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Liu ZH, Zhu BW, Shi M, Qu YR, He XJ, Yuan HL, Ma J, Li W, Zhao DD, Liu ZC, Wang BM, Wang CY, Tao HQ, Ma TH. Profiling of gene fusion involving targetable genes in Chinese gastric cancer. World J Gastrointest Oncol 2022; 14:1528-1539. [PMID: 36160735 PMCID: PMC9412921 DOI: 10.4251/wjgo.v14.i8.1528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/14/2022] [Accepted: 07/19/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.
AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.
METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.
RESULTS We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB.
CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
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Affiliation(s)
- Zhen-Hua Liu
- Department of Medical Oncology, Fujian Medical University, Fuzhou 350001, Fujian Province, China
| | - Bo-Wen Zhu
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Min Shi
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Yu-Rong Qu
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Xun-Jun He
- Department of Genetics and Genomic Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Hong-Ling Yuan
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Wei Li
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Dan-Dan Zhao
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Zheng-Chuang Liu
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Bao-Ming Wang
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Chun-Yang Wang
- Medical Center, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
| | - Hou-Quan Tao
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
- Department of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Tong-Hui Ma
- Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd., Beijing 102200, China
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Hou H, Zhang C, Qi X, Zhou L, Liu D, Lv H, Li T, Sun D, Zhang X. Distinctive targetable genotypes of younger patients with lung adenocarcinoma: a cBioPortal for cancer genomics data base analysis. Cancer Biol Ther 2019; 21:26-33. [PMID: 31594446 DOI: 10.1080/15384047.2019.1665392] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
There is still limited comprehensive genotyping data about young patients with lung adenocarcinoma. Herein, next generation sequencing (NGS) data of lung adenocarcinoma patients was retrospectively analyzed to evaluate the relationship between young age at diagnosis and the comprehensive molecular characteristics. The cBioPortal for Cancer Genomics database was queried for cancer genomic studies of lung adenocarcinoma and a cohort of 773 patients with complete cancer genomics data was selected from 2 of 11 studies. The relationship between age at diagnosis and frequency of targetable genotypes was analyzed and verified in another cohort composed of 177 Chinese lung adenocarcinoma patients undergoing NGS assay. Of the 773 eligible lung adenocarcinoma patients, younger age was associated with an increased likelihood of a targetable genotype (P < .001). Specifically, a higher prevalence of EGFR mutations (P = .005), ALK arrangements, ROS1 arrangements (P = .035) and RET arrangements (P < .001) were identified in younger patients. The frequency of KRAS mutations (P < .001) was significantly associated with older age at diagnosis and a similar trend existed for MET (P = .057) but not BRAF-V600E (P = .686) and ERBB2 (P = .083). Additionally, an age at diagnosis of 45 years was found to be a feasible cutoff point to differentiate the younger from the older patients by comprehensive molecular characteristics. These results indicated that younger patients with lung adenocarcinoma were associated with an increased likelihood of harboring a targetable genotype. Distinctive molecular characteristics were identified in patients younger than 45 years with lung adenocarcinoma, which highlights the importance of the NGS assay and personalized therapy in this subpopulation.
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Affiliation(s)
- Helei Hou
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chuantao Zhang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaogai Qi
- Department of Radiotherapy, Qingdao Central Hospital, The Second Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Zhou
- Department of Pathology, The Municipal Hospital of Qingdao, Qingdao, China
| | - Dong Liu
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongying Lv
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tianjun Li
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dantong Sun
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaochun Zhang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Salgia R. Diagnostic challenges in non-small-cell lung cancer: an integrated medicine approach. Future Oncol 2015; 11:489-500. [PMID: 25675128 DOI: 10.2217/fon.14.275] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The discovery of diverse driver mutations in lung cancer has heralded a new era of personalized medicine in thoracic oncology, with targeted therapies approved for specific subgroups of patients. The increasing number of patient subgroups that may respond to targeted therapy has resulted in a greater reliance upon effective and increasingly complex diagnostics, which must be interpreted in an interactive multidisciplinary forum. This review discusses the molecular diagnostics available and under development for established and emerging targets, and how these may be integrated into current treatment algorithms. The roles of the pulmonologist, interventional radiologist, thoracic surgeon and molecular pathologist are discussed, and their interactions with the medical oncologist, and/or thoracic surgeon and radiation oncologist in making individual treatment decisions.
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Heigener DF, Gandara DR, Reck M. Targeting of MEK in lung cancer therapeutics. THE LANCET RESPIRATORY MEDICINE 2015; 3:319-27. [PMID: 25801412 DOI: 10.1016/s2213-2600(15)00026-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The MAP-kinase pathway, consisting of the kinases RAS, RAF, MEK, and ERK, is crucial for cell proliferation, inhibition of apoptosis, and migration of cells. Direct inhibition of RAS is not yet possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small-cell lung cancer (NSCLC). Due to their structure and function, the MEK proteins are attractive targets for cancer therapy and are also under investigation in NSCLC. We discuss strategies of targeting the RAS-RAF-MEK-ERK pathway with emphasis on MEK inhibition, either alone or in combination with other targets or conventional chemotherapy.
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Affiliation(s)
- David F Heigener
- Department of Thoracic Oncology, LungenClinic Grosshansdorf; member of the Airway research center north (ARCN) as part of the German Centre for Lung Research (DZL), Grosshansdorf, Germany.
| | - David R Gandara
- Division of Hematology/Oncology, UC Davis Comprehensive Cancer Center, Sacramento, USA
| | - Martin Reck
- Department of Thoracic Oncology, LungenClinic Grosshansdorf; member of the Airway research center north (ARCN) as part of the German Centre for Lung Research (DZL), Grosshansdorf, Germany
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Parker D, Belaud-Rotureau MA. Micro-cost Analysis of ALK Rearrangement Testing by FISH to Determine Eligibility for Crizotinib Therapy in NSCLC: Implications for Cost Effectiveness of Testing and Treatment. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2014; 8:145-52. [PMID: 25520569 PMCID: PMC4260793 DOI: 10.4137/cmo.s19236] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 10/12/2014] [Accepted: 10/20/2014] [Indexed: 11/30/2022]
Abstract
Break-apart fluorescence in situ hybridization (FISH) is the gold standard test for anaplastic lymphoma kinase (ALK) gene rearrangement. However, this methodology often is assumed to be expensive and potentially cost-prohibitive given the low prevalence of ALK-positive non-small cell lung cancer (NSCLC) cases. To more accurately estimate the cost of ALK testing by FISH, we developed a micro-cost model that accounts for all cost elements of the assay, including laboratory reagents, supplies, capital equipment, technical and pathologist labor, and the acquisition cost of the commercial test and associated reagent kits and controls. By applying a set of real-world base-case parameter values, we determined that the cost of a single ALK break-apart FISH test result is $278.01. Sensitivity analysis on the parameters of batch size, testing efficiency, and the cost of the commercial diagnostic testing products revealed that the cost per result is highly sensitive to batch size, but much less so to efficiency or product cost. This implies that ALK testing by FISH will be most cost effective when performed in high-volume centers. Our results indicate that testing cost may not be the primary determinant of crizotinib (Xalkori®) treatment cost effectiveness, and suggest that testing cost is an insufficient reason to limit the use of FISH testing for ALK rearrangement.
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Affiliation(s)
| | - Marc-Antoine Belaud-Rotureau
- Université de Rennes 1, Faculté de Médecine, Rennes, France. ; Service de Cytogénétique et Biologie Cellulaire, CHU de Rennes, Rennes, France. ; UMR 6290 IGDR, Cancer du Rein-BIOSIT, Rennes, France
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Wang Y, Wang S, Xu S, Qu J, Liu B. Clinicopathologic features of patients with non-small cell lung cancer harboring the EML4-ALK fusion gene: a meta-analysis. PLoS One 2014; 9:e110617. [PMID: 25360721 PMCID: PMC4215846 DOI: 10.1371/journal.pone.0110617] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 09/19/2014] [Indexed: 11/25/2022] Open
Abstract
Background The frequencies of EML4-ALK fusion gene in non-small cell lung cancer (NSCLC) with different clinicopathologic features described by previous studies are inconsistent. The key demographic and pathologic features associated with EML4-ALK fusion gene have not been definitively established. This meta-analysis was conducted to compare the frequency of the EML4-ALK fusion gene in patients with different clinicopathologic features and to identify an enriched population of patients with NSCLC harboring EML4-ALK fusion gene. Methods The Pubmed and Embase databases for all studies on EML4-ALK fusion gene in NSCLC patients were searched up to July 2014. A criteria list and exclusion criteria were established to screen the studies. The frequency of the EML4-ALK fusion gene and the clinicopathologic features, including smoking status, pathologic type, gender, and EGFR status were abstracted. Results Seventeen articles consisting of 4511 NSCLC cases were included in this meta-analysis. A significant lower EML4-ALK fusion gene positive rate was associated with smokers (pooled OR = 0.40, 95% CI = 0.30–0.54, P<0.00001). A significantly higher EML4-ALK fusion gene positivity rate was associated with adenocarcinomas (pooled OR = 2.53, 95% CI = 1.66–3.86, P<0.0001) and female (pooled OR = 0.61, 95% CI = 0.41–0.90, P = 0.01). We found that a significantly lower EML4-ALK fusion gene positivity rate was associated with EGFR mutation (pooled OR = 0.07, 95% CI = 0.03–0.19, P<0.00001). No publication bias was observed in any meta-analysis (all P value of Egger's test >0.05); however, because of the small sample size, no results were in the meta-analysis regarding EGFR gene status. Conclusion This meta-analysis revealed that the EML4-ALK fusion gene is highly correlated with a never/light smoking history, female and the pathologic type of adenocarcinoma, and is largely mutually exclusive of EGFR.
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Affiliation(s)
- Ying Wang
- Department of Pathology, Shenyang Medical College, Shenyang, Liaoning, People's Republic of China
| | - Shumin Wang
- Thoracic Department, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, People's Republic of China
| | - Shiguang Xu
- Thoracic Department, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, People's Republic of China
| | - Jiaqi Qu
- Thoracic Department, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, People's Republic of China
| | - Bo Liu
- Thoracic Department, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, People's Republic of China
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