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The evolution of cancer genomic medicine in Japan and the role of the National cancer center Japan

cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National cancer center research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National cancer center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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Genomic medicine in clinical practice:national genomic medicine program in Japan

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cancer Biology & Medicine 2024年第1期21卷 4-9页

cancer statistics in Japan cancer is the most common cause of death in Japan based on Statistics 2021~*** statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have been the main causes of death in *** surpassed cerebrovascular disease as the main cause of death in 1981,and the number of cancer deaths has *** 38,000 people died of cancer in *** National cancer center(NCC)reported that the 5-year survival rate for patients with cancer was improving(62%for males and 66.9%for females)in a population-based cancer registry.

关键词： cancer cancer death

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Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer

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World Journal of Gastrointestinal Surgery 2024年第5期16卷 1395-1406页

作者： Qiu-Xiao Yu Ping-Ying Fu Chi Zhang Li Li Wen-Ting Huang Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen 518116Guangdong ProvinceChina

BACKGROUND Colorectal cancer(CRC)is the third most common cancer and the second most common cause of cancer-related mortality ***-epithelial transition factor(MET)gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor *** amplification has been reported in CRC,but data are very *** pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical *** To determine the pathological significance of MET amplification in CRC and to propose a feasible screening *** A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen cancer Hospital of Chinese Academy of Medical Sciences were *** patients were without RAS/RAF mutation or microsatellite *** amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization(FISH)and immunohistochemistry(IHC),*** between MET aberration and pathological features were detected using the chi-squared *** free survival(PFS)during the two-year follow-up was detected using the Kaplan-Meier method and log rank *** results of MET FISH and IHC were com pared using one-way *** Polysomy-induced MET amplification was observed in 14.4%of cases,and focal MET amplification was not ***-induced MET amplification was associated with a higher frequency of lymph node metastasis(LNM)(P<0.001)and higher tumor budding grade(P=0.02).In the survival analysis,significant difference was detected between patients with amplified-and non-amplified MET in a two-year follow-up after the first diagnosis(P=0.001).C-MET scores of 0,1+,2+,and 3+were observed in 1.4%,24.9%,54.7%,and 19.0%of tumors,respectively.C-MET overexpression correlated with higher frequency of LNM(P=0.002),but no significant difference of PFS was dete

关键词： Colorectal cancer MET Amplification Pathological features Prognosis Fluorescence in situ hybridization

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The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major genetic Risk Factor for Colorectal cancer with Heterogeneous Clinical Phenotypes

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research 2024年第3期6卷 191-203页

作者： Yun Xu Kai Liu Cong Li Minghan Li Fangqi Liu Xiaoyan Zhou Menghong Sun Megha Ranganathan Liying Zhang Sheng Wang Xin Hu Ye Xu Department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of Pathology Fudan University Shanghai Cancer CenterShanghaiP.R.China Department of Pathology Tissue BankFudan University Shanghai Cancer CenterShanghaiP.R.China Department of Medicine Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of Pathology and Laboratory Medicine David Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA Precision cancer Medical center Fudan University Shanghai Cancer CenterShanghaiP.R.China

While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk.

关键词： susceptibility category Major

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan University Shanghai cancer center&Institutes of Biomedical Sciences/State Key Laboratory of genetic Engineering/cancer Institutes/Department of Oncology/Key Laboratory of Breast cancer in Shanghai/Shanghai Key Laboratory of Medical Epigenetics/Shanghai Key Laboratory of Radiation Oncology/International Co-laboratory of Medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis cancer stem cell Ecosystem Tumor microenvironment Mouse model

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Modeling human gastric cancers in immunocompetent mice

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cancer Biology & Medicine 2024年第7期21卷 553-570页

作者： Weihong Zhang Shilong Wang Hui Zhang Yan Meng Shi Jiao Liwei An Zhaocai Zhou Department of Stomatology Department of Medical UltrasoundShanghai Tenth People's HospitalTongji University Cancer CenterTongji University School of MedicineShanghai 200072China State Key Laboratory of genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China Collaborative Innovation center for cancer Personalized Medicine School of Public HealthNanjing Medical UniversityNanjing 211166China

Gastric cancer(GC)is a major cause of cancer-related mortality *** is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular *** heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient *** the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and *** mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic ***,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.

关键词： Gastric cancer heterogeneity mouse model GEMM immunocompetent

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Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

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cancer Communications 2024年第2期44卷 287-293页

作者： Kouya Shiraishi Atsushi Takahashi Yukihide Momozawa Yataro Daigo Syuzo Kaneko Takahisa Kawaguchi Hideo Kunitoh Shingo Matsumoto Hidehito Horinouchi Akiteru Goto Takayuki Honda Kimihiro Shimizu Masahiro Torasawa Daisuke Takayanagi Motonobu Saito Akira Saito Yuichiro Ohe Shun-ichi Watanabe Koichi Goto Masahiro Tsuboi Katsuya Tsuchihara Sadaaki Takata Tomomi Aoi Atsushi Takano Masashi Kobayashi Yohei Miyagi Kazumi Tanaka Hiroyuki Suzuki Daichi Maeda Takumi Yamaura Maiko Matsuda Yoko Shimada Takaaki Mizuno Hiromi Sakamoto Teruhiko Yoshida Yasushi Goto Tatsuya Yoshida Taiki Yamaji Makoto Sonobe Shinichi Toyooka Kazue Yoneda Katsuhiro Masago Fumihiro Tanaka Megumi Hara Nobuo Fuse Satoshi S.Nishizuka Noriko Motoi Norie Sawada Yuichiro Nishida Kazuki Kumada Kenji Takeuchi Kozo Tanno Yasushi Yatabe Kuniko Sunami Tomoyuki Hishida Yasunari Miyazaki Hidemi Ito Mitsuhiro Amemiya Hirohiko Totsuka Haruhiko Nakayama Tomoyuki Yokose Kazuyoshi Ishigaki Toshiteru Nagashima Yoichi Ohtaki Kazuhiro Imai Ken Takasawa Yoshihiro Minamiya Kazuma Kobayashi Kenichi Okubo Kenji Wakai Atsushi Shimizu Masayuki Yamamoto Motoki Iwasaki Koichi Matsuda Johji Inazawa Yuichi Shiraishi Hiroyoshi Nishikawa Yoshinori Murakami Michiaki Kubo Fumihiko Matsuda Yoichiro Kamatani Ryuji Hamamoto Keitaro Matsuo Takashi Kohno Division of Genome Biology National Cancer Center Research InstituteTokyoJapan Department of Clinical Genomics National Cancer Center Research InstituteTokyoJapan Laboratory for Statistical Analysis Center for Integrative Medical SciencesRIKENYokohamaJapan Department of Genomic Medicine Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan Laboratory for Genotyping Development Center for Integrative Medical SciencesRIKENYokohamaJapan center for Antibody and Vaccine Therapy Research HospitalInstitute of Medical ScienceThe University of TokyoTokyoJapan Department of Medical Oncology and cancer center and Center for Advanced Medicine against CancerShiga University of Medical ScienceOtsuJapan Division of Medical AI research and Development National Cancer Center Research InstituteTokyoJapan center for Genomic Medicine Graduate School of MedicineKyoto UniversityKyotoJapan Department of Medical Oncology Japanese Red Cross Medical CenterTokyoJapan Department of Thoracic Oncology National Cancer Center Hospital EastJapan Department of Thoracic Oncology National Cancer Center HospitalTokyoJapan Department of Cellular and Organ Pathology Graduate School of MedicineAkita UniversityAkitaJapan Department of Respiratory Medicine Tokyo Medical and Dental UniversityBunkyo-kuTokyoJapan Division of General Thoracic Surgery Department of SurgeryShinshu University School of MedicineMatsumotoNaganoJapan Department of General Surgical Science Division of General Thoracic SurgeryGunma University Graduate School of MedicineIntegrative Center of General SurgeryGunma University HospitalGunmaJapan Department of Gastrointestinal Tract Surgery Fukushima Medical University School of MedicineFukushimaJapan StaGen Co. LtdTokyoJapan Division of Thoracic Surgery National Cancer Center HospitalTokyoJapan Department of Thoracic Surgery National Cancer Center Hospital EastChibaJapan Division of Translational Informatics Exploratory Oncology Research and Clinical Trial Center(EPOC

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

关键词： adenocarcinoma lung Lung

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Small-molecule agents for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 905-952页

作者： Fang Wang Kai Fu Yujue Wang Can Pan Xueping Wang Zeyu Liu Chuan Yang Ying Zheng Xiaopeng Li Yu Lu Kenneth Kin Wah To Chenglai Xia Jianye Zhang Zhi Shi Zeping Hu Min Huang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmaceutical Sciences Tsinghua-Peking Center for Life SciencesBeijing Frontier Research Center for Biological StructureTsinghua UniversityBeijing 100084China State Key Laboratory of Drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China School of Pharmacy The Chinese University of Hong KongHong Kong 999077China Affiliated Foshan Maternity and Child Healthcare Hospital Southern Medical UniversityFoshan 528000China

cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer *** induce long-term tumor regression and overall survival benefit in many types of *** the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for *** molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively *** of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor ***,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

关键词： cancer immunotherapy Small-molecule agents Immune checkpoints Oncogenic signaling Metabolic pathways Cytokine/chemokine signaling Antitumor immunity Tumor immune microenvironment

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Effectiveness of colorectal cancer screening integrating non-genetic and genetic risk: a prospective study based on UK Biobank data

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cancer Biology & Medicine 2024年第8期21卷 712-723页

作者： Yu Zhang Chao Sheng Zhangyan Lyu Hongji Dai Fangfang Song Fengju Song Yubei Huang Kexin Chen Department of Epidemiology and Biostatistics Key Laboratory of Molecular Cancer EpidemiologyKey Laboratory of Prevention and Control of Human Major DiseasesMinistry of EducationNational Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjin Medical UniversityTianjin 300060China

Objective: Few studies have evaluated the benefits of colorectal cancer(CRC) screening integrating both non-genetic and genetic risk factors. Here, we aimed to integrate an existing non-genetic risk model(Qcancer-10) and a 139-variant polygenic risk score to evaluate the effectiveness of screening on CRC incidence and ***: We applied the integrated model to calculate 10-year CRC risk for 430,908 participants in the UK Biobank, and divided the participants into low-, intermediate-, and high-risk groups. We calculated the screening-associated hazard ratios(HRs) and absolute risk reductions(ARRs) for CRC incidence and mortality according to risk ***: During a median follow-up of 11.03 years and 12.60 years, we observed 5,158 CRC cases and 1,487 CRC deaths, respectively. CRC incidence and mortality were significantly lower among screened than non-screened participants in both the intermediateand high-risk groups [incidence: HR: 0.87, 95% confidence interval(CI): 0.81±0.94;0.81, 0.73±0.90;mortality: 0.75, 0.64±0.87;0.70, 0.58±0.85], which composed approximately 60% of the study population. The ARRs(95% CI) were 0.17(0.11±0.24) and 0.43(0.24±0.61), respectively, for CRC incidence, and 0.08(0.05±0.11) and 0.24(0.15±0.33), respectively, for mortality. Screening did not significantly reduce the relative or absolute risk of CRC incidence and mortality in the low-risk group. Further analysis revealed that screening was most effective for men and individuals with distal CRC among the intermediate to high-risk ***: After integrating both genetic and non-genetic factors, our findings provided priority evidence of risk-stratified CRC screening and valuable insights for the rational allocation of health resources.

关键词： Colorectal cancer screening polygenic risk score incidence mortality

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Tumor initiation and early tumorigenesis:molecular mechanisms and interventional targets

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2900-2935页

作者： Shaosen Zhang Xinyi Xiao Yonglin Yi Xinyu Wang Lingxuan Zhu Yanrong Shen Dongxin Lin Chen Wu Department of Etiology and Carcinogenesis National Cancer Center/National Clinical Research Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021 BeijingChina Key Laboratory of cancer Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical College100021 BeijingChina Changping Laboratory 100021 BeijingChina Collaborative Innovation center for cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China Sun Yat-sen University cancer center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China CAMS Oxford Institute Chinese Academy of Medical Sciences100006 BeijingChina

Tumorigenesis is a multistep process,with oncogenic mutations in a normal cell conferring clonal advantage as the initial ***,despite pervasive somatic mutations and clonal expansion in normal tissues,their transformation into cancer remains a rare event,indicating the presence of additional driver events for progression to an irreversible,highly heterogeneous,and invasive ***,researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution,independently of inducing ***,clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into ***,the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully *** this review,we summarize the genetic,epigenetic,and external driver events,and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution.A deeper understanding of the earliest molecular events holds promise for translational applications,predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

关键词： alterations mechanisms restrain

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