Danila Seidel, Prudence A. Russell, Peter Nürnberg, Philipp Schaub, Martin Peifer, David Engelmann, Nadine Jahchan, Pierre P. Massion, Roman K. Thomas, Stefan A. Haas, Peter M. Schneider, Elisabeth Brambilla, Julie George, Dian Yang, Maia Segura Wang, Christian Reinhardt, Benjamin Solomon, Anthony N. Karnezis, Koji Tsuta, Roopika Menon, Julien Sage, Dragana Jovanovic, Esmeralda Castaños-Vélez, Takashi Kohno, Ulrich Lang, Helga B. Salvesen, Xin Lu, Ángela Torres, Michael Lindner, Se Jin Jang, Milica Kontic, Hans Hoffmann, Reika Iwakawa, Reinhard Büttner, Berit Pinther, Martin Vingron, Kwon-Sik Park, Sascha Ansén, Yasushi Yatabe, Martin Schuler, Christian Müller, O.T. Brustugun, Jun Yokota, Johan Botling, Neil Hayes, Yupeng Cun, Magdalena Bogus, Deokhoon Kim, Jens Köhler, Jan O. Korbel, William D. Travis, Sebastian Michels, Jürgen Wolf, Martin Sandelin, Marius Lund-Iversen, Brigitte M. Pützer, Verena Tischler, Ina Koch, Ignacija Vlasic, Yuan Chen, Janine Altmüller, Masayuki Noguchi, Michael Hallek, Jing Shan Lim, Alex Soltermann, Lynnette Fernandez-Cuesta, Thomas Zander, Gu Kong, Christian Becker, Luca Roz, Yong Zou, Graziella Bosco, Iver Petersen, Philipp A. Schnabel, Sven Perner, Marko Jakopović, Chang-Min Choi, Jelena Knezevic, Ugo Pastorino, Thomas Muley, Annamaria la Torre, Erik Thunnissen, Pathology, and CCA - Oncogenesis
- Subjects
Male ,Lung Neoplasms ,Medizin ,Gene mutation ,medicine.disease_cause ,Retinoblastoma Protein ,Mice ,Chromosome Breakpoints ,0302 clinical medicine ,Receptors ,2.1 Biological and endogenous factors ,Cyclin D1 ,Aetiology ,Lung ,Cancer ,Genetics ,0303 health sciences ,Mutation ,Multidisciplinary ,Chromothripsis ,Tumor ,Genome ,Receptors, Notch ,Lung Cancer ,Nuclear Proteins ,Genomics ,3. Good health ,DNA-Binding Proteins ,ASCL1 ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Human ,Notch ,General Science & Technology ,Comprehensive genomic profiles ,Small cell lung cancer ,TP53 and RB1 tumor supressors ,Notch signaling pathway ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,neoplasms ,Alleles ,030304 developmental biology ,Genome, Human ,Animal ,Tumor Suppressor Proteins ,Gene Expression Profiling ,Human Genome ,Rovalpituzumab tesirine ,Tumor Protein p73 ,medicine.disease ,Neurosecretory Systems ,Small Cell Lung Carcinoma ,respiratory tract diseases ,Gene expression profiling ,Disease Models, Animal ,Genòmica ,Disease Models ,Cancer research ,Càncer de pulmó ,Tumor Suppressor Protein p53 - Abstract
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Deltaex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
- Published
- 2015
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