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Lung and Thoracic cancer
Cancer-Specific Sequences in the Diagnosis and Treatment of NUT Carcinoma
Mi-Sook Lee, Sungbin An, Ji-Young Song, Minjung Sung, Kyungsoo Jung, Eun Sol Chang, Juyoung Choi, Doo-Yi Oh, Yoon Kyung Jeon, Hobin Yang, Chaithanya Lakshmi, Sehhoon Park, Joungho Han, Se-Hoon Lee, Yoon-La Choi
Cancer Res Treat. 2023;55(2):452-467.   Published online October 14, 2022
DOI: https://doi.org/10.4143/crt.2022.910
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
NUT carcinoma (NC) is a solid tumor caused by the rearrangement of NUTM1 that usually develops in midline structures, such as the thorax. No standard treatment has been established despite high lethality. Thus, we investigated whether targeting the junction region of NUTM1 fusion breakpoints could serve as a potential treatment option for NC.
Materials and Methods
We designed and evaluated a series of small interfering RNAs (siRNAs) targeting the junction region of BRD4-NUTM1 fusion (B4N), the most common form of NUTM1 fusion. Droplet digital polymerase chain reaction using the blood of patients was also tested to evaluate the treatment responses by the junction sequence of the B4N fusion transcripts.
Results
As expected, the majority of NC fusion types were B4N (12 of 18, 67%). B4N fusion-specific siRNA treatment on NC cells showed specific inhibitory effects on the B4N fusion transcript and fusion protein without affecting the endogenous expression of the parent genes, resulting in decreased relative cell growth and attenuation of tumor size. In addition, the fusion transcript levels in platelet-rich-plasma samples of the NC patients with systemic metastasis showed a negative correlation with therapeutic effect, suggesting its potential as a measure of treatment responsiveness.
Conclusion
This study suggests that tumor-specific sequences could be used to treat patients with fusion genes as part of precision medicine for a rare but deadly disease.

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Citations to this article as recorded by  
  • Indirect targeting of MYC and direct targeting in combination with chemotherapies are more effective than direct mono-targeting in triple negative breast cancer
    Negesse Mekonnen, Hobin Yang, Nirmal Rajasekaran, Kyoung Song, Yoon-La Choi, Young Kee Shin
    Translational Oncology.2025; 51: 102204.     CrossRef
  • NUT-midline carcinoma of the lung with rare BRD3-NUTM1 fusion
    Prerana Jha, Vaishakhi Trivedi, Nandini Menon, Minit Shah, Irene A George, Rohit Mishra, Trupti Pai, Fuzail Ahmad, Venkataramanan Ramachandran, Vanita Noronha, Kumar Prabhash, Prashant Kumar
    Cancer Research, Statistics, and Treatment.2024; 7(1): 110.     CrossRef
  • 5,969 View
  • 245 Download
  • 2 Web of Science
  • 2 Crossref
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Basic
TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis
Kyungsoo Jung, Joon-Seok Choi, Beom-Mo Koo, Yu Jin Kim, Ji-Young Song, Minjung Sung, Eun Sol Chang, Ka-Won Noh, Sungbin An, Mi-Sook Lee, Kyoung Song, Hannah Lee, Ryong Nam Kim, Young Kee Shin, Doo-Yi Oh, Yoon-La Choi
Cancer Res Treat. 2021;53(1):9-24.   Published online September 16, 2020
DOI: https://doi.org/10.4143/crt.2020.434
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
To find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be ‘some sort of problem.’ Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2).
Materials and Methods
Modified Tukey’s fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes.
Results
TM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell lines
Conclusion
Our modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.

Citations

Citations to this article as recorded by  
  • TM4SF19—A New Biomarker for Diagnosis and Prognosis of Bladder Urothelial Carcinoma
    蕴博 刘
    Advances in Clinical Medicine.2024; 14(02): 3616.     CrossRef
  • Validating linalool as a potential drug for breast cancer treatment based on machine learning and molecular docking
    Qian Zhang, Dengfeng Chen
    Drug Development Research.2024;[Epub]     CrossRef
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    Taha Mohammadzadeh-Vardin, Amin Ghareyazi, Ali Gharizadeh, Karim Abbasi, Hamid R. Rabiee, Amgad Muneer
    PLOS ONE.2024; 19(7): e0307649.     CrossRef
  • TM4SF4 is a diagnostic biomarker accelerating progression of papillary thyroid cancer via AKT pathway
    Lizhi Lin, Jialiang Wen, Tiansheng Xu, Yuhao Si
    Cancer Biology & Therapy.2024;[Epub]     CrossRef
  • Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance
    Nur Syafiqah Rahim, Yuan Seng Wu, Maw Shin Sim, Appalaraju Velaga, Srinivasa Reddy Bonam, Subash C. B. Gopinath, Vetriselvan Subramaniyan, Ker Woon Choy, Sin-Yeang Teow, Ismail M. Fareez, Chandramathi Samudi, Shamala Devi Sekaran, Mahendran Sekar, Rhanye
    Pharmaceuticals.2023; 16(1): 110.     CrossRef
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    Yeting Hu, Xiaoqin Lv, Wenwu Wei, Xiang Li, Kaixuan Zhang, Linlin Zhu, Tao Gan, Hongjuan Zeng, Jinlin Yang, Nini Rao
    Advanced Biology.2023;[Epub]     CrossRef
  • Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis
    Muttanagouda Giriyappagoudar, Basavaraj Vastrad, Rajeshwari Horakeri, Chanabasayya Vastrad
    Biomedicines.2023; 11(12): 3109.     CrossRef
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    Joon Yan Selene Lee, Jing Han Ng, Seyed Ehsan Saffari, Eng-King Tan
    Aging.2022; 14(5): 2148.     CrossRef
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    Zhisong Yang, Li Zhou, Haiyan Ge, Weimin Shen, Lin Shan
    Open Medicine.2022; 17(1): 1148.     CrossRef
  • LncRNA ST8SIA6-AS1 facilitates hepatocellular carcinoma progression by governing miR-651-5p/TM4SF4 axis
    Yanjie Mou, Xiaoming Ding
    Anti-Cancer Drugs.2022; 33(8): 741.     CrossRef
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    Mingfeng Yu, Yi Long, Yuchao Yang, Manjun Li, Theodosia Teo, Benjamin Noll, Stephen Philip, Shudong Wang
    European Journal of Medicinal Chemistry.2021; 218: 113391.     CrossRef
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    Ka-Won Noh, Reinhard Buettner, Sebastian Klein
    Biomolecules.2021; 11(9): 1310.     CrossRef
  • 11,553 View
  • 383 Download
  • 12 Web of Science
  • 12 Crossref
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Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients
Mi-Sook Lee, Eun Ah Jung, Sung Bin An, Yu Jin Kim, Doo-Yi Oh, Ji-Young Song, Sang-Won Um, Joungho Han, Yoon-La Choi
Cancer Res Treat. 2017;49(4):1065-1076.   Published online January 25, 2017
DOI: https://doi.org/10.4143/crt.2016.347
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer.
Materials and Methods
We selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays.
Results
We identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant–bearing cells.
Conclusion
Our results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.

Citations

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  • Potentially functional variants of PARK7 and DDR2 in ferroptosis‐related genes predict survival of non‐small cell lung cancer patients
    Huilin Wang, Hongliang Liu, Xiaozhun Tang, Guojun Lu, Sheng Luo, Mulong Du, David C. Christiani, Qingyi Wei
    International Journal of Cancer.2025; 156(4): 744.     CrossRef
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    OncoTargets and Therapy.2024; Volume 17: 1095.     CrossRef
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    Xiaoxiao Xu, Tong Yu, Zhenxing Wang
    Oncology Research and Treatment.2022; 45(4): 205.     CrossRef
  • Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing
    Sungbin An, Hyun Hee Koh, Eun Sol Chang, Juyoung Choi, Ji-Young Song, Mi-Sook Lee, Yoon-La Choi
    Frontiers in Oncology.2022;[Epub]     CrossRef
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    Sally C.M. Lau, Yuanwang Pan, Vamsidhar Velcheti, Kwok Kin Wong
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    V. Mehta, H. Chander, A. Munshi
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    Sandra Majo, Patrick Auguste
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    Charles Ricordel, Alexandra Lespagnol, Francisco Llamas-Gutierrez, Marie de Tayrac, Mallorie Kerjouan, Alice Fievet, Houda Hamdi-Rozé, Amyrat Aliouat, Benoit Desrues, Jean Mosser, Hervé Léna
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    Matrix Biology.2018; 73: 105.     CrossRef
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    Weihua Li, Tian Qiu, Yun Ling, Shugeng Gao, Jianming Ying
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    Ugo Testa, Germana Castelli, Elvira Pelosi
    Cancers.2018; 10(8): 248.     CrossRef
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  • 251 Download
  • 15 Web of Science
  • 12 Crossref
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Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies
Eun Jin Heo, Young Jae Cho, William Chi Cho, Ji Eun Hong, Hye-Kyung Jeon, Doo-Yi Oh, Yoon-La Choi, Sang Yong Song, Jung-Joo Choi, Duk-Soo Bae, Yoo-Young Lee, Chel Hun Choi, Tae-Joong Kim, Woong-Yang Park, Byoung-Gie Kim, Jeong-Won Lee
Cancer Res Treat. 2017;49(4):915-926.   Published online January 4, 2017
DOI: https://doi.org/10.4143/crt.2016.322
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research.
Materials and Methods
We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues.
Results
Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor–overexpressing PDX with clear cell histology (p=0.023).
Conclusion
PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

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    E Sun Paik, Tae-Hyun Kim, Young Jae Cho, Jiyoon Ryu, Jung-Joo Choi, Yoo-Young Lee, Tae-Joong Kim, Chel-Hun Choi, Woo Young Kim, Jason K. Sa, Jin-Ku Lee, Byoung-Gie Kim, Duk-Soo Bae, Hee Dong Han, Hyung Jun Ahn, Jeong-Won Lee
    Scientific Reports.2020;[Epub]     CrossRef
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    Suad M. Abdirahman, Michael Christie, Adele Preaudet, Marie C. U. Burstroem, Dmitri Mouradov, Belinda Lee, Oliver M. Sieber, Tracy L. Putoczki
    Cancers.2020; 12(9): 2340.     CrossRef
  • Epithelial/mesenchymal heterogeneity of high‐grade serous ovarian carcinoma samples correlates with miRNA let‐7 levels and predicts tumor growth and metastasis
    Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee R. Martinez, Christine Castañón, Saied Mirshahidi, Marcelo E. Vazquez, Pamela Wat, Kerby C. Oberg, Yevgeniya J. Ioffe, J
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    Kadi Lõhmussaar, Matteo Boretto, Hans Clevers
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    Anca Onaciu, Raluca Munteanu, Vlad Cristian Munteanu, Diana Gulei, Lajos Raduly, Richard-Ionut Feder, Radu Pirlog, Atanas G. Atanasov, Schuyler S. Korban, Alexandru Irimie, Ioana Berindan-Neagoe
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    Joseph J. Noh, Myeong-Seon Kim, Young-Jae Cho, Soo-Young Jeong, Yoo-Young Lee, Ji-Yoon Ryu, Jung-Joo Choi, Illju Bae, Zhaoyan Wu, Byoung-Gie Kim, Jae Ryoung Hwang, Jeong-Won Lee
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