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Hu K, Shi A, Shu Y, Sudesh S, Ling J, Chen Y, Hua F, Yu S, Zhang J, Yu P. Novel Identification of CD74 as a Biomarker for Diagnosing and Prognosing Sepsis Patients. J Inflamm Res 2025; 18:3829-3842. [PMID: 40115322 PMCID: PMC11922779 DOI: 10.2147/jir.s509089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/04/2025] [Indexed: 03/23/2025] Open
Abstract
Purpose Sepsis, a life-threatening inflammatory condition due to an imbalanced response to infections, has been a major concern. Necroptosis, a newly discovered programmed cell death form, plays a crucial role in various inflammatory diseases. Our study aims to identify necroptosis - related genes (NRGs) and explore their potential for sepsis diagnosis. Patients and methods We used weighted gene co-expression network analysis to identify gene modules associated with sepsis. Cox regression and Kaplan-Meier methods were employed to assess the diagnostic and prognostic value of these genes. Single-cell and immune infiltration analyses were carried out to explore the immune environment in sepsis. Plasma CD74 protein levels were quantified in our samples, and relevant clinical data from electronic patient records were analyzed for correlation. Results CD74 was identified through the intersection of the hub genes of sepsis and NRGs related modules. Septic patients had lower CD74 expression compared to healthy controls. The CD74-based diagnostic model showed better performance in the training dataset (AUC, 0.79 [95% CI, 0.75-0.84]), was cross-validated in external datasets, and demonstrated better performances than other published diagnostic models. Pathway analysis and single-cell profiling supported further exploration of CD74-related inflammation and immune response in sepsis. Conclusion This study presents the first quantitative assessment of human plasma CD74 in sepsis patients. CD74 levels were significantly lower in the sepsis cohort. CD74 warrants further exploration as a potential prognostic and therapeutic target for sepsis.
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Affiliation(s)
- Kaibo Hu
- Department of Endocrinology and Metabolism, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
- The second Clinical Medical College, Nanchang University, Nanchang, People's Republic of China
| | - Ao Shi
- Faculty of Medicine, St George's University of London, London, UK
| | - Yuan Shu
- Department of Endocrinology and Metabolism, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
- The second Clinical Medical College, Nanchang University, Nanchang, People's Republic of China
| | - Shivon Sudesh
- Faculty of Medicine, St George's University of London, London, UK
| | - Jitao Ling
- Department of Endocrinology and Metabolism, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
- The second Clinical Medical College, Nanchang University, Nanchang, People's Republic of China
| | - Yixuan Chen
- The second Clinical Medical College, Nanchang University, Nanchang, People's Republic of China
- Department of Anesthesiology, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Fuzhou Hua
- Department of Anesthesiology, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Shuchun Yu
- Department of Anesthesiology, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Jing Zhang
- Department of Anesthesiology, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
| | - Peng Yu
- Department of Endocrinology and Metabolism, second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
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Alves de Souza G, Dornellas DMS, Campregher PV, Teixeira CHA, Schvartsman G. Complete response to capmatinib in a patient with metastatic lung adenocarcinoma harboring CD47-MET fusion: a case report. Oncologist 2024; 29:764-767. [PMID: 38832711 PMCID: PMC11379643 DOI: 10.1093/oncolo/oyae106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/17/2024] [Indexed: 06/05/2024] Open
Abstract
Comprehensive genomic profiling is highly recommended for treatment decision in nonsquamous, non-small cell lung cancer (NSCLC). However, rare genomic alterations are still being unveiled, with scarce data to guide therapy. Herein, we describe the treatment journey of a 56-year-old, never-smoker Caucasian woman with a metastatic NSCLC harboring a CD47-MET fusion, initially classified as a variant of unknown significance. She had undergone 3 lines of therapy over the course of 3 years, including chemotherapy, immunotherapy, and anti-angiogenic therapy. After reanalysis of her next-generation sequencing data in our service, the fusion was reclassified as likely oncogenic. The patient was started with fourth-line capmatinib, with a good tolerance so far and a complete metabolic response in the active sites of disease, currently ongoing for 18 months. In conclusion, we highlight the sensitivity of a novel MET fusion to capmatinib and emphasize the need for comprehensive panels in NSCLC and molecular tumor board discussions with specialized centers when rare findings arise.
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Centonza A, Mazza T, Trombetta D, Sparaneo A, Petrizzelli F, Castellana S, Centra F, Fabrizio FP, Di Micco CM, Benso F, Tabbò F, Righi L, Merlini A, Graziano P, Muscarella LA. Clinical and Molecular Traits of a Novel SPECC1L-ALK Fusion in a Patient with Advanced Non-Small Cell Lung Cancer. J Pers Med 2024; 14:670. [PMID: 39063924 PMCID: PMC11278239 DOI: 10.3390/jpm14070670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 07/28/2024] Open
Abstract
Anaplastic lymphoma kinase (ALK) fusions account for 5-7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel ALK gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments.
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Affiliation(s)
- Antonella Centonza
- Unit of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (A.C.); (C.M.D.M.)
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (T.M.); (F.P.)
| | - Domenico Trombetta
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.T.); (A.S.); (F.C.); (F.P.F.)
| | - Angelo Sparaneo
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.T.); (A.S.); (F.C.); (F.P.F.)
| | - Francesco Petrizzelli
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (T.M.); (F.P.)
| | - Stefano Castellana
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (T.M.); (F.P.)
| | - Flavia Centra
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.T.); (A.S.); (F.C.); (F.P.F.)
| | - Federico Pio Fabrizio
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.T.); (A.S.); (F.C.); (F.P.F.)
| | - Concetta Martina Di Micco
- Unit of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (A.C.); (C.M.D.M.)
| | - Federica Benso
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, TO, Italy; (F.B.); (L.R.); (A.M.)
| | - Fabrizio Tabbò
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, TO, Italy; (F.B.); (L.R.); (A.M.)
- SOC Oncologia ASLCN2 Alba e Bra, Ospedale Michele e Pietro Ferrero, 12060 Verduno, CN, Italy
| | - Luisella Righi
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, TO, Italy; (F.B.); (L.R.); (A.M.)
| | - Alessandra Merlini
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, TO, Italy; (F.B.); (L.R.); (A.M.)
| | - Paolo Graziano
- Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy;
| | - Lucia Anna Muscarella
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.T.); (A.S.); (F.C.); (F.P.F.)
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Li H, Xu L, Cao H, Wang T, Yang S, Tong Y, Wang L, Liu Q. Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer. Front Oncol 2024; 14:1405380. [PMID: 38957319 PMCID: PMC11217482 DOI: 10.3389/fonc.2024.1405380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/06/2024] [Indexed: 07/04/2024] Open
Abstract
Lung cancer persistently leads as the primary cause of morbidity and mortality among malignancies. A notable increase in the prevalence of lung adenocarcinoma has become evident in recent years. Although targeted therapies have shown in treating certain subsets of non-small cell lung cancers (NSCLC), a significant proportion of patients still face suboptimal therapeutic outcomes. Neuregulin-1 (NRG1), a critical member of the NRG gene family, initially drew interest due to its distribution within the nascent ventricular endocardium, showcasing an exclusive presence in the endocardium and myocardial microvessels. Recent research has highlighted NRG1's pivotal role in the genesis and progression across a spectrum of tumors, influencing molecular perturbations across various tumor-associated signaling pathways. This review provides a concise overview of NRG1, including its expression patterns, configuration, and fusion partners. Additionally, we explore the unique features and potential therapeutic strategies for NRG1 fusion-positive occurrences within the context of NSCLC.
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Affiliation(s)
- Hongyan Li
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Lina Xu
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Hongshun Cao
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Tianyi Wang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Siwen Yang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Yixin Tong
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Linlin Wang
- Department of Thoracic Surgery, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
| | - Qiang Liu
- Oncology Department of Integrated Traditional Chinese and Western Medicine, Shenyang Chest Hospital & Tenth People’s Hospital, Shenyang, Liaoning, China
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Zacharias M, Konjic S, Kratochwill N, Absenger G, Terbuch A, Jost PJ, Wurm R, Lindenmann J, Kashofer K, Gollowitsch F, Gorkiewicz G, Brcic L. Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology. Cancers (Basel) 2024; 16:903. [PMID: 38473263 DOI: 10.3390/cancers16050903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 02/19/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.
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Affiliation(s)
- Martin Zacharias
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Selma Konjic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Nikolaus Kratochwill
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Gudrun Absenger
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Angelika Terbuch
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Philipp J Jost
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Robert Wurm
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Jörg Lindenmann
- Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, 8010 Graz, Austria
| | - Karl Kashofer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Franz Gollowitsch
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Gregor Gorkiewicz
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Luka Brcic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
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Zhang N, Li Y. Receptor tyrosine kinases: biological functions and anticancer targeted therapy. MedComm (Beijing) 2023; 4:e446. [PMID: 38077251 PMCID: PMC10701465 DOI: 10.1002/mco2.446] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 10/16/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.
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Affiliation(s)
- Nan Zhang
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
- Department of Medical OncologyChongqing University Cancer HospitalChongqingChina
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Zhou Q, Zhao J, Chang J, Wang H, Fan Y, Wang K, Wu G, Nian W, Sun Y, Sun M, Wang X, Shi H, Zheng X, Yao S, Qin M, Shen Z, Yang J, Wu YL. Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer. Cancer 2023; 129:3239-3251. [PMID: 37282666 DOI: 10.1002/cncr.34897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 06/08/2023]
Abstract
BACKGROUND Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. METHODS Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. RESULTS Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. CONCLUSION Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. CLINICAL TRIAL REGISTRATION NCT03037385.
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Affiliation(s)
- Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jun Zhao
- Beijing Cancer Hospital, Beijing, China
| | - Jianhua Chang
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Huijie Wang
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yun Fan
- Zhejiang Cancer Hospital, Hangzhou, China
| | - Ke Wang
- West China Hospital Sichuan University, Chengdu, China
| | - Gang Wu
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiqi Nian
- Chongqing Cancer Hospital, Chongqing, China
| | | | - Meili Sun
- Jinan Central Hospital, Jinan, China
| | - Xiangcai Wang
- First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Huaqiu Shi
- First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiangqian Zheng
- Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Sheng Yao
- CStone Pharmaceuticals (Su Zhou) Co., Ltd., Suzhou, China
| | - Mengmeng Qin
- CStone Pharmaceuticals (Su Zhou) Co., Ltd., Suzhou, China
| | - Zhenwei Shen
- CStone Pharmaceuticals (Su Zhou) Co., Ltd., Suzhou, China
| | - Jason Yang
- CStone Pharmaceuticals (Su Zhou) Co., Ltd., Suzhou, China
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Spagnolo CC, Ciappina G, Giovannetti E, Squeri A, Granata B, Lazzari C, Pretelli G, Pasello G, Santarpia M. Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story? Int J Mol Sci 2023; 24:10119. [PMID: 37373267 PMCID: PMC10299133 DOI: 10.3390/ijms241210119] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal-epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients.
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Affiliation(s)
- Calogera Claudia Spagnolo
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy; (C.C.S.); (G.C.); (A.S.); (B.G.)
| | - Giuliana Ciappina
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy; (C.C.S.); (G.C.); (A.S.); (B.G.)
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrje Universiteit, 1081HV Amsterdam, The Netherlands;
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, 56017 San Giuliano, Italy
| | - Andrea Squeri
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy; (C.C.S.); (G.C.); (A.S.); (B.G.)
| | - Barbara Granata
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy; (C.C.S.); (G.C.); (A.S.); (B.G.)
| | - Chiara Lazzari
- Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia (FPO)-IRCCS, 10060 Torino, Italy;
| | - Giulia Pretelli
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (G.P.); (G.P.)
| | - Giulia Pasello
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (G.P.); (G.P.)
- Oncologia Medica 2, Istituto Oncologico Veneto, IRCCS, 35128 Padova, Italy
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98122 Messina, Italy; (C.C.S.); (G.C.); (A.S.); (B.G.)
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Heydt C, Ihle MA, Merkelbach-Bruse S. Overview of Molecular Detection Technologies for MET in Lung Cancer. Cancers (Basel) 2023; 15:cancers15112932. [PMID: 37296895 DOI: 10.3390/cancers15112932] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
MET tyrosine kinase receptor pathway activation has become an important actionable target in solid tumors. Aberrations in the MET proto-oncogene, including MET overexpression, the activation of MET mutations, MET mutations that lead to MET exon 14 skipping, MET gene amplifications, and MET fusions, are known to be primary and secondary oncogenic drivers in cancer; these aberrations have evolved as predictive biomarkers in clinical diagnostics. Thus, the detection of all known MET aberrations in daily clinical care is essential. In this review, current molecular technologies for the detection of the different MET aberrations are highlighted, including the benefits and drawbacks. In the future, another focus will be on the standardization of detection technologies for the delivery of reliable, quick, and affordable tests in clinical molecular diagnostics.
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Affiliation(s)
- Carina Heydt
- Faculty of Medicine, Institute of Pathology, University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Michaela Angelika Ihle
- Faculty of Medicine, Institute of Pathology, University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Sabine Merkelbach-Bruse
- Faculty of Medicine, Institute of Pathology, University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
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10
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Sakamoto M, Patil T. MET alterations in advanced non-small cell lung cancer. Lung Cancer 2023; 178:254-268. [PMID: 36924573 DOI: 10.1016/j.lungcan.2023.02.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/23/2023] [Accepted: 02/21/2023] [Indexed: 03/05/2023]
Abstract
Targeting the MET pathway in advanced NSCLC has been of particular interest due to its role as both a primary oncogenic driver and secondary oncogenic driver of acquired resistance. Activation of the MET pathway can occur through several mechanisms, which can complicate the diagnostic and treatment approach. Recently, several MET-directed therapies have been developed with promising results. In this narrative review, we summarize the biology and mechanism of MET as a clinically relevant driver mutation, distinct MET alterations including diagnostic challenges, significance in the setting of acquired resistance, and novel treatment strategies in advanced NSCLC.
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Affiliation(s)
- Mandy Sakamoto
- Department of Medicine, Division of Medical Oncology, United States
| | - Tejas Patil
- Department of Medicine, Division of Medical Oncology, United States.
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Yang Y, Zhang Y, Zhao D, Li X, Ma T. A Novel PRKAR1A::MET Fusion Dramatic Response to Crizotinib in a Patient with Unresectable Lung Cancer. Clin Lung Cancer 2023; 24:e50-e54. [PMID: 36323591 DOI: 10.1016/j.cllc.2022.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/29/2022] [Accepted: 10/01/2022] [Indexed: 02/03/2023]
Affiliation(s)
- Yang Yang
- Department of Respiratory Diseases, Harbin Medical University Cancer Hospital, Heilongjiang Province, Harbin, China
| | - Yanxiang Zhang
- Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
| | - Dandan Zhao
- Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
| | - Xiaoli Li
- Department of Respiratory Diseases, Harbin Medical University Cancer Hospital, Heilongjiang Province, Harbin, China.
| | - Tonghui Ma
- Department of Translational Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China.
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12
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Moiseenko F, Bogdanov A, Egorenkov V, Volkov N, Moiseyenko V. Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance. Curr Treat Options Oncol 2022; 23:1664-1698. [PMID: 36269457 DOI: 10.1007/s11864-022-01019-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 01/30/2023]
Abstract
OPINION STATEMENT MET-driven tumors are a heterogenous group of non-small cell lung cancers (NSCLC) with activating mutations. Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations. While checkpoint inhibitors have modest efficacy in MET-driven tumors, several approaches of targeted blockade are available. Among them the most promising are small tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Unfortunately, resistance is virtually inevitable. Resistance to small kinase inhibitors might be mediated by kinase domain mutations or activation of shunting cascades. Various resistance mechanisms might be present in one patient, making it overcoming an unresolved problem.
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Affiliation(s)
- Fedor Moiseenko
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia. .,N.N. Petrov National Medical Research Center of Oncology, Ministry of Public Health of the Russian Federation, 68, Leningradskaya st., Pesochny, St. Petersburg, 197758, Russia. .,State Budget Institution of Higher Education "North-Western State Medical University named after I.I Mechnikov" under the Ministry of Public Health of the Russian Federation, 41, Kirochnaya str, Saint Petersburg, 191015, Russia.
| | - Alexey Bogdanov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Vitaliy Egorenkov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Nikita Volkov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Vladimir Moiseyenko
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
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13
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Wang T, Wei L, Lu Q, Shao Y, You S, Yin JC, Wang S, Shao Y, Chen Z, Wang Z. Landscape of potentially targetable receptor tyrosine kinase fusions in diverse cancers by DNA-based profiling. NPJ Precis Oncol 2022; 6:84. [DOI: 10.1038/s41698-022-00325-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 10/19/2022] [Indexed: 11/13/2022] Open
Abstract
AbstractRecurrent fusions of receptor tyrosine kinases (RTKs) are often driving events in tumorigenesis that carry important diagnostic value and are potentially targetable by the increasing number of tyrosine kinase inhibitors (TKIs). Here, we characterized the spectrum of 1324 RTK fusions with intact kinase domains in solid tumors by DNA-based high-throughput sequencing. Overall, the prevalence of RTK fusions were 4.7%, with variable frequencies and diverse genomic structures and fusion partners across cancer types. Cancer types, such as thyroid cancers, urological cancers and neuroendocrine tumors are selective in the RTK fusions they carry, while others exhibit highly complex spectra of fusion events. Notably, most RTKs were promiscuous in terms of the partner genes they recombine with. A large proportion of RTK fusions had one of the breakpoints localized to intergenic regions. Comprehensive genomic profiling revealed differences in co-mutational patterns pre- and post-TKI treatments across various RTK fusions. At baseline, multiple cases were detected with co-occurring RTK fusions or concomitant oncogenic mutations in driver genes, such as KRAS and EGFR. Following TKI resistance, we observed differences in potential on- and off-target resistance mutations among fusion variants. For example, the EML4-ALK v3 variant displayed more complex on-target resistance mechanisms, which might explain the reduced survival outcome compared with the v1 variant. Finally, we identified two lung cancer patients with MET+ and NTRK1+ tumors, respectively, who responded well to crizotinib treatment. Taken together, our findings demonstrate the diagnostic and prognostic values of screening for RTK fusions using DNA-based sequencing in solid tumors.
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Vellichirammal NN, Albahrani A, Guda C. Fusion gene recurrence in non-small cell lung cancers and its association with cigarette smoke exposure. Transl Lung Cancer Res 2022; 11:2022-2039. [PMID: 36386463 PMCID: PMC9641034 DOI: 10.21037/tlcr-22-113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 08/22/2022] [Indexed: 01/19/2025]
Abstract
BACKGROUND Lung cancer remains the leading cause of cancer-related deaths in the US despite novel treatment protocols, with about 235,000 new cases and 131,000 deaths expected from this cancer in 2021 alone. Lung adenocarcinoma and squamous cell carcinoma, which are both subtypes of non-small cell lung cancer, account for most lung cancer cases, and comparing the molecular signatures in these two cancers can identify novel mechanisms that contribute to non-small cell lung cancer oncogenesis. METHODS We, in this study, performed a comprehensive gene fusion profiling of these cancers, which is understudied in lung cancers. Using an alignment-free fusion detection tool, 'ChimeRScope', we screened for gene fusions in lung adenocarcinoma and squamous cell carcinoma datasets from The Cancer Gene Atlas database. Fusion profiles in these two cancer subtypes were essentially different with minimal overlap. RESULTS Our analysis revealed a positive association of smoking to fusion frequency in lung adenocarcinoma but not in squamous cell carcinoma and identified several fusion genes that could be explored as markers associated with cigarette smoke exposure. We also identified differentially regulated pathways linked to E2F, G2M checkpoint, and MTORC1 signaling upregulated and P53 pathway downregulated in samples containing high fusions in lung adenocarcinoma. Our results indicate that downregulation of the P53 pathway leads to higher gene fusion formation in lung adenocarcinoma. CONCLUSIONS This manuscript provides a strong rationale for investigating the molecular mechanisms of cigarette smoke-induced gene fusion formation associated with lung cancer. Novel recurrent fusions associated with cigarette smoke were identified in our study, which could further be investigated for patient stratification, personalized therapy, and therapeutic monitoring.
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Affiliation(s)
| | - Abrar Albahrani
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
- Center for Biomedical Informatics Research and Innovation (CBIRI), University of Nebraska Medical Center, Omaha, NE, USA
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15
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Saigí M, Carcereny E, Morán T, Cucurull M, Domènech M, Hernandez A, Martinez-Cardús A, Pros E, Sanchez-Cespedes M. Biological and clinical perspectives of the actionable gene fusions and amplifications involving tyrosine kinase receptors in lung cancer. Cancer Treat Rev 2022; 109:102430. [DOI: 10.1016/j.ctrv.2022.102430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/20/2022] [Accepted: 06/15/2022] [Indexed: 11/02/2022]
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16
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Xu ZH, Wang WQ, Liu L, Lou WH. A special subtype: Revealing the potential intervention and great value of KRAS wildtype pancreatic cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188751. [PMID: 35732240 DOI: 10.1016/j.bbcan.2022.188751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 11/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and has devastating consequences on affected families and society. Its dismal prognosis is attributed to poor specificity of symptoms during early stages. It is widely believed that PDAC patients with the wildtype (WT) KRAS gene benefit more from currently available treatments than those with KRAS mutations. The oncogenic genetic changes alternations generally found in KRAS wildtype PDAC are related to either the KRAS pathway or microsatellite instability/mismatch repair deficiency (MSI/dMMR), which enable the application of tailored treatments based on each patient's genetic characteristics. This review focuses on targeted therapies against alternative tumour mechanisms in KRAS WT PDAC.
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Affiliation(s)
- Zhi-Hang Xu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Wen-Hui Lou
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Zhang C, Mei W, Zeng C. Oncogenic Neuregulin 1 gene (NRG1) fusions in cancer: A potential new therapeutic opportunities. Biochim Biophys Acta Rev Cancer 2022; 1877:188707. [PMID: 35247506 DOI: 10.1016/j.bbcan.2022.188707] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 02/27/2022] [Accepted: 02/27/2022] [Indexed: 10/19/2022]
Abstract
It is widely established that chromosomal rearrangements induce oncogenesis in solid tumors. However, discovering chromosomal rearrangements that are targetable and actionable remains a difficulty. Targeting gene fusion or chromosomal rearrangement seems to be a powerful strategy to address malignancies characterized by gene rearrangement. Oncogenic NRG1 fusions are relatively rare drivers that infrequently occur across most tumor types. NRG1 fusions exhibit unique biological properties and are difficult to identify owing to their large intronic regions. NRG1 fusions can be detected using a variety of techniques, including fluorescence in situ hybridization, immunohistochemistry, or next-generation sequencing (NGS), with NGS-based RNA sequencing being the most sensitive. Previous studies have shown that NRG1 fusion protein induces tumorigenesis, and numerous therapies targeting the ErbB signaling pathway, such as ErbB kinase inhibitors and monoclonal antibodies, have initially demonstrated encouraging anticancer efficacy in malignant tumors carrying NRG1 fusions. In this review, we present the characteristics and prevalence of NRG1 fusions in solid tumors. Additionally, we discuss the laboratory approaches for diagnosing NRG1 gene fusions. More importantly, we outline promising strategies for treating malignancies with NRG1 fusion.
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Affiliation(s)
- Congwang Zhang
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen 518110, China
| | - Wuxuan Mei
- Clinical Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China
| | - Changchun Zeng
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen 518110, China.
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18
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KIF5B-MET fusion variant in non-small cell lung cancer. Pulmonology 2022; 28:315-316. [DOI: 10.1016/j.pulmoe.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/02/2022] [Indexed: 11/21/2022] Open
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Kazdal D, Hofman V, Christopoulos P, Ilié M, Stenzinger A, Hofman P. Fusion-positive non-small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications. Genes Chromosomes Cancer 2022; 61:244-260. [PMID: 34997651 DOI: 10.1002/gcc.23022] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/26/2021] [Accepted: 12/27/2021] [Indexed: 12/11/2022] Open
Abstract
Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late-stage non-small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non-squamous NSCLC (NS-NSCLC). Gene fusions can be detected using different approaches, but today RNA next-generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.
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Affiliation(s)
- Daniel Kazdal
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Translational Lung Research Center (TLRC) Heidelberg, Heidelberg, Germany.,German Center for Lung Research (DZL), Heidelberg, Germany
| | - Véronique Hofman
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Université Côte d'Azur, FHU OncoAge, Nice, France.,Centre Antoine Lacassagne Cancer Center, Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU OncoAge, Nice, France.,Hospital-Integrated Biobank BB-0033-00025, Université Côte d'Azur, CHU Nice, FHU OncoAge, Nice, France
| | - Petros Christopoulos
- Translational Lung Research Center (TLRC) Heidelberg, Heidelberg, Germany.,German Center for Lung Research (DZL), Heidelberg, Germany.,Thoraxklinik and National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Marius Ilié
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Université Côte d'Azur, FHU OncoAge, Nice, France.,Centre Antoine Lacassagne Cancer Center, Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU OncoAge, Nice, France.,Hospital-Integrated Biobank BB-0033-00025, Université Côte d'Azur, CHU Nice, FHU OncoAge, Nice, France
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,German Center for Lung Research (DZL), Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Université Côte d'Azur, FHU OncoAge, Nice, France.,Centre Antoine Lacassagne Cancer Center, Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU OncoAge, Nice, France.,Hospital-Integrated Biobank BB-0033-00025, Université Côte d'Azur, CHU Nice, FHU OncoAge, Nice, France
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Li Q, Zhu B, Chen J, Wang H, Wu Y, Chen H, He X. Effects of Oncogene Neuregulin 1 on Breast Cancer Cells. Pak J Biol Sci 2022; 25:345-352. [PMID: 35638529 DOI: 10.3923/pjbs.2022.345.352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
<b>Background and Objectives:</b> The NRG1 fusion protein is a driving factor for the occurrence and development of many tumours. We aimed to evaluate the effects of oncogene Neuregulin 1 (NRG1) on the proliferation and migration of breast cancer cells. <b>Materials and Methods:</b> Target gene NRG1 was transfected into breast cancer cells using the gene transfection technique and the migration ability of cells was observed by wound healing assay. The migration and invasion abilities of cells were further observed by Transwell assay and cell apoptosis was observed by TUNEL staining. The cell cycle distribution of breast cancer cells was detected by flow cytometry. <b>Results:</b> The wound healing assay exhibited that breast cancer cells overexpressing NRG1 exhibited stronger migration (p = 0.0047). More breast cancer cells of up-regulating NRG1 penetrated the transwell chamber, showing enhanced invasion ability (p = 0.0029). The TUNEL assay and flow cytometry demonstrated that NRG1 inhibited cell apoptosis and made them enter the active division stage. <b>Conclusion:</b> The NRG1 can promote the malignant function of breast cancer cells by augmenting migration and invasion abilities. High expression of NRG1 remarkably suppressed the apoptosis of breast cancer cells.
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OUP accepted manuscript. Eur J Cardiothorac Surg 2022; 62:6580206. [DOI: 10.1093/ejcts/ezac297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/19/2022] [Accepted: 04/29/2022] [Indexed: 11/14/2022] Open
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22
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Wang X, Peng W, Zeng Z, Cai J, Liu A. Emerging a Novel VOPP1-EGFR Fusion Coexistent With T790M as an Acquired Resistance Mechanism to Prior Icotinib and Sensitive to Osimertinib in a Patient With EGFR L858R Lung Adenocarcinoma: A Case Report. Front Oncol 2021; 11:720819. [PMID: 35004270 PMCID: PMC8727519 DOI: 10.3389/fonc.2021.720819] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
BackgroundEpidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). Clinical support and evidence to guide management are absent for NSCLC patients harboring EGFR fusion.Case PresentationIn this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in the liver, lung, and bone, and was treated with icotinib. A novel vesicular overexpressed in cancer pro-survival protein 1 (VOPP1)-EGFR fusion gene coexistent with T790M were identified by next-generation sequencing using pericardial effusion and blood samples after icotinib treatment, which led to progression after icotinib six months and suggested a potential resistance mechanism. Subsequently, the patient was switched to osimertinib treatment, which resulted in a progression-free survival interval of more than 11 months.ConclusionsThe present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the present case increases the evidence supporting use of osimertinib for treatment of NSCLC patients harboring EGFR fusion.
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Affiliation(s)
- Xia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weiwei Peng
- Department of Oncology, People’s Hospital of Ganzhou, Ganzhou, China
| | - Zhimin Zeng
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Anwen Liu,
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Li D, Song Z, Dong B, Song W, Cheng C, Zhang Y, Zhang W. Advances in targeted therapy in non-small cell lung cancer with actionable mutations and leptomeningeal metastasis. J Clin Pharm Ther 2021; 47:24-32. [PMID: 34309914 DOI: 10.1111/jcpt.13489] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/19/2021] [Accepted: 07/05/2021] [Indexed: 11/29/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.
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Affiliation(s)
- Ding Li
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Zhenguo Song
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Bingqi Dong
- Department of Urology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wenping Song
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Cheng Cheng
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yongna Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
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Deng C, Zheng Q, Zhang Y, Jin Y, Shen X, Nie X, Fu F, Ma X, Ma Z, Wen Z, Wang S, Li Y, Chen H. Validation of the Novel International Association for the Study of Lung Cancer Grading System for Invasive Pulmonary Adenocarcinoma and Association With Common Driver Mutations. J Thorac Oncol 2021; 16:1684-1693. [PMID: 34302987 DOI: 10.1016/j.jtho.2021.07.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/16/2021] [Accepted: 07/08/2021] [Indexed: 01/21/2023]
Abstract
INTRODUCTION We aimed to validate the use of the novel grading system proposed by the International Association for the Study of Lung Cancer pathology committee for prognosis stratification of invasive pulmonary adenocarcinomas (ADCs) in Chinese patients. Correlations between the grading system, common driver mutations, and adjuvant chemotherapy (ACT) were also investigated. METHODS From 2008 to 2016, the histologic patterns of a large cohort of 950 patients with invasive ADCs (stage I-III) were retrospectively analyzed and classified according to the proposed grading system. Subsequently, tumor grading was correlated with genetic data, ACT, and patient outcome. RESULTS Compared with conventional predominant pattern-based groups, the novel grading system carried improved survival discrimination (area under the curve = 0.768 for recurrence-free survival and 0.775 for overall survival). The area under the curve was not further improved when incorporated lymphovascular invasion status. EGFR mutations (p < 0.001) were correlated with moderate grade, whereas KRAS mutations (p = 0.041) and ALK fusions (p = 0.021) were significantly more prevalent in poor grade. The reclassification of the grading system based on EGFR mutation status revealed excellent survival discrimination (p < 0.001). In particular, patients on stage Ib to III with novel high-grade ADCs had an improved prognosis with ACT. CONCLUSIONS The novel International Association for the Study of Lung Cancer grading system is a practical and efficient discriminator for patient prognosis and should be part of an integrated pathologic-genetic subtyping to improve survival prediction. In addition, it may support patient stratification for aggressive adjuvant chemotherapy.
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Affiliation(s)
- Chaoqiang Deng
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Qiang Zheng
- Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Yang Zhang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Yan Jin
- Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Xuxia Shen
- Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Xiao Nie
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Pathology, Jiangyin People's Hospital, Jiangsu, People's Republic of China
| | - Fangqiu Fu
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Xiangyi Ma
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Zelin Ma
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Zhexu Wen
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Shengping Wang
- Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Yuan Li
- Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Haiquan Chen
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Institute of Thoracic Oncology, Fudan University, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
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Li B, Huang Z, Yu W, Liu S, Zhang J, Wang Q, Wu L, Kou F, Yang L. Molecular subtypes based on CNVs related gene signatures identify candidate prognostic biomarkers in lung adenocarcinoma. Neoplasia 2021; 23:704-717. [PMID: 34139453 PMCID: PMC8208901 DOI: 10.1016/j.neo.2021.05.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/06/2021] [Indexed: 12/26/2022]
Abstract
The classical factors for predicting prognosis currently cannot meet the developing requirements of individualized and accurate prognostic evaluation in lung adenocarcinoma (LUAD). With the rapid development of high-throughput DNA sequencing technologies, genomic changes have been discovered. These sequencing data provide unprecedented opportunities for identifying cancer molecular subtypes. In this article, we classified LUAD into two distinct molecular subtypes (Cluster 1 and Cluster 2) based on Copy Number Variations (CNVs) and mRNA expression data from the Cancer Genome Atlas (TCGA) based on non-negative matrix factorization. Patients in Cluster 1 had worse outcomes than that in Cluster 2. Molecular features in subtypes were assessed to explain this phenomenon by analyzing differential expression genes expression pattern, which involved in cellular processes and environmental information processing. Analysis of immune cell populations suggested different distributions of CD4+ T cells, CD8+ T cells, and dendritic cells in the two subtypes. Subsequently, two novel genes, TROAP and RASGRF1, were discovered to be prognostic biomarkers in TCGA, which were confirmed in GSE31210 and Tianjin Medical University Cancer Institute and Hospital LUAD cohorts. We further proved their crucial roles in cancers by vitro experiments. TROAP mediates tumor cell proliferation, cycle, invasion, and migration, not apoptosis. RASGRF1 has a significant effect on tumor microenvironment. In conclusion, our study provides a novel insight into molecular classification based on CNVs related genes in LUAD, which may contribute to identify new molecular subtypes and target genes.
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Affiliation(s)
- Baihui Li
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Ziqi Huang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Shaochuan Liu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Jian Zhang
- School of Medicine, Nankai University, Tianjin, China; Department of Oncology, Oncology Laboratory, General Hospital of Chinese PLA, Beijing, China
| | - Qingqing Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Lei Wu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Fan Kou
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Lili Yang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
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26
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Zhao R, Yao F, Xiang C, Zhao J, Shang Z, Guo L, Ding W, Ma S, Yu A, Shao J, Zhu L, Han Y. Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population. J Pathol Clin Res 2021; 7:375-384. [PMID: 33768710 PMCID: PMC8185368 DOI: 10.1002/cjp2.208] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 02/09/2021] [Accepted: 02/14/2021] [Indexed: 12/30/2022]
Abstract
The molecular profile of neurotrophic tyrosine kinase receptor (NTRK) gene fusions in lung adenocarcinoma (LUAD) is not fully understood. Next-generation sequencing (NGS) and pan-tyrosine kinase receptor (TRK) immunohistochemistry (IHC) are powerful tools for NTRK fusion detection. In this study, a total of 4,619 LUAD formalin-fixed, paraffin-embedded tissues were collected from patients who underwent biopsy or resection at the Shanghai Chest Hospital during 2017-2019. All specimens were screened for NTRK1 rearrangements using DNA-based NGS. Thereafter, the cases with NTRK1 rearrangements and cases negative for common driver mutations were analyzed for NTRK1/2/3 fusions using total nucleic acid (TNA)-based NGS and pan-TRK IHC. Overall, four NTRK1/2 fusion events were identified, representing 0.087% of the original sample set. At the DNA level, seven NTRK1 rearrangements were identified, while only two TPM3-NTRK1 fusions were confirmed on TNA-based NGS as functional. In addition, two NTRK2 fusions (SQSTM1-NTRK2 and KIF5B-NTRK2) were identified by TNA-based NGS in 350 'pan-negative' cases. Two patients harboring NTRK1/2 fusions were diagnosed with invasive adenocarcinoma, while the other two were diagnosed with adenocarcinoma in situ and minimally invasive adenocarcinoma. All four samples with NTRK fusions were positive for the expression of pan-TRK. The two samples with NTRK2 fusions showed cytoplasmic staining alone, while the other two samples with NTRK1 fusions exhibited both cytoplasmic and membranous staining. In summary, functional NTRK fusions are found in early-stage LUAD; however, they are extremely rare. According to this study's results, they are independent oncogenic drivers, mutually exclusive with other driver mutations. We demonstrated that NTRK rearrangement analysis using a DNA-based approach should be verified with an RNA-based assay.
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Affiliation(s)
- Ruiying Zhao
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Feng Yao
- Department of Thoracic Surgery, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Chan Xiang
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Jikai Zhao
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Zhanxian Shang
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Lianying Guo
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Wenjie Ding
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Shengji Ma
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Anbo Yu
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Jinchen Shao
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Lei Zhu
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
| | - Yuchen Han
- Department of Pathology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiPR China
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27
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Ptáková N, Martínek P, Holubec L, Janovský V, Vančurová J, Grossmann P, Navarro PA, Rodriguez Moreno JF, Alaghehbandan R, Hes O, Májek O, Pešek M, Michal M, Ondič O. Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database. Genes Chromosomes Cancer 2021; 60:474-481. [PMID: 33583086 DOI: 10.1002/gcc.22942] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 02/02/2021] [Accepted: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.
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Affiliation(s)
- Nikola Ptáková
- Molecular Genetics Department, Bioptická Laboratoř s.r.o., Pilsen, Czech Republic
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Martínek
- Molecular Genetics Department, Bioptická Laboratoř s.r.o., Pilsen, Czech Republic
| | - Luboš Holubec
- Department of Clinical Oncology, Na Homolce Hospital, Prague, Czech Republic
- Second Department of Internal Medicine, Medical Faculty in Pilsen, Charles University Prague, Pilsen, Czech Republic
| | - Václav Janovský
- Department of Oncology, Hospital České Budějovice, České Budějovice, Czech Republic
| | - Jana Vančurová
- Department of Oncology, Hospital České Budějovice, České Budějovice, Czech Republic
| | - Petr Grossmann
- Molecular Genetics Department, Bioptická Laboratoř s.r.o., Pilsen, Czech Republic
| | - Paloma Alcaraz Navarro
- Department of Pathology, FiHM-Centro Integral Oncológico Hospital de Madrid Clara Campal, Madrid, Spain
| | - Juan F Rodriguez Moreno
- Department of Pathology, FiHM-Centro Integral Oncológico Hospital de Madrid Clara Campal, Madrid, Spain
| | - Reza Alaghehbandan
- Department of Pathology, University of British Columbia, Royal Columbian Hospital, Vancouver, British Columbia, Canada
| | - Ondřej Hes
- Department of Pathology, Medical Faculty in Pilsen, Charles University Prague, Pilsen, Czech Republic
| | - Ondřej Májek
- Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Miloš Pešek
- Department of Pneumology and Phthisiology, Medical Faculty in Pilsen, Charles University Prague, Pilsen, Czech Republic
| | - Michal Michal
- Department of Pathology, Medical Faculty in Pilsen, Charles University Prague, Pilsen, Czech Republic
| | - Ondrej Ondič
- Molecular Genetics Department, Bioptická Laboratoř s.r.o., Pilsen, Czech Republic
- Department of Pathology, Medical Faculty in Pilsen, Charles University Prague, Pilsen, Czech Republic
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28
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Deng C, Zhang Y, Fu F, Ma X, Wen Z, Ma Z, Wang S, Li Y, Chen H. Genetic-pathological prediction for timing and site-specific recurrence pattern in resected lung adenocarcinoma. Eur J Cardiothorac Surg 2021; 60:1223-1231. [PMID: 34172990 DOI: 10.1093/ejcts/ezab288] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 04/26/2021] [Accepted: 05/13/2021] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVES We aimed to describe accurately the timing and site-specific recurrence pattern for surgical resected lung adenocarcinoma and develop genetic-pathological risk prediction models to guide individual postoperative surveillance strategies. METHODS We retrospectively analysed radiological, pathological and sequencing data concerning 9 common oncogenic driver mutations from 1531 patients with resected lung adenocarcinoma between 2008 and 2015. The first recurrence site and time-to-recurrence were recorded. Independent risk factors were identified by multivariable regression analysis and consequently incorporated into prediction models. RESULTS With a median follow-up of 53.2 months, postoperative recurrences were noted in 483 (31.5%) patients. Bone and brain recurrence tended to occur early (median 11.7 and 17.0 months, respectively) while thorax recurrence occurred later (median 22.2 months), which was validated across different tumour stages. EGFR mutation was an independent predictor for brain and bone recurrence and KRAS mutation for early recurrence. Both internal and external validation of the nomograms for brain and bone recurrence prediction showed optimal discrimination (concordance index: internal, 0.75 and 0.81, respectively; external, 0.77 and 0.84, respectively) and calibration. Recurrence occurred relatively evenly during the follow-up period in low-risk groups but mainly occurred within 2 years in high-risk groups. CONCLUSIONS Unique biological differences exist among lung adenocarcinoma leading to distinct patterns of recurrence. These user-friendly genetic-pathological nomograms may help physicians to better stratify patients and make individual postoperative follow-up plans.
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Affiliation(s)
- Chaoqiang Deng
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yang Zhang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangqiu Fu
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiangyi Ma
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhexu Wen
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zelin Ma
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shengping Wang
- Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yuan Li
- Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Haiquan Chen
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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29
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Wang X, Huang L, Cai J, Liu A. A Novel KIF5B-EGFR Fusion Variant in Non-Small-Cell Lung Cancer and Response to Afatinib: A Case Report. Onco Targets Ther 2021; 14:3739-3744. [PMID: 34163176 PMCID: PMC8214534 DOI: 10.2147/ott.s313896] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). With advances in detection technology, some uncommon genomic mutation events, including EGFR fusions, have been detected. There are no standard treatment options for NSCLC patients harboring EGFR fusion. Herein, we report a case of KIF5B-EGFR fusion in NSCLC responding to tyrosine kinase inhibitors (TKIs). A 50-year-old male underwent left upper lobectomy followed by adjuvant chemotherapy for pathological stage IA3 lung adenocarcinoma. The tumor tissue was subjected to next-generation sequencing (NGS) and showed a KIF5B-EGFR fusion. When cancer recurrence occurred thirteen months later, the patient received afatinib (40 mg qd) as second-line treatment, and a partial response was observed, which resulted in an 11-month progression-free survival (PFS). This case provides valuable information on the response to afatinib in an NSCLC patient with a novel KIF5B-EGFR fusion. The NGS assay provides a powerful tool for identifying rare or atypical EGFR gene mutations in patients with NSCLC, which should be encouraged in clinical practice.
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Affiliation(s)
- Xia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Long Huang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China.,Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, 330000, Jiangxi Province, People's Republic of China
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30
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Lee M, Jain P, Wang F, Ma PC, Borczuk A, Halmos B. MET alterations and their impact on the future of non-small cell lung cancer (NSCLC) targeted therapies. Expert Opin Ther Targets 2021; 25:249-268. [PMID: 33945380 DOI: 10.1080/14728222.2021.1925648] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: The MET gene and its pathway normally plays a crucial role in cell homeostasis, motility, and apoptosis. However, when the MET gene is altered, there is an imbalance toward cell proliferation and invasion commonly seen in numerous different types of cancers. The heterogeneous group of MET alterations that includes MET amplification, MET exon 14 skipping mutation, and MET fusions has been difficult to diagnose and treat. Currently, treatments are focused on tyrosine kinase inhibitors but now there is emerging data on novel MET-targeted therapies including monoclonal antibodies and antibody-drug conjugates that have emerged.Areas covered: We introduce new emerging data on MET alterations in non-small cell lung cancer (NSCLC) that has contributed to advances in MET targeted therapeutics. We offer our perspective and examine new information on the mechanisms of the MET alterations in this review.Expert opinion: Given the trends currently involving the targeting of MET altered malignancies, there will most likely be a continued rapid expansion of testing, novel tyrosine kinase inhibitors and potent antibody approaches. Combination treatments will be necessary to optimize management of advanced and early disease.
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Affiliation(s)
- Matthew Lee
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Prantesh Jain
- Division of Medical Oncology, Department of Medicine, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Feng Wang
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Patrick C Ma
- Penn State CancerInstitute, PennState College of Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
| | - Alain Borczuk
- Department of Pathology, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA
| | - Balazs Halmos
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
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31
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Wu ZW, Sha Y, Chen Q, Hou J, Sun Y, Lu WK, Chen J, Yu LJ. Novel intergenic KIF5B-MET fusion variant in a patient with gastric cancer: A case report. World J Clin Cases 2021; 9:3350-3355. [PMID: 34002144 PMCID: PMC8107910 DOI: 10.12998/wjcc.v9.i14.3350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/20/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MET fusion is a key driver mutation, but it is rare in gastric cancer (GC). Several MET (hepatocyte growth factor receptor) inhibitors have been approved for the treatment of MET-positive patients, but the tumor response is heterogeneous. With the development of next-generation sequencing, diverse MET fusion partner genes have been identified. We herein report a fusion variant involving KIF5B-MET in GC.
CASE SUMMARY After thoracoscopic inferior lobectomy plus lymph node dissection under general anesthesia, a “tumor within a tumor” was found in the lung tumor tissue of a 64-year-old non-smoking male patient. Combining the medical history and the results of enzyme labeling, the focal area was considered to be GC. To seek potential therapeutic regimens, an intergenic region between KIF5B and MET fusion was identified. This fusion contains a MET kinase domain and coil-coiled domains encoded by KIF5B exons 1-25, which might drive the oncogenesis.
CONCLUSION Our finding could extend the spectrum and genomic landscape of MET fusions in GC and favor the development of personalized therapy.
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Affiliation(s)
- Zhi-Wei Wu
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Yu Sha
- Department of Pathology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Qing Chen
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Juan Hou
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Yan Sun
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Wang-Kun Lu
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Jing Chen
- Department of Pathology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
| | - Li-Jiang Yu
- Department of Oncology, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang People's Hospital, Jingjiang 214500, Jiangsu Province, China
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32
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Zhang H, Huang W, Liu C, Giaccone G, Zhao X, Sun X, Li J, Cheng R, Huang Q, Mo H, Zhang Z, Zhang B, Wang C. The Prognostic Value of Non-Predominant Micropapillary Pattern in a Large Cohort of Resected Invasive Lung Adenocarcinoma Measuring ≤3 cm. Front Oncol 2021; 11:657506. [PMID: 34026636 PMCID: PMC8137894 DOI: 10.3389/fonc.2021.657506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/06/2021] [Indexed: 01/11/2023] Open
Abstract
The aim of this study was to analyze the influence of non-predominant micropapillary pattern in small sized invasive lung adenocarcinoma. A total of 986 lung adenocarcinoma patients with tumor size ≤3 cm were identified and classified according to the IALSC/ATS/ERS classification. Emphasis was placed on the impact of non-predominant micropapillary pattern on disease-free survival (DFS) and overall survival (OS). The relationship between lung adenocarcinoma subtype and lymph node involvement, EGFR mutation and KRAS mutation was also evaluated. A nomogram was developed to predict the probability of 3- and 5-year OS for these patients. The concordance index and calibration plot were used to validate this model. Among all 986 patients, the percentages of lymph node involvement were: 58.1, 50.0, 33.5, 21.4, 21.1, 10.9, 0, and 0% for micropapillary predominant, solid predominant, acinar predominant, papillary predominant, invasive mucinous adenocarcinoma (IMA), lepidic predominant, minimally invasive adenocarcinoma (MIA), adenocarcinoma in situ (AIS), respectively. The frequency of EGFR mutation in the cases of lepidic predominant, acinar predominant, MIA, micropapillary predominant, papillary predominant, solid predominant, IMA, and AIS were 51.1, 45.2, 44.4, 36.8, 29.3, 26.8, 8.3, and 0%, respectively. A non-predominant micropapillary pattern was observed in 344 (38.4%) invasive adenocarcinoma (IAC), and its presence predicted a poorer DFS (median: 56.0 months vs. 66.0 months, P <0.001) and OS (median: 61.0 months vs. 70.0 months, P <0.001). After propensity score matching, non-predominant micropapillary pattern retained its unfavorable effect on DFS (P = 0.007) and OS (P = 0.001). Multivariate analysis showed that non-predominant micropapillary pattern was identified as an independent prognostic factor for DFS (P = 0.003) and OS (P <0.001) in IAC. The nomogram showed good calibration and reliable discrimination ability (C-index = 0.775) to evaluated the 3- and 5-year OS. This retrospective analysis of patients with small sized IAC suggests the value of non-predominant micropapillary pattern to predict poor prognosis. A reliable nomogram model was constructed to provide personalized survival predictions.
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Affiliation(s)
- Hua Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wuhao Huang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chang Liu
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | | | - Xiaoliang Zhao
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiaoyan Sun
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jingjing Li
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Runfen Cheng
- Department of Lung Cancer Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiujuan Huang
- Department of Lung Cancer Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Huilan Mo
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhenfa Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Bin Zhang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Changli Wang
- Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Zito Marino F, Alì G, Facchinetti F, Righi L, Fontanini G, Rossi G, Franco R. Fusion proteins in lung cancer: addressing diagnostic problems for deciding therapy. Expert Rev Anticancer Ther 2021; 21:887-900. [PMID: 33715580 DOI: 10.1080/14737140.2021.1903875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Gene fusions are frequent chromosomal aberrations in solid tumors. In Lung cancer (LC) several druggable-fusions involving tyrosine kinase receptor genes have been described, including ALK, ROS1, RET and NTRK. In non-small cell lung cancer, testing for targetable fusions has become a part of routine clinical practice, greatly impacting therapeutic choice for patients with these aberrations. Although substantial technologies for gene fusion detection have been implemented over time including; cytogenetic, Fluorescence in situ hybridization (FISH), Immunohistochemistry (IHC), Retro-transcription Real-Time PCR (RT-qPCR), to Next Generation Sequencing (NGS), nCounter system (Nanostring technology), several critical issues remain. To date, only the companion diagnostic tests FISH and IHC for ALK-rearrangements and NGS for ROS1-rearrangments were approved. Other fusion approved tests are currently unavailable.Areas covered: In this review, we explore current diagnostic problems of gene fusion detection relative to the technologies available, in order to clarify future standardization of analyses which determine therapeutic choices.Expert opinion: The establishment of a gold standard, an effective diagnostic algorithm, and a standardized interpretation for the analysis of each druggable-fusions in lung cancer is essential for adequate therapeutic management.
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Affiliation(s)
- Federica Zito Marino
- Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Greta Alì
- Department of Surgical Pathology, Medical, Molecular, and Critical Area, University of Pisa, Pisa, Italy
| | - Francesco Facchinetti
- Université Paris-Saclay, Institut Gustave Roussy, INSERM, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Villejuif, France.,Medical Oncology Unit, University Hospital of Parma, Italy
| | - Luisella Righi
- Department of Oncology, University of Turin, Pathology Division, San Luigi Hospital, University of Turin, Turin, Italy
| | - Gabriella Fontanini
- Department of Surgical Pathology, Medical, Molecular, and Critical Area, University of Pisa, Pisa, Italy
| | - Giulio Rossi
- Operative Unit of Pathologic Anatomy, Azienda Della Romagna, Teaching Hospital S. Maria Delle Croci, Ravenna, Italy
| | - Renato Franco
- Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
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Wu TM, Liu JB, Liu Y, Shi Y, Li W, Wang GR, Ma YS, Fu D. Power and Promise of Next-Generation Sequencing in Liquid Biopsies and Cancer Control. Cancer Control 2021; 27:1073274820934805. [PMID: 32806937 PMCID: PMC7791471 DOI: 10.1177/1073274820934805] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Traditional methods of cancer treatment are usually based on the morphological
and histological diagnosis of tumors, and they are not optimized according to
the specific situation. Precision medicine adjusts the existing treatment
regimen based on the patient’s genomic information to make it most suitable for
patients. Detection of genetic mutations in tumors is the basis of precise
cancer medicine. Through the analysis of genetic mutations in patients with
cancer, we can tailor the treatment plan for each patient with cancer to
maximize the curative effect, minimize damage to healthy tissues, and optimize
resources. In recent years, next-generation sequencing technology has developed
rapidly and has become the core technology of precise targeted therapy and
immunotherapy for cancer. From early cancer screening to treatment guidance for
patients with advanced cancer, liquid biopsy is increasingly used in cancer
management. This is as a result of the development of better noninvasive,
repeatable, sensitive, and accurate tools used in early screening, diagnosis,
evaluation, and monitoring of patients. Cell-free DNA, which is a new
noninvasive molecular pathological detection method, often carries
tumor-specific gene changes. It plays an important role in optimizing treatment
and evaluating the efficacy of different treatment options in clinical trials,
and it has broad clinical applications.
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Affiliation(s)
- Ting-Miao Wu
- Department of Radiology, 12485The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ji-Bin Liu
- Cancer Institute, 377323Nantong Tumor Hospital, Nantong, China
| | - Yu Liu
- National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, 12571Central South University of Forestry and Technology, Chaha, China
| | - Yi Shi
- National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, 12571Central South University of Forestry and Technology, Chaha, China
| | - Wen Li
- National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, 12571Central South University of Forestry and Technology, Chaha, China
| | - Gao-Ren Wang
- Cancer Institute, 377323Nantong Tumor Hospital, Nantong, China
| | - Yu-Shui Ma
- Cancer Institute, 377323Nantong Tumor Hospital, Nantong, China.,Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, 12476Tongji University School of Medicine, Shanghai, China
| | - Da Fu
- Department of Radiology, 12485The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China.,Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, 12476Tongji University School of Medicine, Shanghai, China
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De Toma A, Lo Russo G, Signorelli D, Pagani F, Randon G, Galli G, Prelaj A, Ferrara R, Proto C, Ganzinelli M, Zilembo N, de Braud F, Garassino MC. Uncommon targets in non-small cell lung cancer: Everyone wants a slice of cake. Crit Rev Oncol Hematol 2021; 160:103299. [PMID: 33722699 DOI: 10.1016/j.critrevonc.2021.103299] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/14/2020] [Accepted: 03/10/2021] [Indexed: 01/15/2023] Open
Abstract
Target therapies completely changed the clinical approach in EGFR mutated and ALK rearranged non-small cell lung cancer, ensuring these patients exceptional outcomes with a better toxicity profile compared to conventional chemotherapy. In recent years, beyond EGFR and ALK alterations, new data are emerging about less common alterations, new drugs have been already approved and others agents have been recently investigated or are currently under investigation. In this review we will discuss some uncommon alterations in non-small cell lung cancer such as ROS1, BRAF, RET, HER2, NTRK, MET and other targets that are in an early evaluation phase. We will summarize the characteristics of patients harboring these alterations, the already approved or under investigation therapies and the related resistance mechanisms.
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Affiliation(s)
- Alessandro De Toma
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Giuseppe Lo Russo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Diego Signorelli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pagani
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giulia Galli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Arsela Prelaj
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Electronics, Information, and Bioengineering, Polytechnic University of Milan, Milan, Italy
| | - Roberto Ferrara
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Claudia Proto
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Ganzinelli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Nicoletta Zilembo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marina Chiara Garassino
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Santarpia M, Massafra M, Gebbia V, D’Aquino A, Garipoli C, Altavilla G, Rosell R. A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations. Transl Lung Cancer Res 2021; 10:1536-1556. [PMID: 33889528 PMCID: PMC8044480 DOI: 10.21037/tlcr-20-1113] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.
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Affiliation(s)
- Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Patology “G. Barresi”, University of Messina, Messina, Italy
| | - Marco Massafra
- Medical Oncology Unit, Department of Human Patology “G. Barresi”, University of Messina, Messina, Italy
| | - Vittorio Gebbia
- Medical Oncology and Supportive Care Unit, La Maddalena Cancer Center, Palermo, Italy;,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Antonio D’Aquino
- Medical Oncology Unit, Department of Human Patology “G. Barresi”, University of Messina, Messina, Italy
| | - Claudia Garipoli
- Medical Oncology Unit, Department of Human Patology “G. Barresi”, University of Messina, Messina, Italy
| | - Giuseppe Altavilla
- Medical Oncology Unit, Department of Human Patology “G. Barresi”, University of Messina, Messina, Italy
| | - Rafael Rosell
- Catalan Institute of Oncology, Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol, Badalona, Barcelona, Spain;,Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain;,Universitat Autònoma de Barcelona, Barcelona, Spain
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Montero JC, Pandiella A. PDCD4 limits prooncogenic neuregulin-ErbB signaling. Cell Mol Life Sci 2021; 78:1799-1815. [PMID: 32804243 PMCID: PMC11073242 DOI: 10.1007/s00018-020-03617-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/21/2020] [Accepted: 08/07/2020] [Indexed: 11/26/2022]
Abstract
The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion.
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Affiliation(s)
- Juan Carlos Montero
- Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC) and CIBERONC, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
| | - Atanasio Pandiella
- Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC) and CIBERONC, Campus Miguel de Unamuno, 37007, Salamanca, Spain
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Abstract
Neuregulins, members of the largest subclass of growth factors of the epidermal growth factor family, mediate a myriad of cellular functions including survival, proliferation, and differentiation in normal tissues through binding to receptor tyrosine kinases of the ErbB family. However, aberrant neuregulin signaling in the tumor microenvironment is increasingly recognized as a key player in initiation and malignant progression of human cancers. In this chapter, we focus on the role of neuregulin signaling in the hallmarks of cancer, including cancer initiation and development, metastasis, as well as therapeutic resistance. Moreover, role of neuregulin signaling in the regulation of tumor microenvironment and targeting of neuregulin signaling in cancer from the therapeutic perspective are also briefly discussed.
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Forsythe A, Zhang W, Phillip Strauss U, Fellous M, Korei M, Keating K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther Adv Med Oncol 2020; 12:1758835920975613. [PMID: 33425024 PMCID: PMC7758559 DOI: 10.1177/1758835920975613] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/29/2020] [Indexed: 12/21/2022] Open
Abstract
Introduction The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase (NTRK) gene fusion frequency in solid tumors. Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence. Results The SLR identified 222 studies from North America (n = 122), Europe (n = 33), Asia (n = 41), Brazil (n = 5), Australia (n = 2), and multi-continental (n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective (n = 43) and retrospective (n = 179). Testing methods involved DNA (n = 93), RNA (n = 72), combined DNA/RNA (n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported (n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42-100.00), secretory breast cancer (92.87%, 95% CI 72.62-100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06-32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09-0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15-0.36), cutaneous melanoma (0.31%, 95% CI 0.07-0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00-1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively. Conclusion This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.
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Affiliation(s)
- Anna Forsythe
- Purple Squirrel Economics, 4 Lexington Ave, Suite 15K, New York, NY 10010, USA
| | - Wei Zhang
- Bayer Pharmaceuticals, Inc., Whippany, NJ, USA
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40
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Suda K, Mitsudomi T. Emerging oncogenic fusions other than ALK, ROS1, RET, and NTRK in NSCLC and the role of fusions as resistance mechanisms to targeted therapy. Transl Lung Cancer Res 2020; 9:2618-2628. [PMID: 33489822 PMCID: PMC7815361 DOI: 10.21037/tlcr-20-186] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent evidence has shown that gene fusions caused by chromosomal rearrangements are frequent events in the initiation and during progression of solid tumors, including non-small cell lung cancers (NSCLCs). Since the discoveries of ALK and ROS1 fusions in 2007 and the subsequent successes of pharmacological targeting for these fusions, numerous efforts have identified additional oncogenic driver fusions in NSCLCs, especially in lung adenocarcinomas. In this review, we will summarize recent advances in this field focusing on novel oncogenic fusions other than ALK, ROS1, NTRK, and RET fusions, which are summarized in other articles in this thematic issue. These novel gene fusions include neuregulin-1 (NRG1) fusions, MET fusions, fusion genes involving fibroblast growth factor receptor (FGFR) family members, EGFR fusions, and other rare fusions. In addition, evidence has suggested that acquisition of gene fusions by cancer cells can be a molecular mechanism of acquired resistance to targeted therapies. Most of the current data are from analyses of resistance mechanisms to EGFR tyrosine kinase inhibitors in lung cancers with oncogenic EGFR mutations. However, a few recent studies suggest that gene fusions can also be a resistance mechanism to ALK-tyrosine kinase inhibitors in lung cancers with oncogenic ALK fusions. Detection, validation, and pharmacological inhibition of these fusion genes are becoming more important in the treatment of NSCLC patients.
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Affiliation(s)
- Kenichi Suda
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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41
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Laskin J, Liu SV, Tolba K, Heining C, Schlenk RF, Cheema P, Cadranel J, Jones MR, Drilon A, Cseh A, Gyorffy S, Solca F, Duruisseaux M. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol 2020; 31:1693-1703. [PMID: 32916265 DOI: 10.1016/j.annonc.2020.08.2335] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/03/2020] [Accepted: 08/31/2020] [Indexed: 10/23/2022] Open
Abstract
Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.
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Affiliation(s)
- J Laskin
- Division of Medical Oncology, Department of Medicine, University of British Columbia, BC Cancer, Vancouver, BC, Canada.
| | - S V Liu
- Georgetown University Medical Center, Washington, USA
| | - K Tolba
- Oregon Health and Science University, Portland, OR, USA
| | - C Heining
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany; Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden at Technical University Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany
| | - R F Schlenk
- National Center of Tumor Diseases Heidelberg, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - P Cheema
- William Osler Health System, University of Toronto, Toronto, ON, Canada
| | - J Cadranel
- Assistance Publique Hôpitaux de Paris, Hôpital Tenon and Sorbonne Université, Paris, France
| | - M R Jones
- QIAGEN Digital Insights, QIAGEN Inc., Redwood City, CA, USA
| | - A Drilon
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A Cseh
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - S Gyorffy
- AstraZeneca Canada Ltd, Mississauga, ON, Canada
| | - F Solca
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - M Duruisseaux
- Hospices Civils de Lyon Cancer Institute, Anticancer Antibodies Lab Cancer Research Center of Lyon INSERM 1052 CNRS 528, Université Claude Bernard Lyon 1, Lyon, France
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Fujino T, Suda K, Mitsudomi T. Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Expert Opin Emerg Drugs 2020; 25:229-249. [PMID: 32615820 DOI: 10.1080/14728214.2020.1791821] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction MET aberrations, including MET exon 14 skipping mutation and amplification, are present in ~5% of non-small cell lung cancer (NSCLC) cases, and these levels are comparable to the frequency of ALK fusion. MET amplification also occurs as an acquired resistance mechanism in EGFR-mutated NSCLC after EGFR tyrosine kinase inhibitors (TKI) treatment failure. Therefore, the development of therapies for activated MET is urgently needed. Areas covered This review summarizes (1) the mechanisms and frequencies of MET aberrations in NSCLC, (2) the efficacies and toxicities of MET-TKIs under clinical development and (3) the mechanisms of inherent and acquired resistance to MET-TKIs. Expert opinion Type Ia, Ib and II MET-TKIs are currently under clinical development, and phase I/II studies have shown the potent activities of tepotinib, capmatinib and savolitinib; in fact, tepotinib and capmatinib were approved for use by health authorities. However, inherent and acquired resistance through on- and off-target mechanisms has been detected, and strategies to overcome this resistance are being developed.
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Affiliation(s)
- Toshio Fujino
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
| | - Kenichi Suda
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
| | - Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
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Qian C, Liu H, Feng Y, Meng S, Wang D, Nie M, Xu M. Clinical characteristics and risk of second primary lung cancer after cervical cancer: A population-based study. PLoS One 2020; 15:e0231807. [PMID: 32756555 PMCID: PMC7406086 DOI: 10.1371/journal.pone.0231807] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/09/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Lung cancer is increasingly common as a second primary malignancy. However, the clinical characteristics of second primary non-small cell lung cancer after cervical cancer (CC-NSCLC) compared with first primary non-small cell lung cancer (NSCLC1) is unknown. METHODS The Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1998 and 2010 was used to conduct a large population-based cohort analysis. The demographic and clinical characteristics, as well as prognostic data, were systematically analyzed. The overall survival (OS) in the two cohorts was further compared. The risk factors of second primary lung cancer in patients with cervical cancer were also analyzed. RESULTS A total of 557 patients (3.52%) developed second primary lung cancer after cervical cancer, and 451 were eligible for inclusion in the final analyses. Compared with NSCLC1, patients with CC-NSCLC had a higher rate of squamous cell carcinoma (SCC) (36.59% vs 19.07%, P < 0.01). The median OS was longer for CC-NSCLC than for NSCLC1 before propensity score matching (PSM) (16 months vs. 13 months) but with no significant difference after PSM (16 months vs. 17 months). The high-risk factors for the development of cervical cancer to CC-NSCLC include age 50-79 years, black race [odds ratio (OR) 1.417; 95% confidence interval (CI) 1.095-1.834; P < 0.05], and history of radiotherapy (OR 1.392; 95% CI 1.053-1.841; P < 0.05). CONCLUSION Age 50-79 years, black race, and history of radiotherapy were independent risk factors for second primary lung cancer in patients with cervical cancer. Patients with CC-NSCLC had distinctive clinical characteristics and better prognosis compared with patients with NSCLC1.
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Affiliation(s)
- Chengyuan Qian
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Hong Liu
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Yan Feng
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Shenglan Meng
- Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Dong Wang
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Mao Nie
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingfang Xu
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
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Kunte S, Stevenson J. A Case of HLA-DRB1-MET Rearranged Lung Adenocarcinoma With Rapid Response to Crizotinib. Clin Lung Cancer 2020; 22:e298-e300. [PMID: 32654927 DOI: 10.1016/j.cllc.2020.05.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/21/2020] [Accepted: 05/06/2020] [Indexed: 11/19/2022]
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Guo R, Luo J, Chang J, Rekhtman N, Arcila M, Drilon A. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat Rev Clin Oncol 2020; 17:569-587. [PMID: 32514147 DOI: 10.1038/s41571-020-0377-z] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
Attempts to develop MET-targeted therapies have historically focused on MET-expressing cancers, with limited success. Thus, MET expression in the absence of a genomic marker of MET dependence is a poor predictor of benefit from MET-targeted therapy. However, owing to the development of more sensitive methods of detecting genomic alterations, high-level MET amplification and activating MET mutations or fusions are all now known to be drivers of oncogenesis. MET mutations include those affecting the kinase or extracellular domains and those that result in exon 14 skipping. The activity of MET tyrosine kinase inhibitors varies by MET alteration category. The likelihood of benefit from MET-targeted therapies increases with increasing levels of MET amplification, although no consensus exists on the optimal diagnostic cut-off point for MET copy number gains identified using fluorescence in situ hybridization and, in particular, next-generation sequencing. Several agents targeting exon 14 skipping alterations are currently in clinical development, with promising data available from early-phase trials. By contrast, the therapeutic implications of MET fusions remain underexplored. Here we summarize and evaluate the utility of various diagnostic techniques and the roles of different classes of MET-targeted therapies in cancers with MET amplification, mutation and fusion, and MET overexpression.
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Affiliation(s)
- Robin Guo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jia Luo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jason Chang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander Drilon
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. .,Weill Cornell Medical College, New York, NY, USA.
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Ma L, Zhang Q, Dong Y, Li H, Wang J. SPECC1L-ALK: A novel gene fusion response to ALK inhibitors in non-small cell lung cancer. Lung Cancer 2020; 143:97-100. [PMID: 32216970 DOI: 10.1016/j.lungcan.2020.03.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 03/14/2020] [Indexed: 11/27/2022]
Affiliation(s)
- Li Ma
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, China
| | - Quan Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, China
| | - Yujie Dong
- Departments of Pathology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Haoyang Li
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, China
| | - Jinghui Wang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, China.
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Ou SHI, Zhu VW, Nagasaka M. Catalog of 5' Fusion Partners in ALK-positive NSCLC Circa 2020. JTO Clin Res Rep 2020; 1:100015. [PMID: 34589917 PMCID: PMC8474466 DOI: 10.1016/j.jtocrr.2020.100015] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 02/05/2020] [Indexed: 12/17/2022] Open
Abstract
Since the discovery of anaplastic lymphoma kinase fusion-positive (ALK+) NSCLC in 2007, the methods to detect ALK+ NSCLC have evolved and expanded from fluorescence in situ hybridization and immunohistochemistry to next-generation DNA sequencing, targeted RNA sequencing, and whole transcriptome sequencing. As such, the deep sequencing methods have resulted in the expansion of distinct fusion partners identified in ALK+ NSCLC to 90 (one variant PLEKHM2-ALK is found in small cell lung cancer but included in this catalog) by the end of January 2020; about 65 of them (since 2018) and most of the recent novel fusion partners were reported from China. Thirty-four of the distinct fusion partners are located on the short arm of chromosome 2; 28 of these 34 fusion partners are located on 2p21-25, in which ALK is located on 2p23.2-p23.1. Many of these new ALK+ NSCLC fusion variants have responded to ALK tyrosine kinase inhibitors (TKIs). Several of these novel ALK fusion variants were identified as being resistant to EGFR TKIs or as dual 3'ALK fusions. In addition, at least 28 intergenic ALK rearrangements have also been reported, with three of them reported as responding to crizotinib. This review aims to serve as a central source of reference of fusion partners in ALK+ NSCLC for clinicians and scientists. We aim to update and improve the list going forward.
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Affiliation(s)
- Sai-Hong Ignatius Ou
- Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
| | - Viola W. Zhu
- Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
| | - Misako Nagasaka
- Department of Oncology, Karmanos Cancer Institute/Wayne State University School of Medicine, Detroit, Michigan
- Department of Advanced Medical Innovations, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa, Japan
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Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis. Lung Cancer 2020; 139:207-215. [DOI: 10.1016/j.lungcan.2019.11.022] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/18/2019] [Accepted: 11/25/2019] [Indexed: 01/16/2023]
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Zhang Z, Yang S, Wang Q. Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-mutant lung cancer. Biomark Res 2019; 7:27. [PMID: 31832192 PMCID: PMC6873421 DOI: 10.1186/s40364-019-0179-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/08/2019] [Indexed: 12/24/2022] Open
Abstract
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have achieved remarkable outcomes in the treatment of patients with EGFR-mutant non-small-cell lung cancer, but acquired resistance is still the main factor restricting their long-term use. In addition to the T790 M mutation of EGFR, amplification of the MET (or c-MET) gene has long been recognized as an important resistance mechanism for first- or second-generation EGFR-TKIs. Recent studies suggest that a key mechanism of acquired resistance to third-generation EGFR-TKIs (such as osimertinib) may be MET amplification and/or protein overactivation, especially when they are used as a first-line treatment. Therefore, in patients resistant to first-generation EGFR-TKIs caused by MET amplification and/or protein overactivation, the combination of osimertinib with MET or MEK inhibitors may be considered.
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Affiliation(s)
- Zhe Zhang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Sen Yang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Qiming Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008 China
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