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Tajè R, Ambrogi V, Tacconi F, Gallina FT, Alessandrini G, Forcella D, Buglioni S, Visca P, Patirelis A, Cecere FL, Melis E, Vidiri A, Sperduti I, Cappuzzo F, Novello S, Caterino M, Facciolo F. Kirsten Rat Sarcoma Virus Mutations Effect On Tumor Doubling Time And Prognosis Of Solid Dominant Stage I Lung Adenocarcinoma. Clin Lung Cancer 2025; 26:210-220.e1. [PMID: 39863430 DOI: 10.1016/j.cllc.2025.01.001] [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: 09/20/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025]
Abstract
INTRODUCTION To analyze the impact of Kirsten-Rat-Sarcoma Virus (KRAS) mutations on tumor-growth as estimated by tumor-doubling-time (TDT) among solid-dominant clinical-stage I lung adenocarcinoma. Moreover, to evaluate the prognostic role of KRAS mutations, TDT and their combination in completely-resected pathologic-stage I adenocarcinomas. METHODS In this single-center retrospective analysis, completely resected clinical-stage I adenocarcinomas presenting as solid-dominant nodules (consolidation-to-tumor ratio > 0.5) in at least 2 preoperative computed-tomography scans were enrolled. Nodules' growth was scored as fast (TDT < 400 days) or slow (TDT > 400 days). KRAS-mutated adenocarcinomas were identified with next-generation sequencing. Logistic- and Cox-regressions were used to identify predictors of fast-growth and disease-free survival (DFS), respectively. RESULTS Among 151 patients, 83 (55%) had fast-growing nodules and 64 (42.4%) were KRAS-mutated. Fast-growing nodules outnumbered in the KRAS-mutated group (n = 45; 70.3%), median TDT 95-days (interquartile range, IQR 43.5-151.5) compared to the KRAS wild-type group (38, 43.7%), median TDT 138-days (IQR 70.3-278.5). KRAS-mutations predicted faster-growth at multivariable analysis (P = .009). In a subgroup analysis including 108 pathologic-stage I adenocarcinomas, neither KRAS-mutations (P = .081) nor fast-growing pattern (P = .146) affected DFS. Nevertheless, the association of KRAS-mutations and fast-growing pattern identified a subgroup of patients with worse DFS (P = .02). The combination of fast-growing and KRAS-mutations (hazard-ratio 2.97 [95%CI 1.22-7.25]; P = .017) and average nodule diameter at diagnosis (hazard-ratio 1.08 [95%CI 1.03-1.14]; P = .004) were independent predictors of worse DFS. CONCLUSION KRAS mutations are associated to faster growth, in clinical-stage I adenocarcinoma presenting at diagnosis as solid-dominant nodules undergoing complete resection. Moreover, faster-growth identifies a subgroup of pathologic-stage I KRAS-mutated adenocarcinomas with higher recurrences.
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Affiliation(s)
- Riccardo Tajè
- Doctoral School of Microbiology, Immunology, Infectious Diseases and Transplants, MIMIT, University of Rome "Tor Vergata", Rome, Italy; Thoracic Surgery Unit, IRCCS National Cancer Institute Regina Elena, Rome, Italy.
| | - Vincenzo Ambrogi
- Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
| | - Federico Tacconi
- Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
| | | | | | - Daniele Forcella
- Thoracic Surgery Unit, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Simonetta Buglioni
- Department of pathology, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Paolo Visca
- Department of pathology, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | | | | | - Enrico Melis
- Thoracic Surgery Unit, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Antonello Vidiri
- Department of radiology, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Isabella Sperduti
- Biostatistics, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Federico Cappuzzo
- Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Silvia Novello
- Department of Oncology, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy
| | - Mauro Caterino
- Department of radiology, IRCCS National Cancer Institute Regina Elena, Rome, Italy
| | - Francesco Facciolo
- Thoracic Surgery Unit, IRCCS National Cancer Institute Regina Elena, Rome, Italy
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Zhang C, Yang C, Shi Q. Effects of Tp53 Gene Mutations on the Survival of Non-Small Cell Lung Cancer (NSCLC); A Short Review. Cancer Manag Res 2025; 17:65-82. [PMID: 39830995 PMCID: PMC11742633 DOI: 10.2147/cmar.s495006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/14/2024] [Indexed: 01/22/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Mutations within the TP53 gene represent critical molecular events in NSCLC, contributing to the tumorigenesis in the pulmonary epithelial tissues. TP53 is a widely researched prognostic indicator in NSCLC, and pathological investigations have revealed a weak to mild negative predictive effect for TP53. Mutated p53 protein may have some pro-oncogenic impact, and the variations may change tumor inhibitors into oncogenes. The diverse mutational spectrum of TP53 in NSCLC with different mutations is linked to varied treatment responses. In contrast, first-line chemotherapeutics to this progress are limited, however, randomized trials with new chemotherapeutics have shown significant survival benefits. This review highlighted the critical influence of TP53 gene mutations on pathological-sensitivity and overall survival outcomes in NSCLC. Further research is needed to explore TP53 mutation-specific pathways and their effects on NSCLC progression and treatment effectiveness.
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Affiliation(s)
- Chi Zhang
- Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China
- Anhui Medical University Clinical College of Chest, Hefei, 230022, People’s Republic of China
| | - Chao Yang
- Department of Urology, Anhui Provincial Children’s Hospital, Hefei, 230022, People’s Republic of China
| | - Qingming Shi
- Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China
- Anhui Medical University Clinical College of Chest, Hefei, 230022, People’s Republic of China
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Cui S, Yang Y, Lou S, Huang R, Wang J, Chen Z, Xie J. Establish a novel immune-related gene prognostic risk index (IRGPRI) associated with CD8+ cytotoxic T lymphocytes in non-small-cell lung cancer (NSCLC). Heliyon 2024; 10:e38324. [PMID: 39397989 PMCID: PMC11466668 DOI: 10.1016/j.heliyon.2024.e38324] [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: 04/22/2024] [Revised: 09/22/2024] [Accepted: 09/22/2024] [Indexed: 10/15/2024] Open
Abstract
Background The aim of this study is to create an index called IRGPRI (immune-related gene prognostic risk index) that can be utilized for predicting the prognosis and assessing the efficacy of immune checkpoint inhibitors (ICIs) therapy in patients with non-small-cell lung cancer (NSCLC). Methods Distinguishing gene expression patterns (DEGs) were detected in CD8+ cytotoxic T lymphocytes (CTLs) compared to other cellular types such as CD4 T cells, B cells, plasma cells, and CD8 Tex using the advanced technology of Single-cell RNA Sequencing (scRNA-seq). The construction of IRGPRI was accomplished by employing LASSO Cox regression analysis. We conducted a comparative analysis on clinical characteristics and molecular features, such as pathway enrichment and gene mutation, among the distinct subgroups of IRGPRI. Furthermore, we explored the correlation between immunological characteristics and IRGPRI subgroups to comprehensively assess the effectiveness of ICIs in NSCLC patients. Results A total of 109 genes were identified by intersecting immune-related genes with DEGs obtained from single-cell RNA sequencing data (GSE131907), specifically comparing CTLs to other cell types. From these, we selected 7 prognosis-related genes, namely TRBC1, HLA-DMA, CTSH, RAC1, CTSL, ANXA2, and CEBPB. These genes were used to construct the IRGPRI. The prognosis of patients diagnosed with NSCLC was found to be significantly better in the low-risk group compared to the high-risk group, as demonstrated by Kaplan-Meier (K-M) survival analysis. This observation was further confirmed through the utilization of data from the GEO cohort. The low-risk group demonstrated an increase in pathways linked with immune response, whereas the high-risk group exhibited a higher prevalence of pathways related to cancer. Furthermore, it was noted in the TCGA cohort that there existed a significant rise in the mutation frequency of every gene within the high-risk group as opposed to the low-risk group. Missense variation emerged as the most prevalent form of mutation. According to the analysis of immune cell infiltration and function, the comprehensive findings suggest that the group with a low risk is characterized by an increased presence of plasma cells, CTLs, T cells follicular helper, Tregs, and Dendritic cell resting. Additionally, they exhibit a higher score in terms of immune function for B cells, CD8+ T cells, checkpoint activity, T cell inhibition and stimulation. Moreover, this low-risk group demonstrates greater efficacy when treated with ICIs therapy compared to the high-risk group. Conclusions Our research effectively developed and verified a unique IRGPRI, showcasing its association with immune-related characteristics. As a result, the potential of IRGPRI as a valuable biomarker for predicting prognosis and evaluating the effectiveness of ICIs treatment in cancer is evident.
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Affiliation(s)
- Shenjing Cui
- Department of Clinical Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yikun Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Shuang Lou
- Department of Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Rong Huang
- Department of Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jing Wang
- Department of Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhongbiao Chen
- Department of Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jingjing Xie
- Department of Medical Administration, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Song Y, Zhou D, Zhang P, Zhu N, Guo R, Wang T, Zhuang F, Sun D. Heparanase accelerates the angiogenesis and inhibits the ferroptosis of p53-mutant non-small cell cancers in VEGF-dependent manner. Cytotechnology 2024; 76:503-517. [PMID: 39188651 PMCID: PMC11344742 DOI: 10.1007/s10616-024-00632-3] [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: 11/09/2023] [Accepted: 04/17/2024] [Indexed: 08/28/2024] Open
Abstract
The aim of this study is to explore the effects and specific mechanisms of heparanase on angiogenesis and iron deficiency anemia in TP53 mutant cancer. For this purpose, we conducted in vitro cell experiments and in vivo animal experiments respectively. In this study, we first analyzed the differential expression of heparanase in TP53 wild-type and mutant cells, and analyzed its effects on iron removal and angiogenesis in two types of CALU-1 and NCI-H358 cells. Secondly, we validated whether the mechanism of action of heparanase on TP53 mutant cells for iron removal and angiogenesis is related to VEGF. We applied the iron removal agonist erastin and VEGF inhibitor bevacizumab in both in vitro and in vivo experiments to validate the relationship between heparanase and VEGF in the mechanisms of iron removal and angiogenesis. The experimental results show that heparanase is highly expressed in TP53 mutated cancer cells, and has anti-ferroptosis and pro-angiogenic effects. Our experiment also confirmed that the effect of heparanase on TP53 mutant cancer's iron removal and angiogenesis is related to VEGF. In short, heparanase is highly expressed in p53 mutated lung cancer, and the mechanism of ferroptosis tolerance to TP53 mutated cancer is related to VEGF.
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Affiliation(s)
- Yaobo Song
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Dongmei Zhou
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Ping Zhang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Na Zhu
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Ruijuan Guo
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Tian Wang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Feifei Zhuang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Dengjun Sun
- Department of Medical Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000 Shandong Province China
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Haddad B, Khalil J, Al Khashali H, Ray R, Goel S, Darweesh B, Coleman KL, Wozniak C, Ranzenberger R, Lopo B, Guthrie J, Heyl D, Evans HG. The role of leptin in regulation of the soluble amyloid precursor protein α (sAPPα) levels in lung cancer cell media. Sci Rep 2024; 14:4921. [PMID: 38418632 PMCID: PMC10901813 DOI: 10.1038/s41598-024-55717-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/27/2024] [Indexed: 03/02/2024] Open
Abstract
Previously, we found that the levels of soluble amyloid precursor protein α (sAPPα) are regulated, in part, by acetylcholinesterase (AChE) in human A549 (p53 wild-type) and H1299 (p53-null) NSCLC cell lines. In this study, we found regulation of sAPPα levels in the media by leptin, a widely recognized obesity-associated adipokine that has recently been shown to play a possible role in cancer signaling. Increased levels of sAPPα, that were accompanied by lower Aβ40/42 levels in the media of A549 and H1299 cells, were detected upon cell incubation with leptin. Conversely, knockdown of leptin or its receptor led to reduced levels of sAPPα and increased levels of Aβ40/42 in the media of A549 and H1299 cells, suggesting that leptin likely shifts APP processing toward the non-amyloidogenic pathway. A549 cell treatment with leptin increased acetylcholine levels and blocked the activities of AChE and p53. Treatment with leptin resulted in increased activation of PKC, ERK1/2, PI3K, and the levels of sAPPα, effects that were reversed by treatment with kinase inhibitors and/or upon addition of AChE to A549 and H1299 cell media. Cell viability increased by treatment of A549 and H1299 cells with leptin and decreased upon co-treatment with AChE and/or inhibitors targeting PKC, ERK1/2, and PI3K. This study is significant as it provides evidence for a likely carcinogenic role of leptin in NSCLC cells via upregulation of sAPPα levels in the media, and highlights the importance of targeting leptin as a potential therapeutic strategy for NSCLC treatment.
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Affiliation(s)
- Ben Haddad
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Jeneen Khalil
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Hind Al Khashali
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Ravel Ray
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Stuti Goel
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Ban Darweesh
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Kai-Ling Coleman
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Caroline Wozniak
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Robert Ranzenberger
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Brooke Lopo
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Jeffrey Guthrie
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Deborah Heyl
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA
| | - Hedeel Guy Evans
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI, 48197, USA.
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Mendoza RP, Chen‐Yost HI, Wanjari P, Wang P, Symes E, Johnson DN, Reeves W, Mueller J, Antic T, Biernacka A. Lung adenocarcinomas with isolated TP53 mutation: A comprehensive clinical, cytopathologic and molecular characterization. Cancer Med 2024; 13:e6873. [PMID: 38164123 PMCID: PMC10824142 DOI: 10.1002/cam4.6873] [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: 10/11/2023] [Revised: 11/14/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND TP53 mutation is present in about 50.8% of lung adenocarcinomas, frequently in combination with other genetic alterations. However, a rare subset harbors the TP53 mutation alone. METHODS Next-generation sequencing was performed in 844 lung adenocarcinomas diagnosed by fine needle aspiration. Fourteen cases (1.7%) showed isolated TP53 alteration and were subjected to a comprehensive analysis. RESULTS The average age at diagnosis was 65.7 years (range 48-79); 9 males and 5 females. All were smokers with an average pack-year of 40.7 (range 10-70). Ten had metastases, mostly in the brain (n = 4) and pleura (n = 4). After a follow-up period of up to 102 months, 9 died, 3 were alive free of disease, 1 was alive with disease, and 1 was lost to follow-up. The median survival was 12.2 months. Most tumors exhibited poor differentiation, composed of solid sheets with moderate to severe atypia, increased mitotic activity, and necrotic background. Half were positive for TTF-1 and showed p53 overexpression. PD-L1 was positive in 5 cases. Most alterations were missense mutations in exons 5-8, and this mutation type was associated with p53 overexpression. Tumors with combined missense mutation and truncated protein had higher PD-L1 expression along with a trend towards an increase in tumor mutational burden (TMB). CEBPA deletion of undetermined significance was the most common copy number alteration. CONCLUSION Isolated TP53 mutation was seen in association with smoking, high-grade cytomorphologic features, adverse prognosis, and recurrent CEBPA deletions. These tumors tend to have strong PD-L1 expression and high TMB, suggesting potential benefit from immune checkpoint inhibitors. Hence, the recognition of this molecular group has prognostic and therapeutic implications.
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Affiliation(s)
- Rachelle P. Mendoza
- Department of PathologyUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | | | - Pankhuri Wanjari
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Peng Wang
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Emily Symes
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Daniel N. Johnson
- Department of PathologyOSF Little Company of Mary Medical CenterEvergreen ParkIllinoisUSA
| | - Ward Reeves
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Jeffrey Mueller
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Tatjana Antic
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
| | - Anna Biernacka
- Department of PathologyThe University of Chicago HospitalsChicagoIllinoisUSA
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Zhong J, Li L, Zhang Q, Zou J, Liu W, Xu CH. Expression and prognostic value of Cripto-1 in early non-small cell lung cancer. THE CLINICAL RESPIRATORY JOURNAL 2023; 17:1203-1208. [PMID: 37528674 PMCID: PMC10730460 DOI: 10.1111/crj.13680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 04/24/2023] [Accepted: 07/23/2023] [Indexed: 08/03/2023]
Abstract
OBJECTIVE We aim to explore the expression of Cripto-1 (CR-1) protein in patients with early stage non-small cell lung cancer (NSCLC). METHODS We investigated CR-1 expression status in specimens obtained from 240 patients with resected NSCLC and 30 cases of para-carcinous normal lung tissues. RESULTS Compared with normal lung tissue, the positive expression of CR-1 protein in NSCLC was significantly increased (p < 0.005). Cox multivariate regression analysis showed that the expression of CR-1 protein was an independent prognostic factor for early stage NSCLC (p = 0.002). CONCLUSION Detecting CR-1 protein can predict the prognosis and recurrence in patients with NSCLC.
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Affiliation(s)
- Jian Zhong
- Department of Thoracic SurgeryAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
| | - Li Li
- Department of Respiratory MedicineAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
- Clinical Center of Nanjing Respiratory Diseases and ImagingNanjingChina
| | - Qian Zhang
- Department of Respiratory MedicineAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
- Clinical Center of Nanjing Respiratory Diseases and ImagingNanjingChina
| | - Jue Zou
- Department of PathologyAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
| | - Wei Liu
- Department of Respiratory MedicineAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
| | - Chun Hua Xu
- Department of Respiratory MedicineAffiliated Nanjing Brain Hospital, Nanjing Medical UniversityNanjingChina
- Clinical Center of Nanjing Respiratory Diseases and ImagingNanjingChina
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Nasuh S, Balci SO, Bozgeyik I, Ikeda MA, Tekayev M, Saadat KASM. ARID3A and ARID3B exert direct regulatory control over the long non-coding RNAs (lncRNAs) MALAT1 and NORAD within the context of non-small cell lung cancer (NSCLC). Pathol Res Pract 2023; 252:154948. [PMID: 37977034 DOI: 10.1016/j.prp.2023.154948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 11/10/2023] [Indexed: 11/19/2023]
Abstract
Lung cancer, known for its high mortality rates and poor prognosis, remains one of the most prevalent cancer types. Early detection and effective treatment methods are crucial for improving survival rates. Non-small cell lung cancer (NSCLC) accounts for approximately 85 % of all lung cancer cases. Long non-coding RNAs (lncRNAs), which play vital roles in various biological processes, have been implicated in the development of cancer and can impact key therapeutic targets in different cancer types. In NSCLC, the dysregulation of specific lncRNAs, such as MALAT1 and NORAD, has been associated with neoplastic initiation, progression, metastasis, tumor angiogenesis, chemoresistance, and genomic instability. Both MALAT1 and NORAD directly regulate the expression of the transcription factor E2F1, thereby influencing cell cycle progression. Additionally, MALAT1 has been reported to affect the expression of p53 target genes, leading to cell cycle progression through the repression of p53 promoter activity. NORAD, on the other hand, is indirectly regulated by p53. The AT-rich interaction domain (ARID) family of DNA-binding proteins, particularly ARID3A and ARID3B, are involved in various biological processes such as cell proliferation, differentiation, and development. They also play significant roles in E2F-dependent transcription and are transcriptional targets of p53. The intricate balance between promoting cellular proliferation through the pRB-E2F pathway and inducing growth arrest through the p53 pathway underscores the crucial regulatory role of ARID3A, ARID3B, and their interaction with lncRNAs MALAT1 and NORAD. In this study, we aimed to investigate the potential interactive and functional connections among ARID3A, ARID3B, MALAT1, and NORAD in NSCLC, considering their involvement in the pRB-E2F and p53 pathways. Our findings strongly suggest that ARID3A and ARID3B play a regulatory role in controlling MALAT1 and NORAD in NSCLC. Specifically, our study demonstrates that the activities of MALAT1 and NORAD were markedly increased upon the overexpression of ARID3A and ARID3B. Therefore, we can conclude that ARID3A and ARID3B likely contribute significantly to the oncogenic functions of MALAT1 and NORAD in NSCLC. Consequently, targeting ARID3A and ARID3B could hold promise as a therapeutic approach in NSCLC, given their direct control over the expression of MALAT1 and NORAD.
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Affiliation(s)
- Sedin Nasuh
- Department of Medical Biology and Genetics, Faculty of Medicine, Graduate Institute of Health Sciences, Gaziantep University, Gaziantep 27310, Turkey
| | - Sibel Oguzkan Balci
- Department of Medical Biology and Genetics, Faculty of Medicine, Graduate Institute of Health Sciences, Gaziantep University, Gaziantep 27310, Turkey
| | - Ibrahim Bozgeyik
- Department of Medical Biology, Faculty of Medicine Adiyaman University, Adiyaman 02040, Turkey
| | - Masa-Aki Ikeda
- Department of Regenerative and Reconstructive Dental Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Molecular Craniofacial Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Muhammetnur Tekayev
- Department of Medical Biology and Genetics, Faculty of Medicine, Graduate Institute of Health Sciences, Gaziantep University, Gaziantep 27310, Turkey; Department of Histology and Embryology, Hamidiye Faculty of Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul 34668, Turkey
| | - Khandakar A S M Saadat
- Department of Medical Biology and Genetics, Faculty of Medicine, Graduate Institute of Health Sciences, Gaziantep University, Gaziantep 27310, Turkey.
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Ray R, Goel S, Al Khashali H, Darweesh B, Haddad B, Wozniak C, Ranzenberger R, Khalil J, Guthrie J, Heyl D, Evans HG. Regulation of Soluble E-Cadherin Signaling in Non-Small-Cell Lung Cancer Cells by Nicotine, BDNF, and β-Adrenergic Receptor Ligands. Biomedicines 2023; 11:2555. [PMID: 37760996 PMCID: PMC10526367 DOI: 10.3390/biomedicines11092555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/11/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
The ectodomain of the transmembrane protein E-cadherin can be cleaved and released in a soluble form referred to as soluble E-cadherin, or sE-cad, accounting for decreased E-cadherin levels at the cell surface. Among the proteases implicated in this cleavage are matrix metalloproteases (MMP), including MMP9. Opposite functions have been reported for full-length E-cadherin and sE-cad. In this study, we found increased MMP9 levels in the media of two non-small cell lung cancer (NSCLC) cell lines, A549 and H1299, treated with BDNF, nicotine, or epinephrine that were decreased upon cell treatment with the β-adrenergic receptor blocker propranolol. Increased MMP9 levels correlated with increased sE-cad levels in A549 cell media, and knockdown of MMP9 in A549 cells led to downregulation of sE-cad levels in the media. Previously, we reported that A549 and H1299 cell viability increased with nicotine and/or BDNF treatment and decreased upon treatment with propranolol. In investigating the function of sE-cad, we found that immunodepletion of sE-cad from the media of A549 cells untreated or treated with BDNF, nicotine, or epinephrine reduced activation of EGFR and IGF-1R, decreased PI3K and ERK1/2 activities, increased p53 activation, decreased cell viability, and increased apoptosis, while no effects were found using H1299 cells under all conditions tested.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hedeel Guy Evans
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USA; (R.R.); (S.G.); (H.A.K.); (B.D.); (B.H.); (C.W.); (R.R.); (J.K.); (J.G.); (D.H.)
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Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival. Cells 2022; 11:cells11223533. [PMID: 36428962 PMCID: PMC9688904 DOI: 10.3390/cells11223533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/04/2022] [Accepted: 11/05/2022] [Indexed: 11/10/2022] Open
Abstract
In this study, we examined the roles of heparanase and IGFBP-3 in regulating A549 and H1299 non-small-cell lung cancer (NSCLC) survival. We found that H1299 cells, known to be p53-null with no expression of IGFBP-3, had higher heparanase levels and activity and higher levels of heparan sulfate (HS) in the media compared to the media of A549 cells. Inhibiting heparanase activity or its expression using siRNA had no effect on the levels of IGFBP-3 in the media of A549 cells, reduced the levels of soluble HS fragments, and led to decreased interactions between IGFBP-3 and HS in the media. HS competed with HA for binding to IGFBP-3 or IGFBP-3 peptide (215-KKGFYKKKQCRPSKGRKR-232) but not the mutant peptide (K228AR230A). HS abolished the cytotoxic effects of IGFBP-3 but not upon blocking HA-CD44 signaling with the anti-CD44 antibody (5F12). Blocking HA-CD44 signaling decreased the levels of heparanase in the media of both A549 and H1299 cell lines and increased p53 activity and the levels of IGFBP-3 in A549 cell media. Knockdown of p53 led to increased heparanase levels and reduced IGFBP-3 levels in A549 cell media while knockdown of IGFBP-3 in A549 cells blocked p53 activity and increased heparanase levels in the media.
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Di Federico A, De Giglio A, Gelsomino F, De Biase D, Giunchi F, Palladini A, Sperandi F, Melotti B, Ardizzoni A. Genomic Landscape, Clinical Features and Outcomes of Non-Small Cell Lung Cancer Patients Harboring BRAF Alterations of Distinct Functional Classes. Cancers (Basel) 2022; 14:3472. [PMID: 35884534 PMCID: PMC9319412 DOI: 10.3390/cancers14143472] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In non-small cell lung cancer (NSCLC), BRAF class 1 alterations are effectively targeted by BRAF inhibitors. Conversely, targeted therapies have very low or absent activity in patients carrying class 2 and 3 alterations. The spectrum of BRAF alterations in NSCLC patients, and their accompanying clinical features, genomic landscape and treatment outcomes have been poorly reported. PATIENTS AND METHODS We identified BRAF alterations of defined functional class across different tumors through a systematic review. Then, we selected NSCLC patients carrying BRAF alterations, according to the systematic review, in the cBioPortal (cBioPortal cohort) to collect and analyze clinical, biomolecular and survival data. Finally, we identified NSCLC patients carrying BRAF non-V600 mutations enrolled in POPLAR and OAK trials (POPLAR/OAK cohort), extracting clinical and survival data for survival analyses. RESULTS 100 different BRAF non-V600 alterations were identified through the systematic review. In the cBioPortal cohort (n = 139), patients harboring class 2 and 3 alterations were more frequently smokers and had higher tumor mutational burden compared to those carrying class 1 alterations. The spectrum of most frequently co-altered genes was significantly different between BRAF alterations classes, including SETD2, STK11, POM121L12, MUC16, KEAP1, TERT, TP53 and other genes. In the POPLAR/OAK cohort, patients carrying non-V600 BRAF alterations were characterized by poor prognosis compared to BRAF wild-type patients. CONCLUSIONS Different classes of BRAF alterations confer distinctive clinical features, biomolecular signature and disease behavior to NSCLC patients. Non-V600 alterations are characterized by poor prognosis, but key gene co-alterations involved in cancer cell survival and immune pathways may suggest their potential sensitivity to tailored treatments.
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Affiliation(s)
- Alessandro Di Federico
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Andrea De Giglio
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Francesco Gelsomino
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Dario De Biase
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, 40138 Bologna, Italy
| | - Francesca Giunchi
- Pathology Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Arianna Palladini
- Department of Molecular Oncology, University of Pavia, 27100 Pavia, Italy;
| | - Francesca Sperandi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Barbara Melotti
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Andrea Ardizzoni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.G.); (F.G.); (F.S.); (B.M.); (A.A.)
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
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12
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The Therapeutic Potential of the Restoration of the p53 Protein Family Members in the EGFR-Mutated Lung Cancer. Int J Mol Sci 2022; 23:ijms23137213. [PMID: 35806218 PMCID: PMC9267050 DOI: 10.3390/ijms23137213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the recent development of precision medicine and targeted therapies, lung cancer remains the top cause of cancer-related mortality worldwide. The patients diagnosed with metastatic disease have a five-year survival rate lower than 6%. In metastatic disease, EGFR is the most common driver of mutation, with the most common co-driver hitting TP53. EGFR-positive patients are offered the frontline treatment with tyrosine kinase inhibitors, yet the development of resistance and the lack of alternative therapies make this group of patients only fit for clinical trial participation. Since mutant p53 is the most common co-driver in the metastatic setting, therapies reactivating the p53 pathway might serve as a promising alternative therapeutic approach in patients who have developed a resistance to tyrosine kinase inhibitors. This review focuses on the molecular background of EGFR-mutated lung cancer and discusses novel therapeutic options converging on the reactivation of p53 tumor suppressor pathways.
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Twenty-Year Survival of Patients Operated on for Non-Small-Cell Lung Cancer: The Impact of Tumor Stage and Patient-Related Parameters. Cancers (Basel) 2022; 14:cancers14040874. [PMID: 35205621 PMCID: PMC8870355 DOI: 10.3390/cancers14040874] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/01/2022] [Accepted: 02/05/2022] [Indexed: 02/04/2023] Open
Abstract
Surgery is the mainstay treatment of non-small-cell lung cancer (NSCLC), but its impact on very-long-term survival (beyond 15 years) has never been evaluated. METHODS All patients operated on for major lung resection (Jun. 2001-Dec. 2002) for NSCL in the Thoracic Surgery Department at Paris-Hôtel-Dieu-University-Hospital were included. Patients' characteristics were prospectively collected. Vital status was obtained by checking INSEE database and verifying if reported as "non-death" by the hospital administrative database and direct phone interviews with patients of families. RESULTS 345 patients were included. The 15- and 20-year survival rates were 12.2% and 5.7%, respectively. At univariate analysis, predictors of worse survivals were: increasing age at surgery (p = 0.0042), lower BMI (p = 0.009), weight loss (p = 0.0034), higher CRP (p = 0.049), pathological stage (p = 0.00000042), and, among patients with adenocarcinoma, higher grade (p = 0.028). Increasing age (p = 0.004), cumulative smoking (p = 0.045), lower BMI (0.046) and pathological stage (p = 0.0026), were independent predictors of long-term survival at Cox multivariate analysis. In another model, increasing age (p = 0.013), lower BMI (p = 0.02), chronic bronchitis (p = 0.03), lower FEV1% (p = 0.00019), higher GOLD class of COPD (p = 0.0079), and pathological stage (p = 0.000024), were identified as independent risk factors. CONCLUSIONS Very-long-term survivals could be achieved after surgery of NSCLC, and factors classically predicting 5- and 10-years survival also determined longer outcomes suggesting that both initial tumor aggressiveness and host's characteristics act beyond the period usually taken into account in oncology.
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Seyedabadi N, Shoushtari SY, Soofi A, Arabpour J, Shams Z, Akhavan H, Hosseini-Asl S. Molecular profiles of predictive biomarkers for platinum-based chemotherapy in Non-Small Cell Lung Cancer (NSCLC). Meta Gene 2022. [DOI: 10.1016/j.mgene.2021.100993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Contribution of p53 in sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Sci Rep 2021; 11:19667. [PMID: 34608255 PMCID: PMC8490392 DOI: 10.1038/s41598-021-99267-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/13/2021] [Indexed: 11/08/2022] Open
Abstract
The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Furthermore, two cell lines (H1975 and H1975/p53KO) demonstrated the different mechanisms of acquired resistance to osimertinib. Lastly, the introduction of mutant p53-R273H induced the epithelial-to-mesenchymal transition and exerted resistance to EGFR-TKIs in cells with activating EGFR mutations. These findings indicate that p53 mutations can be associated with primary or acquired resistance to EGFR-TKIs. Thus, the status or mutations of p53 may be considered as routes to improving the therapeutic effects of EGFR-TKIs in NSCLC.
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Saleh MM, Scheffler M, Merkelbach-Bruse S, Scheel AH, Ulmer B, Wolf J, Buettner R. Comprehensive Analysis of TP53 and KEAP1 Mutations and Their Impact on Survival in Localized- and Advanced-Stage NSCLC. J Thorac Oncol 2021; 17:76-88. [PMID: 34601169 DOI: 10.1016/j.jtho.2021.08.764] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/12/2021] [Accepted: 08/31/2021] [Indexed: 12/17/2022]
Abstract
INTRODUCTION TP53 and KEAP1 are frequently mutated in NSCLC, but their prognostic value is ambiguous, particularly in localized stage tumors. METHODS This retrospective cohort study included a total of 6297 patients with NSCLC who were diagnosed between November 1998 and February 2020. The primary end point was overall survival. Patients were diagnosed in a central pathology laboratory as part of the Network Genomic Medicine collaboration, encompassing more than 300 lung cancer-treating oncology centers in Germany. All patients underwent molecular testing, including targeted next-generation panel sequencing and in situ hybridization. RESULTS A total of 6297 patients with NSCLC were analyzed. In 1518 surgically treated patients (Union for International Cancer Control [UICC] I-IIIA), truncating TP53 mutations and KEAP1 mutations were independent negative prognostic markers in multivariable analysis (hazard ratio [HR]TP53truncating = 1.43, 95% confidence interval [CI]: 1.07-1.91, p = 0.015; HRKEAP1mut = 1.68, 95% CI:1.24-2.26, p = 0.001). Consistently, these mutations were associated with shorter disease-free survival. In 4779 patients with advanced-stage (UICC IIIB-IV) tumors, TP53 mutations did not predict outcome in univariable analysis. In contrast, KEAP1 mutations remained a negative prognostic factor (HRKEAP1mut = 1.40, 95% CI: 1.23-1.61, p < 0.001) in patients with advanced-stage tumors. Furthermore, those with KEAP1-mutant tumors with co-occurring TP53 missense mutations had longer overall survival than those with KEAP1-mutant tumors with wild-type or truncating TP53 mutations. CONCLUSIONS This study found that TP53 and KEAP1 mutations were prognostic for localized and advanced-stage NSCLC. The increased relative hazard of harboring TP53 or KEAP1 mutations was comparable to an increase in one UICC stage. Our data suggest that molecular stratification on the basis of TP53 and KEAP1 mutation status should be implemented for localized and advanced-stage NSCLC to optimize and modify clinical decision-making.
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Affiliation(s)
- Mohamed Mahde Saleh
- Lung Cancer Group Cologne, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Matthias Scheffler
- Lung Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Sabine Merkelbach-Bruse
- Lung Cancer Group Cologne, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Andreas Hans Scheel
- Lung Cancer Group Cologne, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Bastian Ulmer
- Lung Cancer Group Cologne, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Jürgen Wolf
- Lung Cancer Group Cologne, Department I for Internal Medicine, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany
| | - Reinhard Buettner
- Lung Cancer Group Cologne, Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany.
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Wang X, Bera K, Barrera C, Zhou Y, Lu C, Vaidya P, Fu P, Yang M, Schmid RA, Berezowska S, Choi H, Velcheti V, Madabhushi A. A prognostic and predictive computational pathology image signature for added benefit of adjuvant chemotherapy in early stage non-small-cell lung cancer. EBioMedicine 2021; 69:103481. [PMID: 34265509 PMCID: PMC8282972 DOI: 10.1016/j.ebiom.2021.103481] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 06/24/2021] [Accepted: 06/24/2021] [Indexed: 12/02/2022] Open
Abstract
Poster presentation at the USCAP 108th Annual Meeting, March 16–21, 2019. Background We developed and validated a prognostic and predictive computational pathology risk score (CoRiS) using H&E stained tissue images from patients with early-stage non-small cell lung cancer (ES-NSCLC). Methods 1330 patients with ES-NSCLC were acquired from 3 independent sources and divided into four cohorts D1-4. D1 comprised 100 surgery treated patients and was used to identify prognostic features via an elastic-net Cox model to predict overall and disease-free survival. CoRiS was constructed using the Cox model coefficients for the top features. The prognostic performance of CoRiS was evaluated on D2 (N=331), D3 (N=657) and D4 (N=242). Patients from D2 and D3 which comprised surgery + chemotherapy were used to validate CoRiS as predictive of added benefit to adjuvant chemotherapy (ACT) by comparing survival between different CoRiS defined risk groups. Findings CoRiS was found to be prognostic on univariable analysis, D2 (hazard ratio (HR) = 1.41, adjusted (adj.) P = .01) and D3 (HR = 1.35, adj. P < .001). Multivariable analysis showed CoRiS was independently prognostic, D2 (HR = 1.41, adj. P < .001) and D3 (HR = 1.35, adj. P < .001), after adjusting for clinico-pathologic factors. CoRiS was also able to identify high-risk patients who derived survival benefit from ACT D2 (HR = 0.42, adj. P = .006) and D3 (HR = 0.46, adj. P = .08). Interpretation CoRiS is a tissue non-destructive, quantitative and low-cost tool that could potentially help guide management of ES-NSCLC patients.
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Affiliation(s)
- Xiangxue Wang
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Kaustav Bera
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Cristian Barrera
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Yu Zhou
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Cheng Lu
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Pranjal Vaidya
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA
| | - Pingfu Fu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH, USA
| | - Michael Yang
- Department of Pathology-Anatomic, University Hospitals, OH, USA
| | | | - Sabina Berezowska
- Institute of Pathology, University of Bern, Bern, Switzerland; Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland
| | - Humberto Choi
- Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic Foundation, OH, USA
| | | | - Anant Madabhushi
- Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA.
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Chen Y, Zitello E, Guo R, Deng Y. The function of LncRNAs and their role in the prediction, diagnosis, and prognosis of lung cancer. Clin Transl Med 2021; 11:e367. [PMID: 33931980 PMCID: PMC8021541 DOI: 10.1002/ctm2.367] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 12/24/2022] Open
Abstract
Lung cancer remains a major threat to human health. Low dose CT scan (LDCT) has become the main method of early screening for lung cancer due to the low sensitivity of chest X-ray. However, LDCT not only has a high false positive rate, but also entails risks of overdiagnosis and cumulative radiation exposure. In addition, cumulative radiation by LDCT screening and subsequent follow-up can increase the risk of lung cancer. Many studies have shown that long noncoding RNAs (lncRNAs) remain stable in blood, and profiling of blood has the advantages of being noninvasive, readily accessible and inexpensive. Serum or plasma assay of lncRNAs in blood can be used as a novel detection method to assist LDCT while improving the accuracy of early lung cancer screening. LncRNAs can participate in the regulation of various biological processes. A large number of researches have reported that lncRNAs are key regulators involved in the progression of human cancers through multiple action models. Especially, some lncRNAs can affect various hallmarks of lung cancer. In addition to their diagnostic value, lncRNAs also possess promising potential in other clinical applications toward lung cancer. LncRNAs can be used as predictive markers for chemosensitivity, radiosensitivity, and sensitivity to epidermal growth factor receptor (EGFR)-targeted therapy, and as well markers of prognosis. Different lncRNAs have been implicated to regulate chemosensitivity, radiosensitivity, and sensitivity to EGFR-targeted therapy through diverse mechanisms. Although many challenges need to be addressed in the future, lncRNAs have bright prospects as an adjunct to radiographic methods in the clinical management of lung cancer.
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Affiliation(s)
- Yu Chen
- Department of Quantitative Health SciencesJohn A. Burns School of Medicine, University of Hawaii at ManoaHonoluluHawaiiUSA
- Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human ResourcesUniversity of Hawaii at ManoaHonoluluHawaiiUSA
| | - Emory Zitello
- Department of Quantitative Health SciencesJohn A. Burns School of Medicine, University of Hawaii at ManoaHonoluluHawaiiUSA
- Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human ResourcesUniversity of Hawaii at ManoaHonoluluHawaiiUSA
| | - Rui Guo
- School of Public HealthGuangxi Medical UniversityNanningChina
| | - Youping Deng
- Department of Quantitative Health SciencesJohn A. Burns School of Medicine, University of Hawaii at ManoaHonoluluHawaiiUSA
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Masciale V, Banchelli F, Grisendi G, D’Amico R, Maiorana A, Stefani A, Morandi U, Dominici M, Aramini B. New Perspectives in Different Gene Expression Profiles for Early and Locally Advanced Non-Small Cell Lung Cancer Stem Cells. Front Oncol 2021; 11:613198. [PMID: 33868998 PMCID: PMC8047623 DOI: 10.3389/fonc.2021.613198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Lung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30-55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC). METHODS This cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared. RESULTS Surgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients. CONCLUSIONS Our study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and locally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.
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Affiliation(s)
- Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D’Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Department of Medical and Surgical Sciences, Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Stefani
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Ramos R, Macía I, Navarro-Martin A, Déniz C, Rivas F, Ureña A, Masuet-Aumatell C, Moreno C, Nadal E, Escobar I. Prognostic value of the preoperative lymphocyte-to-monocyte ratio for survival after lung cancer surgery. BMC Pulm Med 2021; 21:75. [PMID: 33653309 PMCID: PMC7927224 DOI: 10.1186/s12890-021-01446-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/23/2021] [Indexed: 11/19/2022] Open
Abstract
Background The aim of this study was to assess the effect of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on overall survival and disease-free survival in patients with lung cancer treated with radical surgery. Methods We performed a retrospective review of patients with lung cancer who prospectively underwent radical resection between 2004 and 2012. Blood samples were taken as part of the preoperative workup. The inflammatory markers studied were absolute values of lymphocytes, monocytes, neutrophils and platelets, with subsequent calculation of ratios. Median follow-up was 52 months. Results Two hundred and sixty-eight patients underwent surgery, of whom 218 (81.3%) were men. Mean age was 62.9 ± 8.7 years. A lymphocyte-to-monocyte ratio ≥ 2.5 was independently associated with longer disease-free survival (hazard ratio [HR] 0.476 (0.307–0.738), p = 0.001) and longer overall survival (HR, 0.546; 95% CI: 0.352–0.846; p = 0.007), in models adjusted for age, sex, stage, and type of resection. No other systemic inflammatory marker showed a significant association. Conclusion Preoperative LMR is an independent prognostic factor of overall survival and recurrence-free survival in patients with surgically-resected early stage lung cancer.
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Affiliation(s)
- Ricard Ramos
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain. .,Unit of Human Anatomy, Department of Pathology and Experimental Therapeutics, Medical School, University of Barcelona, Barcelona, Spain.
| | - Ivan Macía
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain.,Unit of Human Anatomy, Department of Pathology and Experimental Therapeutics, Medical School, University of Barcelona, Barcelona, Spain
| | - Arturo Navarro-Martin
- Department of Radiation Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Carlos Déniz
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain
| | - Francisco Rivas
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain
| | - Anna Ureña
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Masuet-Aumatell
- Department of Preventive Medicine. Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Camilo Moreno
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain
| | - Ernest Nadal
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.,Clinical Research in Solid Tumors Group, OncoBell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ignacio Escobar
- Department of Thoracic Surgery, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga s/n., 08907, L´Hospitalet de Llobregat, Barcelona, Spain
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Wang X, Teng F, Lu J, Mu D, Zhang J, Yu J. Expression and prognostic role of IKBKE and TBK1 in stage I non-small cell lung cancer. Cancer Manag Res 2019; 11:6593-6602. [PMID: 31406474 PMCID: PMC6642623 DOI: 10.2147/cmar.s204924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/27/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The inhibitors of nuclear factor kappa-B kinase subunit epsilon (IKBKE) and TANK-binding kinase 1 (TBK1) are important members of the nonclassical IKK family that share the kinase domain. They are important oncogenes for activation of several signaling pathways in several tumors. This study aims to explore the expression of IKBKE and TBK1 and their prognostic role in stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS A total of 142 surgically resected stage I NSCLC patients were enrolled and immunohistochemistry of IKBKE and TBK1 was performed. RESULTS IKBKE and TBK1 were expressed in 121 (85.2%) and 114 (80.3%) of stage I NSCLC patients respectively. IKBKE expression was significantly associated with TBK1 expression (P=0.004). Furthermore, multivariate regression analyses showed there was a significant relationship between patients with risk factors, the recurrence pattern of metastasis and IKBKE+/TBK1+ co-expression (P=0.032 and P=0.022, respectively). In Kaplan-Meier survival curve analyses, the IKBKE+/TBK1+ co-expression subgroup was significantly associated with poor overall survival (P=0.014). CONCLUSIONS This is the first study to investigate the relationship between IKBKE and TBK1 expression and clinicopathologic characteristics in stage I NSCLC patients. IKBKE+/TBK1+ co-expression was significantly obvious in patients with risk factors and with recurrence pattern of distant metastasis. Furthermore, IKBKE+/TBK1+ is also an effective prognostic predictor for poor overall survival.
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Affiliation(s)
- Xin Wang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei430060, People’s Republic of China
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong250117, People’s Republic of China
| | - Feifei Teng
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong250117, People’s Republic of China
| | - Jie Lu
- Department of Neurosurgery, Shandong Province Qianfoshan Hospital of Shandong University, Jinan, Shandong250014, People’s Republic of China
| | - Dianbin Mu
- Department of Pathology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong250117, People’s Republic of China
| | - Jianbo Zhang
- Department of Pathology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong250117, People’s Republic of China
| | - Jinming Yu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei430060, People’s Republic of China
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong250117, People’s Republic of China
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Aggarwal C, Davis CW, Mick R, Thompson JC, Ahmed S, Jeffries S, Bagley S, Gabriel P, Evans TL, Bauml JM, Ciunci C, Alley E, Morrissette JJD, Cohen RB, Carpenter EL, Langer CJ. Influence of TP53 Mutation on Survival in Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer. JCO Precis Oncol 2018; 2018. [PMID: 30766968 DOI: 10.1200/po.18.00107] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose TP53 mutation (MT) in epidermal growth factor receptor (EGFR) -MT non-small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly established. Patients and Methods We performed an analysis of patients with stage IV EGFR MT NSCLC with available gene sequencing data. Associations between baseline characteristics; molecular profile, including TP53 MT; and survival outcomes were assessed. Results We identified 131 consecutive patients with EGFR MT; 81 (62%) had a TP53 MT, and 55 (42%) had other coexisting oncogenic MTs. Emergent EGFR T790M MT was observed in 42 patients (32%). Overall survival (OS) was longer for younger patients (P = .003), never smokers (P = .002), those with Eastern Cooperative Oncology Group performance status 0 to 1 (P = .004), and emergent T790M MT (P = .018). TP53 MT (P = .021) and other coexisting oncogenic MTs (P = 0.011) were associated with inferior OS. In a multivariable regression analysis adjusted for age, smoking, Eastern Cooperative Oncology Group performance status, and the presence of TP53 MT (P = .063) and other coexisting MTs (P = .064) did not achieve statistical significance. Patients with EGFR T790M/TP53 double MT had worse OS compared with patients with T790M MT alone (46.4 months v 82.9 months). In our series, five patients transformed to small-cell lung cancer (5.6%). All had TP53 MT. In four patients, allelic fraction of TP53 MT increased at the time of transformation. Conclusion The presence of TP53 and other coexisting MTs in EGFR MT NSCLC were associated with inferior OS, including patients with emergent T790M MT. An increase in TP53 mutation allelic fraction may potentially be a useful clinical predictor of small-cell transformation.
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Affiliation(s)
| | | | | | | | - Saman Ahmed
- State University of New York at Buffalo, Buffalo, NY
| | | | | | | | | | | | | | - Evan Alley
- University of Pennsylvania, Philadelphia, PA
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Teng F, Meng X, Wang X, Yuan J, Liu S, Mu D, Zhu H, Kong L, Yu J. Expressions of CD8+TILs, PD-L1 and Foxp3+TILs in stage I NSCLC guiding adjuvant chemotherapy decisions. Oncotarget 2016; 7:64318-64329. [PMID: 27602763 PMCID: PMC5325445 DOI: 10.18632/oncotarget.11793] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 08/13/2016] [Indexed: 11/25/2022] Open
Abstract
PURPOSE Currently, adjuvant chemotherapy is recommended for patients with high risk stage I non-small cell lung cancer (NSCLC). However, identifying high risk patients remains a challenge. This study aims to identify the patient cohorts more likely to benefit from adjuvant chemotherapy based on the tumor micro-immune environment. RESULTS CD8+TILs significantly associated with disease-free survival (DFS) and overall survial (OS) (p=0.002; 0.040). Patients with high risk factors may also predict shorter DFS (P=0.056). When compared together, patients with high-CD8+TILs showed better DFS than patients with low-CD8+TILs, no matter their risk factors status. There's no correlation between PD-L1 expressions and survival. PD-L1 was highly expressed in men, squamous and well differentiated carcinoma. In addition, Foxp3+TILs alone didn't show any prognostic effects, but low-Foxp3/high-CD8+TILs were associated with prolonged DFS (p=0.031). METHODS A total of 126 patients with surgically resected stage I NSCLC were included to perform immunohistochemistry of CD8+ tumor infiltrating lymphocytes (TILs), programmed death ligand-1(PD-L1) and forkhead box P3 (Foxp3)+TILs. CONCLUSION CD8+TILs are effective prognostic predictors. Patients with surgically resected stage I NSCLC showing low CD8+TILs could be considered for adjuvant chemotherapy, even if they have no high risk features.
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Affiliation(s)
- Feifei Teng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Xin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Jupeng Yuan
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Sujing Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Dianbin Mu
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Hui Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Li Kong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
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Stenehjem DD, Bellows BK, Yager KM, Jones J, Kaldate R, Siebert U, Brixner DI. Cost-Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early-Stage Non-Small Cell Lung Cancer. Oncologist 2015; 21:196-204. [PMID: 26614710 DOI: 10.1634/theoncologist.2015-0162] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 10/01/2015] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC. MATERIALS AND METHODS Lifetime costs (2014 U.S. dollars) and effectiveness (quality-adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS Lifetime costs and effectiveness were $137,403 and 5.45 QALYs with the prognostic test and $127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was $35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of $50,000/QALY. CONCLUSION The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost-effective compared with using the SoC based on globally accepted willingness-to-pay thresholds. IMPLICATIONS FOR PRACTICE Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests.
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Affiliation(s)
- David D Stenehjem
- Department of Pharmacotherapy, Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA Huntsman Cancer Institute, University of Utah Hospitals & Clinics, Salt Lake City, Utah, USA
| | - Brandon K Bellows
- Department of Pharmacotherapy, Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA SelectHealth, Salt Lake City, Utah, USA
| | | | - Joshua Jones
- Myriad Genetics, Inc., Salt Lake City, Utah, USA
| | | | - Uwe Siebert
- Department of Public Health, Health Services Research and Health Technology Assessment, University for Health Sciences, Medical Informatics and Technology, Tyrol, Austria Area 4 Health Technology Assessment and Bioinformatics, Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria Department of Health Policy and Management, Center for Health Decision Science, Harvard School of Public Health, Boston, Massachusetts, USA Cardiovascular Research Program, Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Diana I Brixner
- Department of Pharmacotherapy, Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA Program in Personalized Health, University of Utah, Salt Lake City, Utah, USA Department of Public Health, Health Services Research and Health Technology Assessment, University for Health Sciences, Medical Informatics and Technology, Tyrol, Austria Area 4 Health Technology Assessment and Bioinformatics, Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria
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Alifano M, Mansuet-Lupo A, Lococo F, Roche N, Bobbio A, Canny E, Schussler O, Dermine H, Régnard JF, Burroni B, Goc J, Biton J, Ouakrim H, Cremer I, Dieu-Nosjean MC, Damotte D. Systemic inflammation, nutritional status and tumor immune microenvironment determine outcome of resected non-small cell lung cancer. PLoS One 2014; 9:e106914. [PMID: 25238252 PMCID: PMC4169516 DOI: 10.1371/journal.pone.0106914] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 08/02/2014] [Indexed: 12/20/2022] Open
Abstract
Background Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC). Methods and Findings Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p<0.05). In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34 [0.16–0.73], p = 0.0056), CD8+ cell count in tumor tissue (RR = 0.37 [0.16–0.83], p = 0.0162), and disease stage (RR 1.73 [1.03–2.89]; 2.99[1.07–8.37], p = 0.0374- stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% [60.9–91.1] as compared to 18% [7.9–35.6] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced. Conclusions Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome.
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Affiliation(s)
- Marco Alifano
- Deparment of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France
- University Paris Descartes; Paris, France
- * E-mail:
| | - Audrey Mansuet-Lupo
- University Paris Descartes; Paris, France
- Deparments of Pathology, Paris Centre University Hospitals, AP-HP, Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Filippo Lococo
- Unit of thoracic Surgery, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Nicolas Roche
- University Paris Descartes; Paris, France
- Departments of Chest Disease, Paris Centre University Hospitals, AP-HP, Paris, France
| | - Antonio Bobbio
- Deparment of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France
| | - Emelyne Canny
- Deparment of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France
| | - Olivier Schussler
- Deparment of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France
| | - Hervé Dermine
- Unit of thoracic Surgery, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Jean-François Régnard
- Deparment of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France
- University Paris Descartes; Paris, France
| | - Barbara Burroni
- Deparments of Pathology, Paris Centre University Hospitals, AP-HP, Paris, France
| | - Jérémy Goc
- University Paris Descartes; Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Jérôme Biton
- University Paris Descartes; Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Hanane Ouakrim
- University Paris Descartes; Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Isabelle Cremer
- University Paris Descartes; Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Marie-Caroline Dieu-Nosjean
- University Paris Descartes; Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
| | - Diane Damotte
- University Paris Descartes; Paris, France
- Deparments of Pathology, Paris Centre University Hospitals, AP-HP, Paris, France
- INSERM U1138, Cancer and Immune Escape, Cordeliers Research Center, Paris, France
- University Pierre and Marie Curie, UMRS U1138, Paris, France
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Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. J Thorac Dis 2014; 5 Suppl 5:S463-78. [PMID: 24163740 DOI: 10.3978/j.issn.2072-1439.2013.08.43] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 08/19/2013] [Indexed: 12/14/2022]
Abstract
The last decade has seen significant advances in our understanding of lung cancer biology and management. Identification of key driver events in lung carcinogenesis has contributed to the development of targeted lung cancer therapies, heralding the era of personalised medicine for lung cancer. As a result, histological subtyping and molecular testing has become of paramount importance, placing increasing demands on often small diagnostic specimens. This has triggered the review and development of the first structured classification of lung cancer in small biopsy/cytology specimens and a new classification of lung adenocarcinoma from the IASLC/ATS/ERS. These have enhanced the clinical relevance of pathological diagnosis, and emphasise the role of the modern surgical pathologist as an integral member of the multidisciplinary team, playing a crucial role in clinical trials and determining appropriate and timely management for patients with lung cancer.
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Affiliation(s)
- Morgan R Davidson
- University of Queensland Thoracic Research Centre, The Prince Charles Hospital, QLD, Australia; ; Department of Anatomical Pathology, Royal Brisbane and Women's Hospital, QLD, Australia
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27
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Yang Y, Xian L. The association between the GSTP1 A313G and GSTM1 null/present polymorphisms and the treatment response of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients: a meta-analysis. Tumour Biol 2014; 35:6791-9. [DOI: 10.1007/s13277-014-1866-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 03/18/2014] [Indexed: 11/30/2022] Open
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28
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Yang YL, Luo XP, Xian L. The prognostic role of the class III β-tubulin in non-small cell lung cancer (NSCLC) patients receiving the taxane/vinorebine-based chemotherapy: a meta-analysis. PLoS One 2014; 9:e93997. [PMID: 24705847 PMCID: PMC3976369 DOI: 10.1371/journal.pone.0093997] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Accepted: 03/10/2014] [Indexed: 11/18/2022] Open
Abstract
Background A number of studies have examined the relationship between the expression of the class III β-tubulin (TUBB3) and the treatment responses to the taxane/vinorebine-based chemotherapy in patients with non-small cell lung cancer (NSCLC). However, the results of these studies were inconsistent and inconclusive. Therefore, we conducted an up-to-date meta-analysis to evaluate the prognostic role of TUBB3 in the taxane/vinorebine-based chemotherapy. Methods A literature search for relevant studies was conducted in PubMed, Embase, and CNKI. The inclusion criteria were the taxane/vinorebine-based chemotherapy in patients with NSCLC and the evaluation of the clinical outcomes in relation to the expression of TUBB3. The clinical outcomes analyzed in this study included the overall response rate (ORR), overall survival (OS), and event-free survival (EFS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the risk associated with the TUBB3 expression in the taxane/vinorebine-based chemotherapy. Results A total of 28 studies with 2401 NSCLC patients were qualified for this meta-analysis. We found that the positive or high level of TUBB3 expression was associated with a poorer ORR (OR = 0.24, 95% CI = 0.16–0.36, p<0.001), an unfavorable OS (HR = 1.52, 95% CI = 1.27–1.82, p<0.001), and a worse EFS (HR = 1.47, 95% CI = 1.24–1.74, p<0.001) compared to the negative or low level of TUBB3 expression. The statistically significant associations between TUBB3 and chemotherapy responses were also observed in the stratified subgroup analysis, which included the analysis by ethnic subgroup (Asian and Caucasian), chemotherapy regimen (taxane-based and vinorebine-based), TUBB3 detection method (IHC and PCR), and treatment strategy (surgery plus adjuvant chemotherapy and palliative chemotherapy). Conclusions The expression level of TUBB3 may be a useful biomarker to predict the clinical outcomes of the taxane/vinorebine-based chemotherapy in patients with NSCLC.
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Affiliation(s)
- Yan-Long Yang
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xiu-Ping Luo
- Clinical Faculty of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Lei Xian
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
- * E-mail:
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Matsangou M, Santos ES, Raez LE, Gomez JE, Dinh V, Savaraj N. Early-stage non-small-cell lung cancer: overview of adjuvant chemotherapy and promising advances. Lung Cancer Manag 2014. [DOI: 10.2217/lmt.13.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY Adjuvant cisplatin-based chemotherapy for early-stage non-small-cell lung cancer has become standard of care, after three recent meta-analyses validated survival benefit of approximately 5% at 5 years. Subgroup analyses, however, demonstrated that the benefit appears largely confined to patients with stage II disease; however, 25–30% of patients with stage I disease are at high risk of relapse and death within 5 years. Therefore, there is a need to predict more accurately which patients are likely to relapse after surgery and thus benefit from adjuvant therapy. Recent studies indicate that molecular biomarkers, gene-expression profiling and gene-mutation analysis may not only identify those tumors that are more likely to respond to adjuvant chemotherapy, but also to specific cytotoxic agents. These novel bioanalyses will allow physicians to deliver personalized medicine that utilizes cancer therapeutic drugs more cost effectively, thereby improving response rates and, hopefully, conferring survival advantage.
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Affiliation(s)
- Maria Matsangou
- Department of Internal Medicine, Section on Hematology & Oncology, Wake Forest University School of Medicine, Comprehensive Cancer Center of Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - Edgardo S Santos
- Thoracic & Head & Neck Cancer Programs, Cancer Research at Lynn Cancer Institute, 701 Northwest 13th Street, Boca Raton, FL 33486, USA
| | - Luis E Raez
- Thoracic Oncology, Memorial Cancer Institute, 801 North Flamingo Road, Suite 11, Pembroke Pines, FL 33028, USA
| | - Jorge E Gomez
- Thoracic Oncology Program, Mount Sinai Hospital, 1470 Madison Avenue, 3rd floor, New York, NY 1002, USA
| | - Vy Dinh
- University of Miami Leonard M Miller School of Medicine, Sylvester Comprehensive Cancer Center, 1475 Northwest 12th Avenue, Suite 3510, Miami, FL 33136, USA
| | - Niramol Savaraj
- Department of Medicine, Division of Hematology/Medical Oncology, Miami Veterans Affairs Hospital, 1201 Northwest 16th Street, Miami, FL 33125, USA
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30
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Yang Y, Xian L. The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis. Tumour Biol 2013; 35:2905-21. [PMID: 24338713 DOI: 10.1007/s13277-013-1493-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 11/28/2013] [Indexed: 01/04/2023] Open
Abstract
The relationship between the ERCC1/2 single nucleotide polymorphisms (SNPs) and the clinical outcomes of the platinum-based chemotherapy in the non-small cell lung cancer (NSCLC) is still inconsistent and inconclusive despite extensive investigations have been conducted to address this question. In this meta-analysis, we aim to further explore the prognostic value of the ERCC1/2 SNPs in NSCLC by analyzing all currently available evidences. Relevant studies were searched in PubMed, Embase, and China National Knowledge Infrastructure. The inclusion criteria were platinum-based chemotherapy in NSCLC patients and evaluation of clinical outcomes in relation to the ERCC1 C118T, ERCC1 C8092A, ERCC2 Asp312Asn, and ERCC2 Lys751Gln. Clinical outcomes analyzed in this study included the overall response rate, overall survival (OS), and progression-free survival (PFS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard associated with each SNP. A total of 46 studies including 9,407 NSCLC patients were qualified for this meta-analysis. For ERCC1 C118T, the T allele was associated with a poor OS (HR = 1.35, 95% CI = 1.04-1.75); for ERCC2 Asp312Asn, the Asn variant was linked to an unfavorable OS (HR = 2.07, 95% CI = 1.11-3.88); and for ERCC2 Lys751Gln, patients with the Gln variant have a worse OS (HR = 1.22, 95% CI = 1.05-1.41) and PFS (HR = 1.35, 95% CI = 1.07-1.71). In addition, the main findings of the ERCC1/2 SNPs on chemotherapy toxicity were also summarized. This meta-analysis suggested that the ERCC1 C118T, ERCC2 Asp312Asn, and Lys751Gln may be useful biomarkers to predict the clinical outcomes of the platinum-based chemotherapy in NSCLC patients.
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Affiliation(s)
- Yanlong Yang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China,
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Ustaalioglu BBO, Unal OU, Turan N, Bilici A, Kaya S, Eren T, Ulas A, Inal A, Berk V, Demirci U, Alici S, Bal O, Benekli M, Gumus M. Prognostic Factors for Lymph Node Negative Stage I and IIA Non-small Cell Lung Cancer: Multicenter Experiences. Asian Pac J Cancer Prev 2013; 14:6287-92. [DOI: 10.7314/apjcp.2013.14.11.6287] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Tantraworasin A, Saeteng S, Lertprasertsuke N, Arayawudhikul N, Kasemsarn C, Patumanond J. The prognostic value of ERCC1 and RRM1 gene expression in completely resected non-small cell lung cancer: tumor recurrence and overall survival. Cancer Manag Res 2013; 5:327-36. [PMID: 24124391 PMCID: PMC3794893 DOI: 10.2147/cmar.s52073] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Background The roles of excision repair cross-complementing group 1 gene (ERCC1) expression and ribonucleotide reductase subunit M1 gene (RRM1) expression in completely resected non-small cell lung cancer (NSCLC) are still debatable. Previous studies have shown that both genes affected the overall survival and outcomes of patients who received platinum-based chemotherapy; however, some studies did not show this correlation. The aim of this study was to evaluate the prognostic values of ERCC1 and RRM1 gene expression in predicting tumor recurrence and overall survival in patients with completely resected NSCLC who received adjuvant chemotherapy and in those who did not. Patients and methods A retrospective cohort study was conducted in 247 patients with completely resected NSCLC. All patients had been treated with anatomic resection (lobectomy or pneumonectomy) with systematic mediastinal lymphadenectomy between January 2002 and December 2011 at Chiang Mai University Hospital, Chiang Mai, Thailand. They were divided into two groups: recurrence and no recurrence. Protein expression of ERCC1 and RRM1 was determined by immunohistochemistry. Correlations between clinicopathologic variables, including ERCC1 and RRM1 expression and tumor recurrence, were analyzed. Univariate and multivariate Cox proportional hazards regression analysis stratified by nodal involvement, tumor staging, intratumoral blood vessel invasion, intratumoral lymphatic invasion, and tumor necrosis was used to identify the prognostic roles of ERCC1 and RRM1. Results ERCC1 and RRM1 expression did not demonstrate prognostic value for tumor recurrence and overall survival in patients with completely resected NSCLC. In patients who did not receive adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have greater potential for tumor recurrence and shorter overall survival than did those who had low ERCC1 and low RRM1 (hazard ratio [HR] =1.7, 95% confidence interval [CI] =0.6–4.3, P=0.292 and HR =1.6, 95% CI =0.5–4.5, P=0.411, respectively). In contrast, in patients who received adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have benefited from adjuvant chemotherapy and showed good overall survival compared with those who had low ERCC1 and low RRM1 (HR =0.8, 95% CI = 0.4–1.8, P=0.612 and HR = 0.4, 95% CI = 0.1–2.4, P=0.325, respectively). Subgroup analysis in patients whose first-line metastatic chemotherapy failed demonstrated that ERCC1 expression and RRM1 expression were not prognostic factors for tumor recurrence and overall survival; however, patients who had high ERCC1 and high RRM1 expression seemed to have benefited from first-line chemotherapy treatment (HR =0.7, 95% CI =0.3–1.8, P=0.458). Conclusion ERCC1 expression and RRM1 expression were not prognostic of tumor recurrence and overall survival in patients with completely resected NSCLC, either with or without adjuvant chemotherapy. Prospective studies that include a larger number of patients are needed for definite conclusions.
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Affiliation(s)
- Apichat Tantraworasin
- General Thoracic Unit, Department of Surgery, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand
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Li Z, Xie QR, Chen Z, Lu S, Xia W. Regulation of SIRT2 levels for human non-small cell lung cancer therapy. Lung Cancer 2013; 82:9-15. [PMID: 23915912 DOI: 10.1016/j.lungcan.2013.05.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Revised: 05/09/2013] [Accepted: 05/20/2013] [Indexed: 12/28/2022]
Abstract
Seven Sirtuin family members (SIRT1-7), comprising a family of NAD+-dependent protein deacetylases and ADP-ribosyltransferases, are key proteins that regulate multiple physiological processes. SIRT2 was recently reported to play an important role in carcinogenesis. However, its role in non-small cell lung cancer (NSCLC) has not yet been investigated. In this study, we analyzed the expression pattern of SIRT2 in NSCLC tissues from clinical patients and in cell lines, and found that SIRT2 was significantly down-regulated at both the mRNA and protein levels in tumor than non-tumor tissues or cells, which were corroborated by the NSCLC tissue microarray results. Overexpression of SIRT2 in A549 and H1299 cells caused cell proliferation inhibition, cell apoptosis induction and cell cycle arrest. Further analysis showed that SIRT2 overexpression increased the ROS (reactive oxygen species) production and p27 levels. Moreover, up-regulation of SIRT2 in NSCLC cells increased the sensitivity to Cisplatin treatment. Taken together, our results implied that down-regulation of SIRT2 was associated with NSCLC, and regulation of SIRT2 might be an important target for NSCLC therapy.
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Affiliation(s)
- Ziming Li
- Shanghai Lung Cancer Center, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
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Strano S, Lupo A, Lococo F, Schussler O, Loi M, Younes M, Bobbio A, Damotte D, Regnard JF, Alifano M. Prognostic Significance of Vascular and Lymphatic Emboli in Resected Pulmonary Adenocarcinoma. Ann Thorac Surg 2013; 95:1204-10. [DOI: 10.1016/j.athoracsur.2012.12.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 12/03/2012] [Accepted: 12/07/2012] [Indexed: 11/16/2022]
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Yang Y, Xie Y, Xian L. Breast cancer susceptibility gene 1 (BRCA1) predict clinical outcome in platinum- and toxal-based chemotherapy in non-small-cell lung cancer (NSCLC) patients: a system review and meta-analysis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:15. [PMID: 23497550 PMCID: PMC3610101 DOI: 10.1186/1756-9966-32-15] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/08/2013] [Indexed: 12/25/2022]
Abstract
The recent studies have evaluated the relationship between BRCA1 expression and clinical outcome of chemotherapy (mainly focused on platinum-based and toxal-based treatment) in NSCLC patients, but the results were inconclusive and controversial. Our aim of this study was to evaluate this association by literature based system review and meta-analysis.PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases were used to retrieve the relevant articles. The interested outcome included objective response rate (ORR), overall survival (OS) and event-free survival (EFS). The pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) ware estimated.After specific inclusion and exclusion criteria, 23 studies fulfilled the criteria and were included in our analysis. In 17 platinum-based studies, low/negative BRCA1 was in favor of better ORR (OR=1.70, 95%CI=1.32-2.18), longer OS and EFS (HR=1.58, 95%CI=1.27-1.97, and HR=1.60, 95%CI=1.07-2.39 for OS and EFS, respectively). In 4 toxal-based chemotherapy studies, the patients with high/positive BRCA1 had better ORR (OR=0.41, 95%CI=0.26-0.64), OS and EFS were not evaluated as the insufficient data available.Overall, BRCA1 might be a useful biomarker to predict clinical outcome for personal chemotherapy in NSCLC patients in the future.
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Affiliation(s)
- Yanlong Yang
- Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China.
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Kerr KM, Loo PS, Nicolson MC. Pathology and personalized medicine in lung cancer. Lung Cancer Manag 2013. [DOI: 10.2217/lmt.12.53] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
SUMMARY Personalized medicine for patients with non-small-cell lung cancer is a reality now and its use will only increase in the future. Pathology is key in supporting this approach to treatment decision-making, by performing the most complete and accurate histological subtyping of tumors possible, supported by predictive immunohistochemistry and the assessment of relevant biomarkers. The need for these extra diagnostic steps emphasizes the importance of maximizing tissue yields from biopsy procedures. Although multiplex approaches may allow simultaneous assessment of several biomarkers, there will remain a need for different types of test (e.g., immunohistochemistry, as well as mutation testing). Next-generation technologies for DNA sequencing are a great hope for extensive genetic analysis of single samples, provided various technical and logistical problems can be solved. All such laboratory activity must be supported by high-quality internal procedures and external quality-assurance schemes.
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Affiliation(s)
- Keith M Kerr
- Department of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK
| | - Peh Sun Loo
- Department of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK
| | - Marianne C Nicolson
- Department of Oncology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK
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Cao W, Ribeiro RDO, Liu D, Saintigny P, Xia R, Xue Y, Lin R, Mao L, Ren H. EZH2 promotes malignant behaviors via cell cycle dysregulation and its mRNA level associates with prognosis of patient with non-small cell lung cancer. PLoS One 2012; 7:e52984. [PMID: 23300840 PMCID: PMC3534094 DOI: 10.1371/journal.pone.0052984] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 11/22/2012] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epigenetic silencing is a common mechanism to inactivate tumor suppressor genes during carcinogenesis. Enhancer of Zeste 2 (EZH2) is the histone methyltransferase subunit in polycomb repressive complex 2 which mediates transcriptional repression through histone methylation. EZH2 overexpression has been linked to aggressive phenotypes of certain cancers. However, the mechanism that EZH2 played in promoting malignancy in non-small cell lung cancer (NSCLC) remains unclear. In addition, the correlation of EZH2 overexpression and the prognosis of NSCLC patients in non-Asian cohort need to be determined. METHODOLOGY/PRINCIPAL FINDINGS Up-regulation of EZH2 was found in NSCLC cells compared with normal human bronchial epithelial cells by western blot assay. Upon EZH2 knockdown using small interfering RNA (siRNA), the proliferation, anchorage-independent growth and invasion of NSCLC cells were remarkably suppressed with profound induction of G1 arrest. Furthermore, the expression of cyclin D1 was notably reduced whereas p15(INK4B), p21(Waf1/Cip1) and p27(Kip1) were increased in NSCLC cells after EZH2-siRNA delivery. To determine whether EZH2 expression contributes to disease progression in patients with NSCLC, Taqman quantitative real-time RT-PCR was used to measure the expression of EZH2 in paired tumor and normal samples. Univariate analysis revealed that patients with NSCLC whose tumors had a higher EZH2 expression had significantly inferior overall, disease-specific, and disease-free survivals compared to those whose tumors expressed lower EZH2 (P = 0.005, P = 0.001 and P = 0.003, respectively). In multivariate analysis, EZH2 expression was an independent predictor of disease-free survival (hazard ratio = 0.450, 95% CI: 0.270 to 0.750, P = 0.002). CONCLUSIONS/SIGNIFICANCE Our results demonstrate that EZH2 overexpression is critical for NSCLC progression. EZH2 mRNA levels may serve as a prognostic predictor for patients with NSCLC.
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Affiliation(s)
- Wei Cao
- Shanghai Key Laboratory of Stomatology, Department of Oral Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Rachel de Oliveira Ribeiro
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Diane Liu
- Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Pierre Saintigny
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ronghui Xia
- Shanghai Key Laboratory of Stomatology, Department of Oral Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Yuwen Xue
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ruxian Lin
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
| | - Li Mao
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Hening Ren
- Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
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Nygaard AD, Garm Spindler KL, Pallisgaard N, Andersen RF, Jakobsen A. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer 2012; 79:312-7. [PMID: 23238036 DOI: 10.1016/j.lungcan.2012.11.016] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 11/19/2012] [Indexed: 01/08/2023]
Abstract
BACKGROUND Lung cancer is one of the most common malignant diseases worldwide and associated with considerable morbidity and mortality. New agents targeting the epidermal growth factor system are emerging, but only a subgroup of the patients will benefit from the therapy. Cell free DNA (cfDNA) in the blood allows for tumour specific analyses, including KRAS-mutations, and the aim of the study was to investigate the possible prognostic value of plasma mutated KRAS (pmKRAS) in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS Patients with newly diagnosed, advanced NSCLC eligible for chemotherapy were enrolled in a prospective biomarker trial. A pre-treatment blood sample was drawn and subsequently DNA was extracted and pmKRAS analysed. The patients received carboplatin (AUC5) i.v. day 1 and vinorelbine (30mg/m(2) i.v. day 1 and 60mg/m(2) p.o. day 8) for a maximum of six cycles. Response to chemotherapy was evaluated according to RECIST v.1.0 by CT scans of the chest and upper abdomen. The presence of pmKRAS at baseline was assessed by an in-house qPCR method. The primary endpoint was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate. RESULTS The study included 246 patients receiving a minimum of 1 treatment cycle, and all but four were evaluable for response according to RECIST. Forty-three patients (17.5%) presented with a KRAS mutation. OS was 8.9 months and PFS by intention to treat 5.4 months. Patients with a detectable plasma-KRAS mutation had a significantly shorter OS and PFS compared to the wild type (WT) patients (median OS 4.8 months versus 9.5 months, HR 1.87, 95% CI 1.23-2.84, p=0.0002 and median PFS 3.0 months versus 5.6 months, HR 1.60, 95% CI 1.09-2.37, p=0.0043). A multivariate Cox regression analysis confirmed the independent prognostic value of pmKRAS in OS but not in PFS. The response rate to chemotherapy was significantly lower in the group of patients with a mutation compared to WT (p<0.0001). CONCLUSION The presence of KRAS mutations in plasma may be a marker of poor prognosis and may also hold predictive value. Further validation in an independent cohort is highly needed.
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Dietrich D, Hasinger O, Liebenberg V, Field JK, Kristiansen G, Soltermann A. DNA methylation of the homeobox genes PITX2 and SHOX2 predicts outcome in non-small-cell lung cancer patients. DIAGNOSTIC MOLECULAR PATHOLOGY : THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY, PART B 2012; 21:93-104. [PMID: 22555092 DOI: 10.1097/pdm.0b013e318240503b] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Biomarkers that facilitate prediction of disease progression in lung cancer patients might be clinically valuable in optimizing individualized therapy. In this study, the ability of the DNA methylation biomarkers PITX2 and SHOX2 to predict disease outcome in lung cancer patients has been evaluated. Quantitative, methylation-specific (HeavyMethyl), real-time polymerase chain reaction assays were used to measure DNA methylation of PITX2 and SHOX2 in bisulfite-converted DNA from formalin-fixed, paraffin-embedded tissues from 474 non-small-cell lung cancer patients. In univariate Cox Proportional Hazard analysis, high methylation of SHOX2 and PITX2 was a significant predictor of progression-free survival [SHOX2: n=465, hazard ratio (HR)=1.395 (1.130 to 1.721), P=0.002; PITX2: n=445, HR=1.312 (1.059 to 1.625), P=0.013]. Patients with low methylation of either PITX2 and/or SHOX2 (n=319) showed a significantly higher risk of disease progression as compared with patients with higher methylation of both genes [n=126; HR=1.555 (1.210 to 1.999), P=0.001]. This was particularly true for the subgroup of patients receiving no adjuvant radiotherapy or chemotherapy [n=258, HR=1.838 (1.252 to 2.698), P=0.002]. In multivariate analysis, both biomarkers added significant independent prognostic information to pT, pN, pM, and grade. Another interesting finding of this study was that SHOX2 and PITX2 DNA methylation was shown to be inversely correlated with TTF1 (also known as NKX2-1) expression (PITX2: P=0.018, SHOX2: P<0.001). TFF1 expression was previously found to be associated with improved survival in the same patient cohort. DNA methylation of PITX2 and SHOX2 is an independent prognostic biomarker for disease progression in non-small-cell lung cancer patients.
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Affiliation(s)
- Dimo Dietrich
- Institute of Pathology, University Hospital Bonn, Bonn, Germany.
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Bonomi M, Pilotto S, Milella M, Massari F, Cingarlini S, Brunelli M, Chilosi M, Tortora G, Bria E. Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:115. [PMID: 22206620 PMCID: PMC3284429 DOI: 10.1186/1756-9966-30-115] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 12/29/2011] [Indexed: 12/26/2022]
Abstract
Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.
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Affiliation(s)
- Maria Bonomi
- Medical Oncology, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona, Italy
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Abstract
Recent advances in non-small-cell lung cancer (NSCLC) therapy mean the relatively simple discrimination between small-cell and 'non-small-cell' carcinoma is insufficient to determine the best treatment for individual patients. Safety, efficacy and prescribing requirements mandate more specific subtyping of NSCLC for several new drugs: practice made difficult by the tumour heterogeneity combined with the paucity of tissue in most diagnostic samples. Immunohistochemical approaches have emerged as accurate predictors of probable tumour histotype. P63 and/or cytokeratins 5 and 6 and thyroid transcription factor 1 (TTF1) are among the best predictors, respectively, of squamous and adenocarcinoma histology. Molecular characteristics may predict response to both newer molecular targeted agents and traditional cytotoxic agents. Specific mutations in the epidermal growth factor receptor (EGFR) gene as predictors of response to EGFR tyrosine kinase inhibitors (erlotinib, gefitinib) is the first example of markers which predict response to targeted agents. Actual drug targets [e.g. thymidilate synthase (TS) - pemetrexed] or markers of the tumour's ability to repair cytotoxic drug-induced damage [e.g. excision repair cross-complementation group 1 (ERCC1) - cisplatin] may well also complement NSCLC diagnosis. This extended diagnostic requirement from increasingly limited material provided by minimally invasive biopsy techniques poses major challenges for pathology.
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Affiliation(s)
- Keith M Kerr
- Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK.
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Liu C, Liu J, Wang X, Mao W, Jiang L, Ni H, Mo M, Wang W. Prognostic impact of nm23-H1 and PCNA expression in pathologic stage I non-small cell lung cancer. J Surg Oncol 2011; 104:181-6. [PMID: 21495034 DOI: 10.1002/jso.21944] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Accepted: 03/21/2011] [Indexed: 01/26/2023]
Abstract
INTRODUCTION The purpose of this study was to evaluate the value of nm23-H1 and proliferating cell nuclear antigen (PCNA) expression as well as other confirmed prognostic factors in predicting the clinical outcome after definitive surgery of pathologic stage I non-small cell lung cancer (NSCLC). METHODS Four hundred fifty-two consecutive and non-selected patients who underwent definitive surgery for stage I NSCLC were included in this study. Formalin-fixed paraffin-embedded specimens were stained for nm23-H1 and PCNA, the correlation between the staining and its clinicopathological parameters, and its prognostic power were analyzed statistically. RESULTS Of the 452 patients studied, 320 cases (70.8%) were high expression for nm23-H1. A total of 182 carcinomas (40.3%) were PCNA high expression tumors. PCNA expression correlated with serum CEA level (P < 0.001), and differentiation (P < 0.001). In univariate analysis by log-rank test, serum CEA level, pT stage, differentiation, nm23-H1 expression, and PCNA expression were significant prognostic factors (P = 0.037, 0.021, <0.001, 0.042, and 0.014, respectively). In multivariate analysis, pT stage and nm23-H1 expression maintained its independent prognostic influence on overall survival (P = 0.041 and 0.003, respectively). CONCLUSIONS nm23-H1 may be a good biomarker to be applied in clinic to predict the prognosis of patients with completely resected pathologic stage I NSCLC.
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Affiliation(s)
- Chengying Liu
- Department of Respiratory Medicine, Jiangyin People's Hospital, Nantong University, Jiangyin, People's Republic of China
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Fricano MM, Ditewig AC, Jung PM, Liguori MJ, Blomme EAG, Yang Y. Global transcriptomic profiling using small volumes of whole blood: a cost-effective method for translational genomic biomarker identification in small animals. Int J Mol Sci 2011; 12:2502-17. [PMID: 21731455 PMCID: PMC3127131 DOI: 10.3390/ijms12042502] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Revised: 03/28/2011] [Accepted: 04/01/2011] [Indexed: 01/19/2023] Open
Abstract
Blood is an ideal tissue for the identification of novel genomic biomarkers for toxicity or efficacy. However, using blood for transcriptomic profiling presents significant technical challenges due to the transcriptomic changes induced by ex vivo handling and the interference of highly abundant globin mRNA. Most whole blood RNA stabilization and isolation methods also require significant volumes of blood, limiting their effective use in small animal species, such as rodents. To overcome these challenges, a QIAzol-based RNA stabilization and isolation method (QSI) was developed to isolate sufficient amounts of high quality total RNA from 25 to 500 μL of rat whole blood. The method was compared to the standard PAXgene Blood RNA System using blood collected from rats exposed to saline or lipopolysaccharide (LPS). The QSI method yielded an average of 54 ng total RNA per μL of rat whole blood with an average RNA Integrity Number (RIN) of 9, a performance comparable with the standard PAXgene method. Total RNA samples were further processed using the NuGEN Ovation Whole Blood Solution system and cDNA was hybridized to Affymetrix Rat Genome 230 2.0 Arrays. The microarray QC parameters using RNA isolated with the QSI method were within the acceptable range for microarray analysis. The transcriptomic profiles were highly correlated with those using RNA isolated with the PAXgene method and were consistent with expected LPS-induced inflammatory responses. The present study demonstrated that the QSI method coupled with NuGEN Ovation Whole Blood Solution system is cost-effective and particularly suitable for transcriptomic profiling of minimal volumes of whole blood, typical of those obtained with small animal species.
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Affiliation(s)
- Meagan M Fricano
- Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Il 60064, USA; E-Mails: (M.M.F.); (A.C.D.); (P.M.J.); (M.J.L.); (E.A.G.B.)
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TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol 2011; 2011:583929. [PMID: 21331359 PMCID: PMC3035360 DOI: 10.1155/2011/583929] [Citation(s) in RCA: 238] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 11/28/2010] [Accepted: 12/20/2010] [Indexed: 11/17/2022] Open
Abstract
The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.
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Camps C, Jantus-Lewintre E, Cabrera A, Blasco A, Sanmartín E, Gallach S, Caballero C, del Pozo N, Rosell R, Guijarro R, Sirera R. The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients. Lung Cancer 2010; 72:365-9. [PMID: 21074889 DOI: 10.1016/j.lungcan.2010.09.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 09/01/2010] [Accepted: 09/06/2010] [Indexed: 10/18/2022]
Abstract
BACKGROUND Qualitative analysis of circulating DNA in the blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of KRAS mutations at codon 12 and several clinical variables in advanced non-small cell lung cancer (NSCLC) patients. METHODS We examined 308 stage IIIB and IV NSCLC patients who were treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. The KRAS mutational status was determined by an RT-PCR method that is based on allelic discrimination. RESULTS The median age of the patients was 60 years [31-80], 84% were male, 98% had a performance status of 0-1 and 84% of the patients were in stage IV. The histological subtypes were as follows: 30% squamous cell carcinoma (SCC), 51% adenocarcinoma (ADC) and 19% others. Of the 277 response-evaluated patients, 1% achieved a complete response (CR), 26% achieved a partial response (PR), 34% had stable disease (SD) and 39% had progressive disease (PD). Additionally, 27 (8.8%) patients had KRAS mutations; 26 had a KRAS codon 12 TGT mutation, and 1 had a codon 12 GTT mutation. Plasmatic KRAS mutations were found in patients presenting SCC or ADC. Patients with KRAS mutations in plasma DNA had a median progression free survival (PFS) of 5.77 months [3.39-8.14], whereas for patients with wild-type (wt) KRAS, the PFS was 5.43 months [4.65-6.22] (p=0.277). The median overall survival (OS) in KRAS-mutated patients was 9.07 months [4.43-13.70] vs 10.03 months [8.80-11.26] in wt patients (p=0.514). CONCLUSIONS In advanced NSCLC patients, there were no significant differences between patients with or without KRAS mutations in plasma-free DNA with respect to the baseline characteristics, response rates, PFS or OS.
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Affiliation(s)
- Carlos Camps
- Servicio de Oncología Médica, Hospital General Universitario, Valencia, Spain
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Prognostic Value of Fluorodeoxyglucose Uptake in Non-small Cell Lung Cancer: Time for Standardization and Validation. J Thorac Oncol 2010; 5:583-4. [DOI: 10.1097/jto.0b013e3181d95cc8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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