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Ovatodiolide and antrocin synergistically inhibit the stemness and metastatic potential of hepatocellular carcinoma via impairing ribosome biogenesis and modulating ERK/Akt-mTOR signaling axis

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phytomedicine : international journal of phytotherapy and phytopharmacology 2023年 108卷 154478页

作者： Ming-Yao Chen Chia-Hung Hsu Syahru Agung Setiawan david T W Tzeng Hon-Ping Ma Jiann Ruey Ong Yi Cheng Chu Ming-Shou Hsieh Alexander T H Wu Yew-Min Tzeng Chi-Tai Yeh Division of Gastroenterology and Hepatology Department of Internal Medicine School of Medicine College of Medicine Taipei Medical University Taipei City 110 Taiwan Division of Gastroenterology and Hepatology Department of Internal Medicine Taipei Medical University-Shuang Ho Hospital New Taipei City 235 Taiwan. Department of Emergency Medicine Taipei Medical University-Shuang Ho Hospital New Taipei City 235 Taiwan Graduate Institute of Injury Prevention and Control College of Public Health Taipei Medical University Taipei City 110 Taiwan Department of Emergency Medicine School of Medicine Taipei Medical University Taipei City 110 Taiwan. International Ph.D. Program in Medicine College of Medicine Taipei Medical University Taipei City 110 Taiwan Department of Medical Research & Education Taipei Medical University - Shuang-Ho Hospital New Taipei City 235 Taiwan. School of Life Sciences The Chinese University of Hong Kong Hong Kong SAR 999077 China Lifebit Mindspace Shoreditch London England EC2A 2AP UK. Department of Medicine St. George's University School of Medicine St. George Grenada. Department of Applied Science National Taitung University Taitung 95092 Taiwan. Electronic address: ymtzeng@nttu.edu.tw. Department of Medical Research & Education Taipei Medical University - Shuang-Ho Hospital New Taipei City 235 Taiwan Continuing Education Program of Food Biotechnology Applications College of Science and Engineering National Taitung University Taitung 95092 Taiwan. Electronic address: ctyeh@s.tmu.edu.tw.

Activation of mitogen-activated protein kinase (MAPK) and PI3K signaling confers resistance against sorafenib, a mainstay treatment for advanced hepatocellular carcinoma (HCC). Antrocin and ovatodiolide constitute as the most potent secondary metabolites isolated from Antrodia camphorata and Anisomeles indica, respectively. Both natural compounds have recently gained a lot of attention due to their putative inhibition of MAPK and PI3K signaling in various solid cancers. However, whether their combination is effective in HCC remains unknown. Here, we investigated their effect, alone or in various combinations, on MAPK and PI3K signaling pathways in HCC cells. An array of in vitro study were used to investigate anticancer and stemness effects to treat HCC, such as cytotoxicity, drug combination index, migration, invasion, colony formation, and tumor sphere formation. drug effect in vivo was evaluated using mouse xenograft models. In this study, antrocin and ovatodiolide synergistically inhibited the SNU387, Hep3B, Mahlavu, and Huh7 cell lines. Sequential combination treatment of Huh7 and Mahlavu with ovatodiolide followed by antrocin resulted stronger cytotoxic effect than did treatment with antrocin followed by ovatodiolide, their simultaneous administration, antrocin alone, or ovatodiolide alone. In the Huh7 and Mahlavu cell lines, ovatodiolide→antrocin significantly suppressed colony formation and proliferation as well as markedly downregulated ERK1/2, Akt, and mTOR expression. Inhibition of ERK1/2 and Akt/mTOR signaling by ovatodiolide→antrocin suppressed ribosomal biogenesis, autophagy, and cancer stem cell-like phenotypes and promoted apoptosis in Huh7 and Mahlavu cells. The sorafenib-resistant clone of Huh7 was effectively inhibited by synergistic combination of both compound in vitro. Eventually, the ovatodiolide→antrocin combination synergistically suppressed the growth of HCC xenografts. Taken together, our findings suggested that ovatodiolide→antrocin combi

关键词： Advanced HCC Antrocin (ANC) MAPK Ovatodiolide (OVA) PI3K

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Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

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Journal of experimental & clinical cancer research : CR 2023年第1期42卷 171页

作者： Ting-Wan Kao Geng-Hao Bai Tian-Li Wang Ie-Ming Shih Chi-Mu Chuang Chun-Liang Lo Meng-Chen Tsai Li-Yun Chiu Chu-Chien Lin Yao-An Shen Department of Pathology School of Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. Department of Internal Medicine National Taiwan University Hospital College of Medicine National Taiwan University Taipei City 100225 Taiwan. Departments of Pathology Oncology and Gynecology and Obstetrics Johns Hopkins Medical Institutions 1550 Orleans StreetRoom 306 Baltimore MD CRB221231 USA. Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA. Faculty of Medicine School of Medicine National Yang-Ming Chiao Tung University Taipei 112304 Taiwan. Department of Obstetrics and Gynecology Taipei Veterans General Hospital Taipei 112201 Taiwan. Department of Midwifery and Women Health Care National Taipei University of Nursing and Health Sciences Taipei 112303 Taiwan. Department of Biomedical Engineering National Yang-Ming Chiao Tung University Taipei 112304 Taiwan. Medical Device Innovation and Translation Center National Yang Ming Chiao Tung University Taipei 112304 Taiwan. Department of General Medicine Taipei Medical University Hospital Taipei 110301 Taiwan. Department of General Medicine Mackay Memorial Hospital Taipei 104217 Taiwan. School of Medicine College of Medicine Taipei Medical University Taipei City 110301 Taiwan. Department of Pathology School of Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. shen1202@tmu.edu.tw. Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. shen1202@tmu.edu.tw. International Master/Ph.D. Program in Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. shen1202@tmu.edu.tw.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

关键词： Chemotherapy Combination therapy HIF-1 HIF-2 Hypoxia Immunotherapy Metabolic therapy Radiotherapy Target therapy Therapeutic resistance

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Tfe Solberg Award

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Naval Engineers Journal 2009年第5期112卷

作者： dr. Roy L. Streit Since 1992 Dr. Streit has focused a significant amount of his energy to assignment problems in acoustic warfare data fusion systems. This work led him to the formulation of the PDD Principle a broadly useful theoretical method that enables the derivation of new classes of discrete-continuous estimation algorithms for solving assignment problems without requiring enumeration and pruning. In recognition of his outstanding work in this area Dr. Streit received the NAVSEA Scientist of the Year Award for 1997. Dr. Streit has also been pursuing avenues for analyzing the loss in broadband detection performance of an acoustic array in the presence of interferences. Because examining all possible separations between the signal and many interferers is infeasible he has proposed a Poisson process model for the number and location (s) of the interferers. In this same time period Dr. Streit has also been investigating issues in environmental modeling and localization by proposing a novel integral method for solving the bearings-only target motion analysis problem which enables a natural heuristic for compensating for mismatch between the model predictions and the real world. Most recently Dr. Streit has proposed the Numerical ACoustic Hull ARray (NACHAR) Project as a revolutionary and ambitious approach to hull array design. Its premise is that optimizing the detection capability of large hull arrays requires the full integration of hull sensor array and beamformer design processes. Because NACHAR crosses an unusual number of technical disciplines it involves researchers from several departments. The diversity of Dr. Streif s technical background makes him uniquely suited to lead the project Dr. Streifs truly impressive scientific achievements are complemented by a noteworthy list of professional activities that accentuate his value to Division Newport and the Navy. He represents the United States in The Technical Cooperation Program Maritime Activities Panel 9 (Sonar Technology) and participates in the Division New

for his significant engineering research and development in sonar array research and acoustic transient signals as set forth in the following

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Publisher Correction: Global estimates on the number of people blind or visually impaired by cataract: a meta-analysis from 2000 to 2020

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Eye (London, England) 2024年第11期38卷 2229-2231页

作者： Konrad Pesudovs Hugh R. Taylor Tabassom Sedighi Rupert R. A. Bourne Shahina Pardhan Van Charles Lansingh John H. Kempen Ian Tapply Arthur G. Fernandes Maria Vittoria Cicinelli Alessandro Arrigo Nicolas Leveziel Serge Resnikoff Seth Flaxman Mukkharram M. Bikbov Tasanee Braithwaite Alain Bron Ching-Yu Cheng Monte A. del Monte Joshua R. Ehrlich Leon B. Ellwein david Friedman João M. Furtado Gus Gazzard Ronnie George M. Elizabeth Hartnett Jost B. Jonas Rim Kahloun Moncef Khairallah Rohit C. Khanna Janet Leasher Julie-Anne Little Vinay Nangia Michal Nowak Tunde Peto Pradeep Ramulu Fotis Topouzis Mitiadis Tsilimbaris Ya Xing Wang Ningli Wang Paul Svitil Briant Theo Vos Katrin Burkart Kaleb Coberly Xiaochen dai Stephen S. Lim Tomislav Mestrovic Ali H. Mokdad Christopher J. L. Murray Jaimie d. Steinmetz Awoke Misganaw Yohannes Habtegiorgis Abate Mohammad Abdollahi Mozhan Abdollahi Ayele Mamo Abebe Olumide Abiodun Richard Gyan Aboagye Woldu Aberhe Abrha Hasan Abualruz Hiwa Abubaker Ali Eman Abu-Gharbieh Salahdein Aburuz Tadele Girum Girum Adal Mesafint Molla Adane Isaac Yeboah Addo Qorinah Estiningtyas Sakilah Adnani Muhammad Sohail Afzal Muhammad Umair Shahin Aghamiri Bright Opoku Ahinkorah Aqeel Ahmad Sajjad Ahmad Ali Ahmadi Siamak Sabour Ayman Ahmed Haroon Ahmed Ahmad Samir Alfaar Abid Ali Syed Shujait Shujait Ali Awais Altaf Hubert Amu Emmanuel Manu Sofia Androudi Rodrigo Anguita Abhishek Anil Rimple Jeet Kaur Muhammad Aaqib Shamim Saeid Anvari Anayochukwu Edward Anyasodor Francis Appiah Jalal Arabloo Haleh Ayatollahi Mosab Arafat damelash Areda Reza Arefnezhad Brhane Berhe Aregawi Akeza Awealom Asgedom Tahira Ashraf Seyyed Shamsadin Athari Bantalem Tilaye Tilaye Atinafu Birhan Tsegaw Taye Maha Moh’d Wahbi Atout Alok Atreya Ahmed Y. Azzam Hassan Babamohamadi Sara Bagherieh Yogesh Bahurupi Atif Amin Baig Shumaila Nargus Biswajit Banik Mainak Bardhan Saurav Basu Kavita Batra Nebiyou Simegnew Bayileyegn Fatemeh Bazvand Addisu Shunu Beyene Awoke Masrie Asrat derese devidas S. Bhagat Akshaya Srikanth Bhagavathula Pankaj Bh Medicine & Health University of New South Wales Sydney NSW Australia School of Optometry and Vision Science University of New South Wales Sydney NSW Australia School of Population and Global Health University of Melbourne Carlton VIC Australia Vision and Eye Research Institute Anglia Ruskin University Cambridge UK HelpMeSee Instituto Mexicano de Oftalmologia Santiago de Querétaro Mexico University of Miami Gables FL USA University of Utah Salt Lake City UT USA Chief Medical Office HelpMeSee New York NY USA Mexican Institute of Ophthalmology Queretaro Mexico Department of Ophthalmology Massachusetts Eye and Ear/Shepens Eye Research Institute/Harvard Medical School Boston MA USA Eye Unit MyungSung Christian Medical Center (MCM) Comprehensive Specialized Hospital and MyungSun Medical College Addis Ababa Ethiopia Department of Ophthalmology Addis Ababa University Addis Ababa Ethiopia Sight for Souls Bellevue WA USA Department of Ophthalmology Harvard University Boston MA USA Eye Unit MyungSung Medical College Addis Ababa Ethiopia Addenbrooke’s Hospital Cambridge UK Department of Ophthalmology Cambridge University Hospitals Cambridge UK Federal University of Sao Paolo Sao Paolo SP Brazil University of Calgary Calgary AB Canada Department of Ophthalmology and Visual Sciences Federal University of São Paulo Sao Paulo Brazil School of Medicine Vita-Salute San Raffaele University Milan Italy Department of Ophthalmology IRCCS San Raffaele Scientific Institute Milan Italy Department of Ophthalmology San Raffaele Scientific Institute Milano Italy IRCCS San Raffaele Scientific Institute Vita-Salute University Milan Italy Scientific Institute San Raffaele Hospital Vita-Salute University Milan Italy University of Poitiers Poitiers France CHU de Poitiers Poitiers France Ophthalmology Department CHU de Poitiers (Poitiers University Hospital) Poitiers France Unité 1084 National Institute of Health and Medical Research (INSERM) Poitiers France

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Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women

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Genomics 2020年第2期112卷 1223-1232页

作者： Jason Y Y Wong Han Zhang Chao A Hsiung Kouya Shiraishi Kai Yu Keitaro Matsuo Maria Pik Wong Yun-Chul Hong Jiucun Wang Wei Jie Seow Zhaoming Wang Minsun Song Hee Nam Kim I-Shou Chang Nilanjan Chatterjee Wei Hu Chen Wu Tetsuya Mitsudomi Wei Zheng Jin Hee Kim Adeline Seow Neil E Caporaso Min-Ho Shin Lap Ping Chung She-Juan An Ping Wang Yang Yang Hong Zheng Yasushi Yatabe Xu-Chao Zhang Young Tae Kim Qiuyin Cai Zhihua Yin Young-Chul Kim Bryan A Bassig Jiang Chang James Chung Man Ho Bu-Tian Ji Yataro daigo Hidemi Ito Yukihide Momozawa Kyota Ashikawa Yoichiro Kamatani Takayuki Honda H dean Hosgood Hiromi Sakamoto Hideo Kunitoh Koji Tsuta Shun-Ichi Watanabe Michiaki Kubo Yohei Miyagi Haruhiko Nakayama Shingo Matsumoto Masahiro Tsuboi Koichi Goto Jianxin Shi Lei Song Xing Hua Atsushi Takahashi Akiteru Goto Yoshihiro Minamiya Kimihiro Shimizu Kazumi Tanaka Fusheng Wei Fumihiko Matsuda Jian Su Yeul Hong Kim In-Jae Oh Fengju Song Wu-Chou Su Yu-Min Chen Gee-Chen Chang Kuan-Yu Chen Ming-Shyan Huang Li-Hsin Chien Yong-Bing Xiang Jae Yong Park Sun-Seog Kweon Chien-Jen Chen Kyoung-Mu Lee Batel Blechter Haixin Li Yu-Tang Gao Biyun Qian daru Lu Jianjun Liu Hyo-Sung Jeon Chin-Fu Hsiao Jae Sook Sung Ying-Huang Tsai Yoo Jin Jung Huan Guo Zhibin Hu Wen-Chang Wang Charles C Chung Laurie Burdett Meredith Yeager Amy Hutchinson Sonja I Berndt Wei Wu Herbert Pang Yuqing Li Jin Eun Choi Kyong Hwa Park Sook Whan Sung Li Liu C H Kang Meng Zhu Chung-Hsing Chen Tsung-Ying Yang Jun Xu Peng Guan Wen Tan Chih-Liang Wang Michael Hsin Ko-Yung Sit James Ho Ying Chen Yi Young Choi Jen-Yu Hung Jun Suk Kim Ho Il Yoon Chien-Chung Lin In Kyu Park Ping Xu Yuzhuo Wang Qincheng He Reury-Perng Perng Chih-Yi Chen Roel Vermeulen Junjie Wu Wei-Yen Lim Kun-Chieh Chen Yao-Jen Li Jihua Li Hongyan Chen Chong-Jen Yu Li Jin Tzu-Yu Chen Shih-Sheng Jiang Jie Liu Taiki Yamaji Belynda Hicks Kathleen Wyatt Shengchao A Li Juncheng dai Hongxia Ma Guangfu Jin Bao Song Zhehai Wang Sensen Cheng Xuelian Li Yangwu Ren Ping Cui Motoki Iwasaki Taichi Shimazu Shoichiro Tsugane Junjie Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA. Electronic address: jason.wong@nih.gov. Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA. Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan. Division of Genome Biology National Cancer Center Research Institute Tokyo Japan. Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan Department of Cancer Epidemiology Nagoya University Graduate School of Medicine Nagoya Japan. Department of Pathology Queen Mary Hospital The University of Hong Kong Hong Kong. Department of Preventive Medicine Seoul National University College of Medicine Seoul Republic of Korea. Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences Fudan University Shanghai China State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University Shanghai China. Saw Swee Hock School of Public Health National University of Singapore Singapore. Cancer Genomics Research Laboratory Leidos Biomedical Research Inc Gaithersburg MD USA Department of Computational Biology St. Jude Children's Research Hospital Memphis TN USA. Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA Department of Statistics Sookmyung Women's University Seoul Republic of Korea. Department of Preventive Medicine Chonnam National University Medical School Gwangju Republic of Korea. National Institute of Cancer Research National Health Research Institutes Zhunan Taiwan. Bloomberg School of Public Health Johns Hopkins University Baltimore MD USA. Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology Cancer Institute and Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. Division of Thoracic Surgery Kinki University School of Medicine Sayama Japan. Division of

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

关键词： Lung adenocarcinoma Lung cancer Mendelian randomization Pathway analysis Tuberculosis

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Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations

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Human molecular genetics 2017年第2期26卷 454-465页

作者： Wei Jie Seow Keitaro Matsuo Chao Agnes Hsiung Kouya Shiraishi Minsun Song Hee Nam Kim Maria Pik Wong Yun-Chul Hong H dean Hosgood Zhaoming Wang I-Shou Chang Jiu-Cun Wang Nilanjan Chatterjee Margaret Tucker Hu Wei Tetsuya Mitsudomi Wei Zheng Jin Hee Kim Baosen Zhou Neil E Caporaso demetrius Albanes Min-Ho Shin Lap Ping Chung She-Juan An Ping Wang Hong Zheng Yasushi Yatabe Xu-Chao Zhang Young Tae Kim Xiao-Ou Shu Young-Chul Kim Bryan A Bassig Jiang Chang James Chung Man Ho Bu-Tian Ji Michiaki Kubo Yataro daigo Hidemi Ito Yukihide Momozawa Kyota Ashikawa Yoichiro Kamatani Takayuki Honda Hiromi Sakamoto Hideo Kunitoh Koji Tsuta Shun-Ichi Watanabe Hiroshi Nokihara Yohei Miyagi Haruhiko Nakayama Shingo Matsumoto Masahiro Tsuboi Koichi Goto Zhihua Yin Jianxin Shi Atsushi Takahashi Akiteru Goto Yoshihiro Minamiya Kimihiro Shimizu Kazumi Tanaka Tangchun Wu Fusheng Wei Jason Y Y Wong Fumihiko Matsuda Jian Su Yeul Hong Kim In-Jae Oh Fengju Song Victor Ho Fun Lee Wu-Chou Su Yuh-Min Chen Gee-Chen Chang Kuan-Yu Chen Ming-Shyan Huang Pan-Chyr Yang Hsien-Chih Lin Yong-Bing Xiang Adeline Seow Jae Yong Park Sun-Seog Kweon Chien-Jen Chen Haixin Li Yu-Tang Gao Chen Wu Biyun Qian daru Lu Jianjun Liu Hyo-Sung Jeon Chin-Fu Hsiao Jae Sook Sung Ying-Huang Tsai Yoo Jin Jung Huan Guo Zhibin Hu Wen-Chang Wang Charles C Chung Charles Lawrence Laurie Burdett Meredith Yeager Kevin B Jacobs Amy Hutchinson Sonja I Berndt Xingzhou He Wei Wu Junwen Wang Yuqing Li Jin Eun Choi Kyong Hwa Park Sook Whan Sung Li Liu Chang Hyun Kang Lingmin Hu Chung-Hsing Chen Tsung-Ying Yang Jun Xu Peng Guan Wen Tan Chih-Liang Wang Alan dart Loon Sihoe Ying Chen Yi Young Choi Jen-Yu Hung Jun Suk Kim Ho-Il Yoon Qiuyin Cai Chien-Chung Lin In Kyu Park Ping Xu Jing dong Christopher Kim Qincheng He Reury-Perng Perng Chih-Yi Chen Roel Vermeulen Junjie Wu Wei-Yen Lim Kun-Chieh Chen John K C Chan Minjie Chu Yao-Jen Li Jihua Li Hongyan Chen Chong-Jen Yu Li Jin Yen-Li Lo Ying-Hsiang Chen Joseph F Fraumeni Jie Liu Taiki Yamaji Yang Yang Belynda Hicks Kathleen Wyatt Shengchao A Li Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA. Saw Swee Hock School of Public Health National University of Singapore and National University Health System Singapore. Division of Molecular Medicine Aichi Cancer Center Research Institute Nagoya Japan. Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan. Division of Genome Biology National Cancer Center Research Institute Tokyo Japan. Department of Statistics Sookmyung Women's University Seoul Republic of Korea. Department of Preventive Medicine Chonnam National University Medical School Gwangju Republic of Korea. Department of Pathology The University of Hong Kong Queen Mary Hospital Hong Kong. Department of Preventive Medicine Seoul National University College of Medicine Seoul Republic of Korea. Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx NY USA. Department of Computational Biology St. Jude Children's Research Hospital Memphis TN 38105 USA. National Institute of Cancer Research National Health Research Institutes Zhunan Taiwan. Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences Fudan University Shanghai People's Republic of China. State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University Shanghai People's Republic of China. Division of Thoracic Surgery Kinki University School of Medicine Sayama Japan. Division of Epidemiology Department of Medicine Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center Nashville TN USA. Department of Integrative Bioscience & Biotechnology Sejong University Seoul Republic of Korea. Department of Epidemiology School of Public Health China Medical University Shenyang People's Republic of China. Guangdong Lung Cancer Institute Medical Research Center and Cancer Center of Guangdong General Hospital Guangdong Academy of Medical Sciences Guangzhou People's Republic

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/dCBLd1) and rs2179920 (HLA-dPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.

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Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

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Nature communications 2023年第1期14卷 3043页

作者： Jianxin Shi Kouya Shiraishi Jiyeon Choi Keitaro Matsuo Tzu-Yu Chen Juncheng dai Rayjean J Hung Kexin Chen Xiao-Ou Shu Young Tae Kim Maria Teresa Landi dongxin Lin Wei Zheng Zhihua Yin Baosen Zhou Bao Song Jiucun Wang Wei Jie Seow Lei Song I-Shou Chang Wei Hu Li-Hsin Chien Qiuyin Cai Yun-Chul Hong Hee Nam Kim Yi-Long Wu Maria Pik Wong Brian douglas Richardson Karen M Funderburk Shilan Li Tongwu Zhang Charles Breeze Zhaoming Wang Batel Blechter Bryan A Bassig Jin Hee Kim demetrius Albanes Jason Y Y Wong Min-Ho Shin Lap Ping Chung Yang Yang She-Juan An Hong Zheng Yasushi Yatabe Xu-Chao Zhang Young-Chul Kim Neil E Caporaso Jiang Chang James Chung Man Ho Michiaki Kubo Yataro daigo Minsun Song Yukihide Momozawa Yoichiro Kamatani Masashi Kobayashi Kenichi Okubo Takayuki Honda dean H Hosgood Hideo Kunitoh Harsh Patel Shun-Ichi Watanabe Yohei Miyagi Haruhiko Nakayama Shingo Matsumoto Hidehito Horinouchi Masahiro Tsuboi Ryuji Hamamoto Koichi Goto Yuichiro Ohe Atsushi Takahashi Akiteru Goto Yoshihiro Minamiya Megumi Hara Yuichiro Nishida Kenji Takeuchi Kenji Wakai Koichi Matsuda Yoshinori Murakami Kimihiro Shimizu Hiroyuki Suzuki Motonobu Saito Yoichi Ohtaki Kazumi Tanaka Tangchun Wu Fusheng Wei Hongji dai Mitchell J Machiela Jian Su Yeul Hong Kim In-Jae Oh Victor Ho Fun Lee Gee-Chen Chang Ying-Huang Tsai Kuan-Yu Chen Ming-Shyan Huang Wu-Chou Su Yuh-Min Chen Adeline Seow Jae Yong Park Sun-Seog Kweon Kun-Chieh Chen Yu-Tang Gao Biyun Qian Chen Wu daru Lu Jianjun Liu Ann G Schwartz Richard Houlston Margaret R Spitz Ivan P Gorlov Xifeng Wu Ping Yang Stephen Lam Adonina Tardon Chu Chen Stig E Bojesen Mattias Johansson Angela Risch Heike Bickeböller Bu-Tian Ji H-Erich Wichmann david C Christiani Gadi Rennert Susanne Arnold Paul Brennan James McKay John K Field Sanjay S Shete Loic Le Marchand Geoffrey Liu Angeline Andrew Lambertus A Kiemeney Shan Zienolddiny-Narui Kjell Grankvist Mikael Johansson Angela Cox Fiona Taylor Jian-Min Yuan philip Lazarus Matthew B Schabath Melinda C Aldrich Hyo-Sung Jeon Shih Sheng Jiang Jae Sook Sung C Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. jianxin.shi@nih.gov. Division of Genome Biology National Cancer Research Institute Tokyo Japan. Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan. Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Medicine Nanjing Medical University Nanjing China. Prosserman Centre for Population Health Research Lunenfeld-Tanenbaum Research Institute Sinai Health Toronto ON Canada. Department of Epidemiology and Biostatistics National Clinical Research Center for Cancer Key Laboratory of Molecular Cancer Epidemiology of Tianjin Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University Tianjin China. Division of Epidemiology Department of Medicine Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center Nashville TN USA. Cancer Research Institute Seoul National University College of Medicine Seoul Republic of Korea. Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology Cancer Institute and Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. Department of Epidemiology School of Public Health China Medical University Shenyang China. Department of Clinical Epidemiology and Center of Evidence Based Medicine The First Hospital of China Medical University Shenyang China. Department of Oncology Shandong Cancer Hospital and Institute Shandong Academy of Medical Sciences Jinan China. Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences Fudan University Shanghai China. S

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FAdS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

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