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Meng X, Ma J, Meng N, Yun T, Niu B. Case Report: SMARCA4 (BRG1)-deficient undifferentiated carcinoma of gallbladder with genetic analysis. Front Oncol 2023; 13:1086266. [PMID: 37456262 PMCID: PMC10348478 DOI: 10.3389/fonc.2023.1086266] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/26/2023] [Indexed: 07/18/2023] Open
Abstract
SMARCA4 (BRG1)-deficient undifferentiated carcinoma is a rare and highly aggressive malignancy. It has been reported to occur in a multiple range of organs. However, to the best of our knowledge, SMARCA4 (BRG1)-deficient undifferentiated carcinoma of gallbladder has not yet been reported. Here, we describe a case of SMARCA4 (BRG1)-deficient undifferentiated carcinoma of gallbladder. Through comprehensive genetic analysis, we hypothesized that in addition to SMARCA4 (BRG1) deficiency, other genetic changes might also be involved in the tumorigenesis of undifferentiated gallbladder cancer in this patient, particularly somatic mutations in the CTNNB1, KRAS, PIK3CA, TP53, CREBBP, and FANCI genes. To the best of our knowledge, this is the first report of SMARCA4 (BRG1)-deficient undifferentiated carcinoma of gallbladder with genetic analysis.
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Affiliation(s)
- Xiangpeng Meng
- Pancreatic Endocrinology Ward, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jia Ma
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Nan Meng
- Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China
| | - Tianyu Yun
- Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China
| | - Beifang Niu
- Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China
- Computer Network Information Center, Chinese Academy of Sciences, Beijing, China
- University of the Chinese Academy of Sciences, Beijing, China
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Ahn SJ, Kwon H, Kim JW, Park G, Park M, Joo B, Suh SH, Chang YS, Lee JM. Hippocampal Metastasis Rate Based on Non-Small Lung Cancer TNM Stage and Molecular Markers. Front Oncol 2022; 12:781818. [PMID: 35619920 PMCID: PMC9127383 DOI: 10.3389/fonc.2022.781818] [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: 09/23/2021] [Accepted: 04/04/2022] [Indexed: 01/18/2023] Open
Abstract
Hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) is justified because of low hippocampal brain metastases (BM) rate and its prevention of cognitive decline. However, we hypothesize that the risk of developing BM in the hippocampal-avoidance region (HAR) may differ depending on the lung-cancer stage and molecular status. We retrospectively reviewed 123 patients with non-small cell lung cancer (NSCLC) at the initial diagnosis of BM. The number of BMs within the HAR (5 mm expansion) was counted. The cohort was divided into patients with and without BMs in the HAR, and their clinical variables, TNM stage, and epidermal growth factor receptor (EGFR) status were compared. The most influential variable predicting BMs in the HAR was determined using multi-variable logistic regression, classification and regression tree (CART) analyses, and gradient boosting method (GBM). The feasibility of HAR expansion was tested using generalized estimating equation marginal model. Patients with BMs in the HAR were more frequently non-smokers, and more likely to have extra-cranial metastases and EGFR mutations (p<0.05). Multi-variable analysis revealed that extra-cranial metastases were independently associated with the presence of BM in the HAR (odds ratio=8.75, p=0.04). CART analysis and GBM revealed that the existence of extra-cranial metastasis was the most influential variable predicting BM occurrence in the HAR (variable importance: 23% and relative influence: 37.38). The estmated BM incidence of patients without extra-cranial metastases in th extended HAR (7.5-mm and 10-mm expansion) did not differ significantly from that in the conventional HAR. In conclusion, NSCLC patients with extra-cranial metastases were more likely to have BMs in the HAR than those without extra-cranial metastases.
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Affiliation(s)
- Sung Jun Ahn
- Department of Radiology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Hyeokjin Kwon
- Department of Electronic Engineering, Hanyang University, Seoul, South Korea
| | - Jun Won Kim
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Goeun Park
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Mina Park
- Department of Radiology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Bio Joo
- Department of Radiology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Sang Hyun Suh
- Department of Radiology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Yoon Soo Chang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea
| | - Jong-Min Lee
- Department of Biomedical Engineering, Hanyang University, Seoul, South Korea
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Gao Y, Luo XD, Yang XL, Tu D. Clinical significance of breast cancer susceptibility gene 1 expression in resected non-small cell lung cancer: A meta-analysis. World J Clin Cases 2021; 9:9090-9100. [PMID: 34786391 PMCID: PMC8567518 DOI: 10.12998/wjcc.v9.i30.9090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/25/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The clinical significance of breast cancer susceptibility gene 1 (BRCA1) in non-small cell lung cancer (NSCLC) patients undergoing surgery remains unclear up to now.
AIM To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC.
METHODS EMBASE, PubMed, Web of Science, and The Cochrane Library databases were searched to identify the relevant articles. To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients, the combined relative risks or hazard ratios (HRs) with their corresponding 95% confidence intervals [CIs] were estimated.
RESULTS Totally, 11 articles involving 1041 patients were included in the meta-analysis. The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC. Positive BRCA1 expression signified a shorter overall survival (HR = 1.60, 95%CI: 1.25-2.05; P < 0.001) and disease-free survival (HR = 1.78, 95%CI: 1.42-2.23; P < 0.001). However, no significant association of BRCA1 expression with any clinicopathological parameters was observed.
CONCLUSION BRCA1 expression indicates a poor prognosis in resected NSCLC patients. BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.
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Affiliation(s)
- Yang Gao
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Di Luo
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Li Yang
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Dong Tu
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
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Muhseena N K, Mathukkada S, Das SP, Laha S. The repair gene BACH1 - a potential oncogene. Oncol Rev 2021; 15:519. [PMID: 34322202 PMCID: PMC8273628 DOI: 10.4081/oncol.2021.519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 03/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACH1 encodes for a protein that belongs to RecQ DEAH helicase family and interacts with the BRCT repeats of BRCA1. The N-terminus of BACH1 functions in DNA metabolism as DNA-dependent ATPase and helicase. The C-terminus consists of BRCT domain, which interacts with BRCA1 and this interaction is one of the major regulator of BACH1 function. BACH1 plays important roles both in phosphorylated as well as dephosphorylated state and functions in coordination with multiple signaling molecules. The active helicase property of BACH1 is maintained by its dephosphorylated state. Imbalance between these two states enhances the development and progression of the diseased condition. Currently BACH1 is known as a tumor suppressor gene based on the presence of its clinically relevant mutations in different cancers. Through this review we have justified it to be named as an oncogene. In this review, we have explained the mechanism of how BACH1 in collaboration with BRCA1 or independently regulates various pathways like cell cycle progression, DNA replication during both normal and stressed situation, recombination and repair of damaged DNA, chromatin remodeling and epigenetic modifications. Mutation and overexpression of BACH1 are significantly found in different cancer types. This review enlists the molecular players which interact with BACH1 to regulate DNA metabolic functions, thereby revealing its potential for cancer therapeutics. We have identified the most mutated functional domain of BACH1, the hot spot for tumorigenesis, justifying it as a target molecule in different cancer types for therapeutics. BACH1 has high potentials of transforming a normal cell into a tumor cell if compromised under certain circumstances. Thus, through this review, we justify BACH1 as an oncogene along with the existing role of being a tumor suppressant.
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Affiliation(s)
- Katheeja Muhseena N
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Sooraj Mathukkada
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Shankar Prasad Das
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Suparna Laha
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
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Wang T, Guo J, Liu W, Guo Q, Cheng L, Zheng R, Hu X. Downregulation of ARID1A is correlated with poor prognosis in non-small cell lung cancer. Transl Cancer Res 2020; 9:4896-4905. [PMID: 35117851 PMCID: PMC8798606 DOI: 10.21037/tcr-20-2263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/23/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the main type of lung cancer and NSCLC patients always have a low 5-year survival rate. It is vital to identify a biomarker for the prognosis of NSCLC patients. AT-rich interaction domain 1a (ARID1A) is a tumor suppressor that is involved in the progression of a variety of tumors. METHODS The ARID1A protein level in NSCLC tissues and paracancerous normal lung (PCNL) tissues were detected with immunohistochemistry (IHC) and western blotting (WB). The χ2 test and Spearman's rank correlation analysis were carried out to examine the association between ARID1A expression and the clinicopathological features of NSCLC. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) in the ARID1A low expression group and the ARID1A high expression group. RESULTS The results of WB and IHC demonstrated that the ARID1A protein level was significantly reduced in NSCLC tissues compared with PCNL tissues (P<0.05). The low expression of ARID1A in NSCLC tissues was significantly associated with poor differentiation (P=0.005), smoking (P<0.001), lymphatic invasion (P=0.013), distant metastasis (P=0.010), and high TNM stage (P=0.001). The overall five-year survival rate of NSCLC patients was lower in the ARID1A low expression group than in the ARID1A high expression group. Multivariate analysis showed that the expression of ARID1A had an independent prognostic impact on OS (P=0.024). CONCLUSIONS ARID1A may be a novel biomarker for predicting the prognosis of NSCLC patients.
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Affiliation(s)
- Tao Wang
- Department of Thoracic Surgery, Jiangxi Chest Hospital, Nanchang, China
| | - Jinyan Guo
- Department of General Surgery, Anyuan County People's Hospital, Ganzhou, China
| | - Wenhua Liu
- Department of Respiratory, Guixi City People's Hospital, Guixi, China
| | - Qi Guo
- Department of Pathology, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Lvhuan Cheng
- Department of Thoracic Surgery, Jiangxi Chest Hospital, Nanchang, China
| | - Renshan Zheng
- Department of Thoracic Surgery, Jiangxi Chest Hospital, Nanchang, China
| | - Xinchun Hu
- Department of Thoracic Surgery, Jiangxi Chest Hospital, Nanchang, China
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Ghanshela R, Banerjee BD, Siddarth M, Gupta S. DNA repair gene polymorphism (XPA and XPG) and risk of urinary bladder cancer in North-Indian population. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Al-Shaheri FN, Al-Shami KM, Gamal EH, Mahasneh AA, Ayoub NM. Association of DNA repair gene polymorphisms with colorectal cancer risk and treatment outcomes. Exp Mol Pathol 2019; 113:104364. [PMID: 31881200 DOI: 10.1016/j.yexmp.2019.104364] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/16/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, University of Heidelberg, ImNeuenheimer Feld 672, 69120 Heidelberg, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Kamal M Al-Shami
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, 720 South Donahue Drive, Auburn, Alabama 36849, United States of America; Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Eshrak H Gamal
- Department of Oncology, Collage of Medicine, Bonn University, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Amjad A Mahasneh
- Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Nehad M Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
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Lawania S, Singh N, Behera D, Sharma S. XPG polymorphisms and their association with lung cancer susceptibility, overall survival and response in North Indian patients treated with platinum-based doublet chemotherapy. Future Oncol 2019; 15:151-165. [PMID: 30522358 DOI: 10.2217/fon-2018-0408] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 09/19/2018] [Indexed: 12/18/2022] Open
Abstract
AIM The study investigates association of XPG polymorphism with lung cancer susceptibility, overall survival and clinical outcomes in North Indian population. RESULTS A significant protective effect was observed for 2228959 C/A polymorphism with lung cancer and its histological subtypes. An increased hazard ratio (HR) was observed in 17655 G/C variant among small-cell lung carcinoma patients with mutant genotype (HR: 2.55; p = 0.05). Individuals treated with irinotecan-cisplatin/carboplatin regimen showed a longer survival time (HR1: 0.04; median survival time [MST]: 32.5 months). Subjects treated with pemetrexed-cisplatin/carboplain regimen were associated with higher mortality rate in lung cancer patients (HR1: 1.83; MST: 9.13 months). CONCLUSION 2228959 C/A polymorphism contributes to protective effect in lung cancer patients. 2228959 C/A polymorphism might be associated with favorable prognosis in lung cancer risk.
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Affiliation(s)
- Shweta Lawania
- Department of Biotechnology, Thapar University, Punjab 147002, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Post Graduate Institute of Medical & Educational Research (PGIMER), Sector 14, Chandigarh, India
| | - Digambar Behera
- Department of Pulmonary Medicine, Post Graduate Institute of Medical & Educational Research (PGIMER), Sector 14, Chandigarh, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar University, Punjab 147002, India
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Lu Z, Liu Y, Xu J, Yin H, Yuan H, Gu J, Chen YH, Shi L, Chen D, Xie B. Immunohistochemical quantification of expression of a tight junction protein, claudin-7, in human lung cancer samples using digital image analysis method. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2018; 155:179-187. [PMID: 29512497 DOI: 10.1016/j.cmpb.2017.12.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/11/2017] [Accepted: 12/11/2017] [Indexed: 06/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Tight junction proteins are correlated with cancer development. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies. We have previously reported that claudin-7 was strongly expressed in benign bronchial epithelial cells at the cell-cell junction while expression of claudin-7 was either altered with discontinued weak expression or completely absent in lung cancers. Based on these results, we continued working on the expression pattern of claudin-7 and its relationship with lung cancer development. We herein proposed a new Digital Image Classification, Fragmentation index, Morphological analysis (DICFM) method for differentiating the normal lung tissues and lung cancer tissues based on the claudin-7 immunohistochemical staining. METHODS Seventy-seven lung cancer samples were obtained from the Second Affiliated Hospital of Zhejiang University and claudin-7 immunohistochemical staining was performed. Based on C++ and Open Source Computer Vision Library (OpenCV, version 2.4.4), the DICFM processing module was developed. Intensity and fragmentation of claudin-7 expression, as well as the morphological parameters of nuclei were calculated. Evaluation of results was performed using Receiver Operator Characteristic (ROC) analysis. RESULTS Agreement between these computational results and the results obtained by two pathologists was demonstrated. The intensity of claudin-7 expression was significantly decreased while the fragmentation was significantly increased in the lung cancer tissues compared to the normal lung tissues and the intensity was strongly positively associated with the differentiation of lung cancer cells. Moreover, the perimeters of the nuclei of lung cancer cells were significantly greater than that of the normal lung cells, while the parameters of area and circularity revealed no statistical significance. CONCLUSIONS Taken together, our DICFM approach may be applied as an appropriate approach to quantify the immunohistochemical staining of claudin-7 on the cell membrane and claudin-7 may serve as a marker for identification of lung cancer.
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Affiliation(s)
- Zhe Lu
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Yi Liu
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Junfeng Xu
- School of Science, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Hongping Yin
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Haiying Yuan
- Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310000, China
| | - Jinjing Gu
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Yan-Hua Chen
- Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Liyun Shi
- School of Basic Medical Science, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210023, China
| | - Dan Chen
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China
| | - Bin Xie
- School of Science, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China.
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Pilyugin M, Descloux P, André PA, Laszlo V, Dome B, Hegedus B, Sardy S, Janes S, Bianco A, Laurent GJ, Irminger-Finger I. BARD1 serum autoantibodies for the detection of lung cancer. PLoS One 2017; 12:e0182356. [PMID: 28786985 PMCID: PMC5546601 DOI: 10.1371/journal.pone.0182356] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 07/17/2017] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Currently the screening for lung cancer for risk groups is based on Computed Tomography (CT) or low dose CT (LDCT); however, the lung cancer death rate has not decreased significantly with people undergoing LDCT. We aimed to develop a simple reliable blood test for early detection of all types of lung cancer based on the immunogenicity of aberrant forms of BARD1 that are specifically upregulated in lung cancer. METHODS ELISA assays were performed with a panel of BARD1 epitopes to detect serum levels of antibodies against BARD1 epitopes. We tested 194 blood samples from healthy donors and lung cancer patients with a panel of 40 BARD1 antigens. Using fitted Lasso logistic regression we determined the optimal combination of BARD1 antigens to be used in ELISA for discriminating lung cancer from healthy controls. Random selection of samples for training sets or validations sets was applied to validate the accuracy of our test. RESULTS Fitted Lasso logistic regression models predict high accuracy of the BARD1 autoimmune antibody test with an AUC = 0.96. Validation in independent samples provided and AUC = 0.86 and identical AUCs were obtained for combined stages 1-3 and late stage 4 lung cancers. The BARD1 antibody test is highly specific for lung cancer and not breast or ovarian cancer. CONCLUSION The BARD1 lung cancer test shows higher sensitivity and specificity than previously published blood tests for lung cancer detection and/or diagnosis or CT scans, and it could detect all types and all stages of lung cancer. This BARD1 lung cancer test could therefore be further developed as i) screening test for early detection of lung cancers in high-risk groups, and ii) diagnostic aid in complementing CT scan.
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Affiliation(s)
- Maxim Pilyugin
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
- * E-mail:
| | | | - Pierre-Alain André
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
| | - Viktoria Laszlo
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Balazs Dome
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - Balazs Hegedus
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hunagary
| | - Sylvain Sardy
- Departement of Mathematics, University of Geneva, Geneva, Switzerland
| | - Samuel Janes
- Lungs for Living Research Centre, UCL Respiratory, Rayne Institute, University College London, London, United Kingdom
| | - Andrea Bianco
- Dipartimento di Medicina e Scienze della Salute “V. Tiberio”, Università del Molise, Campobasso, Italy
| | - Geoffrey J. Laurent
- Institute for Respiratory Health, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Australia
| | - Irmgard Irminger-Finger
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
- Institute for Respiratory Health, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Australia
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Collagen gel droplet-embedded culture drug sensitivity testing in squamous cell carcinoma cell lines derived from human oral cancers: Optimal contact concentrations of cisplatin and fluorouracil. Oncol Lett 2016; 12:4643-4650. [PMID: 28105171 DOI: 10.3892/ol.2016.5238] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 06/07/2016] [Indexed: 01/15/2023] Open
Abstract
The collagen gel droplet-embedded culture drug sensitivity test (CD-DST) is an anticancer drug sensitivity test that uses a method of three-dimensional culture of extremely small samples, and it is suited to primary cultures of human cancer cells. It is a useful method for oral squamous cell carcinoma (OSCC), in which the cancer tissues available for testing are limited. However, since the optimal contact concentrations of anticancer drugs have yet to be established in OSCC, CD-DST for detecting drug sensitivities of OSCC is currently performed by applying the optimal contact concentrations for stomach cancer. In the present study, squamous carcinoma cell lines from human oral cancer were used to investigate the optimal contact concentrations of cisplatin (CDDP) and fluorouracil (5-FU) during CD-DST for OSCC. CD-DST was performed in 7 squamous cell carcinoma cell lines derived from human oral cancers (Ca9-22, HSC-3, HSC-4, HO-1-N-1, KON, OSC-19 and SAS) using CDDP (0.15, 0.3, 1.25, 2.5, 5.0 and 10.0 µg/ml) and 5-FU (0.4, 0.9, 1.8, 3.8, 7.5, 15.0 and 30.0 µg/ml), and the optimal contact concentrations were calculated from the clinical response rate of OSCC to single-drug treatment and the in vitro efficacy rate curve. The optimal concentrations were 0.5 µg/ml for CDDP and 0.7 µg/ml for 5-FU. The antitumor efficacy of CDDP at this optimal contact concentration in CD-DST was compared to the antitumor efficacy in the nude mouse method. The T/C values, which were calculated as the ratio of the colony volume of the treatment group and the colony volume of the control group, at the optimal contact concentration of CDDP and of the nude mouse method were almost in agreement (P<0.05) and predicted clinical efficacy, indicating that the calculated optimal contact concentration is valid. Therefore, chemotherapy for OSCC based on anticancer drug sensitivity tests offers patients a greater freedom of choice and is likely to assume a greater importance in the selection of treatment from the perspectives of function preservation and quality of life, as well as representing a treatment option for unresectable, intractable or recurrent cases.
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DNA repair gene polymorphisms in non-small-cell lung cancer patients treated with first-line platinum-containing chemotherapy. TUMORI JOURNAL 2016; 102:367-75. [PMID: 27396427 DOI: 10.5301/tj.5000526] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE Single nucleotide polymorphisms (SNPs) in the DNA repair genes are believed to contribute to the clinical outcome of patients receiving platinum-based chemotherapy. We investigated the impact of 2 SNPs of excision repair cross-complementation group 1 and 2 of xeroderma pigmentosum complementation group G on the outcome in patients with non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. METHODS Between October 2007 and March 2012, we collected 374 blood samples from consecutive patients registered in the TAILOR trial. Four SNPs (rs11615, rs3212986, rs17655, rs1047768) were genotyped using real-time polymerase chain reaction. RESULTS The rs11615 polymorphism was associated with histotype (p = 0.0123). No other correlations were found with clinical variables or with EGFR or KRAS mutational status. None of the SNPs had any impact on overall survival or progression-free survival. CONCLUSIONS The findings suggest that the investigated SNPs do not make any significant contribution to the outcome of NSCLC.
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Zeng Y, Wei L, Wang YJ, Liu C. Genetic Association between ERCC5 rs17655 Polymorphism and Colorectal Cancer Risk: Evidence Based on a Meta-analysis. Asian Pac J Cancer Prev 2016. [PMID: 26225711 DOI: 10.7314/apjcp.2015.16.13.5565] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies evaluating the association between the excision repair cross complementing group 5 (ERCC5) gene rs17655 polymorphism and colorectal cancer susceptibility generated controversial results. To generate large-scale evidence on whether the ERCC5 rs17655 polymorphism might indeed be associated with colorectal cancer susceptibility, the present meta-analysis was performed. MATERIALS AND METHODS Data were collected from PubMed, Embase and Web of Science, with the last report up to Apr 03, 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association. RESULTS A total of nine studies including 5,102 cases and 6,326 controls based on the search criteria were included and significant associations were found between ERCC5 rs17655 polymorphism CG vs GG overall (OR=1.29, 95% CI=1.18~1.40) and in the dominant model (OR=1.23, 95% CI=1.13~1.33). On subgroup analysis by ethnicity and source of controls, the ERCC5 rs17655 polymorphism was found to correlate with the pathogenesis of colorectal cancer among Asians and Caucasians and with hospital-based populations. CONCLUSIONS This meta-analysis suggests that the ERCC5 rs17655 polymorphism might contribute to genetic susceptibility to colorectal cancer.
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Affiliation(s)
- Yong Zeng
- Department of Cardiothoracic Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang Province, China E-mail : ,
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Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. Cancer Chemother Pharmacol 2015; 76:163-70. [PMID: 26003539 DOI: 10.1007/s00280-015-2773-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 05/06/2015] [Indexed: 01/10/2023]
Abstract
PURPOSE To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIβ-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. METHODS Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi-square test (χ (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model. RESULTS A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4 %, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P < 0.001, r = 0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P > 0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21 months, HR 1.913, 95 % CI 1.161-3.150, P = 0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23 months, HR 1.931, 95 % CI 1.157-3.224, P = 0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P > 0.05). CONCLUSIONS The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression.
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Massuti B, Sanchez JM, Hernando-Trancho F, Karachaliou N, Rosell R. Are we ready to use biomarkers for staging, prognosis and treatment selection in early-stage non-small-cell lung cancer? Transl Lung Cancer Res 2015; 2:208-21. [PMID: 25806234 DOI: 10.3978/j.issn.2218-6751.2013.03.06] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 03/11/2013] [Indexed: 01/16/2023]
Abstract
Lung cancer accounts for the majority of cancer-related deaths worldwide. At present, platinum-based therapy represents the standard of care in fit stage II and IIIA non-small cell lung cancer (NSCLC) patients following surgical resection. In advanced disease, personalized chemotherapy and targeted biologic therapy based on histological and molecular tumor profiling have already shown promise in terms of optimizing treatment efficacy. While disease stage is associated with outcome and is commonly used to determine adjuvant treatment eligibility, it is known that a subset of patients with early stage disease experience shorter survival than others with the same clinicopathological characteristics. Improved methods for identifying these individuals, at or near the time of initial diagnosis, may inform the decision to pursue adjuvant therapy options. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information, while real-time quantitative polymerase-chain reaction (RT-qPCR) strategy involving relatively small numbers of genes offers a practical alternative with high cross-platform performance. mRNA and/or protein expression levels of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M subunit 1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) are among the most promising potential biomarkers for early disease and their clinical utility is currently being evaluated in randomized phase II and III clinical trials. This review describes the most promising clinicopathological and molecular biomarkers with predictive and prognostic significance in lung cancer that have been identified through advanced research and which could influence adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine clinical practice.
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Affiliation(s)
| | | | | | - Niki Karachaliou
- Breakthrough Cancer Research Unit, Pangaea Biotech S.L, Barcelona, Spain
| | - Rafael Rosell
- Breakthrough Cancer Research Unit, Pangaea Biotech S.L, Barcelona, Spain ; ; Catalan Institute of Oncology, Badalona, Spain
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Relationship between NOB1 expression and prognosis of resected non-small cell lung cancer. Int J Biol Markers 2015; 30:e43-8. [PMID: 25450647 DOI: 10.5301/jbm.5000120] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND The aim of this study was to investigate the relationship between Nin one binding (NOB1) protein expression and prognosis for resected non-small cell lung cancer (NSCLC). METHODS A prospective cohort of 70 consecutive patients with resected NSCLC was studied in 2009. Immunohistochemistry was used in the detection of NOB1 protein expression. Prognosis outcomes included overall survival (OS) and progression-free survival (PFS). The log-rank test and Cox hazard model were used to estimate the relationship between NOB1 expression and prognosis. RESULTS In the 70 NSCLC tissue specimens, 14 (20%) stained -, 24 (34%) stained +, 21 (30%) stained ++ and 11 (16%) stained +++. The NOB1 high expression rate was 16%. NOB1 expression was significantly different between TMN stage (p=0.024) and lymph node metastasis (p=0.001), as well as histopathological grades (p=0.037). Median OS was 43 months (95% confidence interval [95% CI], 35-51 months), and median PFS was 37 months (95% CI, 25-49 months). OS and PFS were related to TMN stage and lymph node metastasis, as well as NOB1 expression (p<0.05). After adjustment for TMN stage and lymph node metastasis, the hazard ratio (HR) for high NOB1 expression was 1.7 (95% CI, 1.1-3.0, p=0.027) for OS, and 1.8 (95% CI, 1.3-3.7, p=0.031) for PFS. CONCLUSIONS Our results suggest that enhanced expression of NOB1 is related to poor overall survival and progression-free survival in patients with resected NSCLC.
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Association study between XPG Asp1104His polymorphism and colorectal cancer risk in a Chinese population. Sci Rep 2014; 4:6700. [PMID: 25332048 PMCID: PMC4204027 DOI: 10.1038/srep06700] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 10/02/2014] [Indexed: 12/11/2022] Open
Abstract
Previous studies have reported that the Asp1104His polymorphism in Xeroderma Pigmentosum complementation group G (XPG) was associated with the susceptibility to colorectal cancer (CRC), although the results were inconsistent. This study was aim to investigate whether there existed an association between XPG Asp1104His polymorphism and CRC risk in the Chinese population, and a further meta-analysis was performed to consolidate the results. We found that XPG Asp1104His polymorphism was associated with a significantly increased CRC risk (dominant model: His/His + Asp/His vs. Asp/Asp, adjusted OR = 1.39, 95% CI = 1.14–1.69). Stratification analysis by clinical characteristics indicated that the His/His + Asp/His genotypes were associated with increased CRC susceptibility in patients with moderately differentiated grade, but not in poorly and well differentiated grade. Furthermore, a total of 5 eligible studies, including 2,649 CRC cases and 2,848 controls, were recruited for the meta-analysis. We identified that the meta-analysis reported a similar result in dominant model (OR = 1.35; 95% CI = 1.20–1.51). Especially, when stratified by ethnicity, an evidently increased risk was identified in the Asian population. In conclusion, our findings suggest that XPG Asp1104His polymorphism may increase the susceptibility of CRC, especially in Asian populations.
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O'Grady S, Finn SP, Cuffe S, Richard DJ, O'Byrne KJ, Barr MP. The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev 2014; 40:1161-70. [PMID: 25458603 DOI: 10.1016/j.ctrv.2014.10.003] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 10/11/2014] [Indexed: 11/19/2022]
Abstract
Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.
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Affiliation(s)
- Shane O'Grady
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College Dublin, Dublin 8, Ireland.
| | - Stephen P Finn
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College Dublin, Dublin 8, Ireland; Department of Histopathology, St James's Hospital and Trinity College Dublin, Ireland.
| | - Sinead Cuffe
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College Dublin, Dublin 8, Ireland.
| | - Derek J Richard
- Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, Australia.
| | - Kenneth J O'Byrne
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College Dublin, Dublin 8, Ireland; Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, Australia.
| | - Martin P Barr
- Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital and Trinity College Dublin, Dublin 8, Ireland.
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Deng N, Liu JW, Sun LP, Xu Q, Duan ZP, Dong NN, Yuan Y. Expression of XPG protein in the development, progression and prognosis of gastric cancer. PLoS One 2014; 9:e108704. [PMID: 25268735 PMCID: PMC4182552 DOI: 10.1371/journal.pone.0108704] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 09/01/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Xeroderma pigmentosum group G (XPG) plays a critical role in preventing cells from oxidative DNA damage. This study aimed to investigate XPG protein expression in different gastric tissues and in patients with diverse prognoses, thus providing insights into its role in the development, progression and prognosis of gastric cancer (GC). METHODS A total of 176 GC, 131 adjacent non-tumour tissues, 53 atrophic gastritis (AG) and 49 superficial gastritis (SG) samples were included. Immunohistochemical staining was used to detect XPG protein expression. RESULTS XPG expression was significantly higher in GC tissues compared with adjacent non-tumour tissues. In the progressive disease sequence SG→AG→GC, XPG expression was significantly higher in AG and GC compared with SG. Analysis of clinicopathological parameters and survival in GC patients demonstrated a significant association between XPG expression level and depth of tumour invasion, macroscopic type, Lauren's classification, smoking, Helicobacter pylori infection and family history. Cox multivariate survival analysis indicated that patients with positive XPG expression had significantly longer overall survival (P = 0.020, HR = 0.394, 95%CI 0.179-0.866), especially in aged younger than 60 years (P = 0.027, HR = 0.361, 95%CI 0.147-0.888) and male patients (P = 0.002, HR = 0.209, 95%CI 0.077-0.571). CONCLUSIONS This study demonstrated that XPG protein expression was related to the development, progression and prognosis of GC, and might thus serve as a potential biomarker for its diagnosis and prognosis.
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Affiliation(s)
- Na Deng
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China; Department of Oncology, The Fourth Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Jing-wei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
| | - Li-ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
| | - Zhi-Peng Duan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
| | - Nan-Nan Dong
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China
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Xu Y, Jiao G, Wei L, Wang N, Xue Y, Lan J, Wang Y, Liu C, Lou M. Current evidences on the XPG Asp1104His polymorphism and melanoma susceptibility: a meta-analysis based on case-control studies. Mol Genet Genomics 2014; 290:273-9. [PMID: 25231183 DOI: 10.1007/s00438-014-0917-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 09/06/2014] [Indexed: 01/11/2023]
Abstract
Previous studies evaluating the association between the XPG Asp1104His polymorphism and melanoma susceptibility remained controversial. To draw a more precise estimation of the relationship, a total of eight published case-control studies containing 5,212 cases and 7,045 controls were included for meta-analysis. Overall, a significant association was found between the XPG Asp1104His polymorphism and melanoma susceptibility for the dominant model (OR = 2.42, 95 % CI = 2.26-2.60). In subgroup analysis by source of control, there was an obvious association was found among Population-based subgroup for the dominant model CC+GC vs GG (OR 2.51, 95 % CI 2.28-2.77), among the Hospital-based subgroup, an obvious association was also found for the dominant model CC+GC vs GG (OR 2.34, 95 % CI 2.12-2.58). This meta-analysis suggested that the XPG Asp1104His polymorphism was a risk factor for melanoma susceptibility.
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Affiliation(s)
- Yuanzhi Xu
- Department of Neurosurgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China,
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Zhang T, Sun J, Lv M, Zhang L, Wang X, Ren JC, Wang B. XPG is predictive gene of clinical outcome in advanced non-small-cell lung cancer with platinum drug therapy. Asian Pac J Cancer Prev 2014; 14:701-5. [PMID: 23621222 DOI: 10.7314/apjcp.2013.14.2.701] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Polymorphisms in XPG are considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We aimed to investigate the role of five potential SNPs of XPG gene on the response to platinum-based chemotherapy in advanced Chinese NSCLC patients. A total of 451 patients with newly diagnosed and histopathologically confirmed primary NSCLC were consecutively collected. XPG rs2296147, rs4150261, rs17655, rs1047768 and rs2094258 were genotyped by the Taqman real-time polymerase chain reaction (PCR). In our study, we found patients carrying rs1057768 TT genotype had a significantly lower treatment response when compared with the CC genotype (OR=0.38, 95% CI=0.18-0.78). Patients carrying rs1047768 TT genotype showed a significantly short median PFS (11.2 months) and OS (13.6 months) than CC genotype, and the hazard ratios (HR) for PFS and OS were 2.06 (1.01-4.50) and 2.29 (1.21-2.49), respectively. Moreover, we found a significant decreased risk of death from NSCLC among patients carrying the rs2296147 TT genotype when compared with the CC genotype, the HR (95% CI) for OS being 0.50 (0.27-0.95). In conclusion, our study found that polymorphisms in rs1047768 C/T and rs2296147 C/T are associated with response to platinum-based chemotherapy in advanced NSCLC, and XPG polymorphisms could be predictive of prognosis.
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Affiliation(s)
- Tian Zhang
- Department of Radiotherapy, Beijing Chaoyang Hospital, Capital Medical University, Changchun, China
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Liang Y, Deng J, Xiong Y, Wang S, Xiong W. Genetic association between ERCC5 rs17655 polymorphism and lung cancer risk: evidence based on a meta-analysis. Tumour Biol 2014; 35:5613-8. [PMID: 24596032 DOI: 10.1007/s13277-014-1742-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/10/2014] [Indexed: 12/14/2022] Open
Abstract
The relationship between excision repair cross-complementing group 5 (ERCC5) rs17655 polymorphism and lung cancer risk remains controversial. To clarify the association, we conducted a comprehensive meta-analysis of all published case-control studies. PubMed, Web of Science, and CNKI were searched to identify the possibly eligible publications. Pooled odds ratio (OR) was estimated using the fixed effect model. Q test and I (2) index were used to evaluate heterogeneity between studies, and Egger's and Begg's tests were utilized to assess publication bias. Meta-analysis of nine case-control studies including 4,044 cases and 5,100 controls indicated that there was no global association between rs17655 polymorphism and lung cancer risk. Subgroup analyses according to ethnicity and histologic type revealed similar results. In summary, our meta-analysis suggests that ERCC5 rs17655 polymorphism may not contribute to genetic susceptibility for lung cancer.
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Affiliation(s)
- Yujia Liang
- Department of Respiratory Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, 646000, Sichuan Province, People's Republic of China,
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Qin X, Yao W, Li W, Feng X, Huo X, Yang S, Zhao H, Gu X. ERCC1 and BRCA1 mRNA expressions are associated with clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. Tumour Biol 2014; 35:4697-704. [DOI: 10.1007/s13277-014-1615-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 01/03/2014] [Indexed: 12/18/2022] Open
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Yuli Y, Zhe S, Xia W, Siqing L, Zhenxuan W, Yu-Hua Z, Bing S, Jun-Wei C. XPG is a novel biomarker of clinical outcome in advanced non-small-cell lung cancer. Pak J Med Sci 2013; 29:762-7. [PMID: 24353624 PMCID: PMC3809298 DOI: 10.12669/pjms.293.3664] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Revised: 01/03/2013] [Accepted: 04/02/2013] [Indexed: 12/28/2022] Open
Abstract
Objective: Polymorphisms in XPG were considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We investigated the impact of several potential SNPs of XPG on the efficacy of platinum-based chemotherapy in NSCLC patients. Methods: A total of 433 patients were consecutively selected between Nov. 2006 and Dec. 2007, and were followed-up up to Nov. 2011. The genotyping of six SNPs (rs2296147, rs751402, rs873601, rs4150375, rs17655 and rs2094258) were genotyped using the Taqman real-time PCR method with a 7900 HT sequence detector system. Results: Patients carrying CT+TT genotype of rs2296147 had a significantly longer median PFS (17.5 months) and OS (26.8 months) than CC genotype. Hazard ratio (HR) for PFS and OS in patients with CT+TT genotype of rs2296147 was respectively 0.73(0.51-0.97) and 0.66(0.48-0.99) when compare CC genotype, respectively. Similarly, patients with rs2094258 AG+GG genotype had a longer median progression time (18.4 months) and overall survival time (27.3 months) when compared with those with AA genotype, and HRs(95% CI) for PFS and OS were 0.44(0.34-0.78) and 0.51(0.39-0.82), respectively. Conclusions: Our study suggests rs2296147 CT+TT and rs2094258 AG+GG genotypes contribute to the better survival of NSCLC. Our study provides significant information on role of prognostic value of XPG SNPs, and detecting of XPG could be used as predictive markers toward individualizing NSCLC treatment strategies.
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Affiliation(s)
- Yi Yuli
- Yi Yuli, Nursing College of Nanchang University, Nanchang, China
| | - Sun Zhe
- Sun Zhe, Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wang Xia
- WANG Xia, The Fourth Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
| | - Li Siqing
- LI Si-qing, The Second Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
| | - Wu Zhenxuan
- WU Zhen-xuan, The Fourth Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
| | - Zhu Yu-Hua
- ZHU Yu-hua, The Fourth Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
| | - Sun Bing
- Sun Bing, The Second Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
| | - Cui Jun-Wei
- Cui Jun-wei, The First Department of Tuberculosis, The First Affiliated Hospital, Xinxiang Medical College, Weihui, China
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Han Y, Wang XB, Xiao N, Liu ZD. mRNA Expression and Clinical Significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in Postoperative Patients with Non-Small Cell Lung Cancer. Asian Pac J Cancer Prev 2013; 14:2987-90. [DOI: 10.7314/apjcp.2013.14.5.2987] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Tiseo M, Bordi P, Bortesi B, Boni L, Boni C, Baldini E, Grossi F, Recchia F, Zanelli F, Fontanini G, Naldi N, Campanini N, Azzoni C, Bordi C, Ardizzoni A. ERCC1/BRCA1 expression and gene polymorphisms as prognostic and predictive factors in advanced NSCLC treated with or without cisplatin. Br J Cancer 2013; 108:1695-703. [PMID: 23549037 PMCID: PMC3669730 DOI: 10.1038/bjc.2013.127] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/08/2013] [Accepted: 03/01/2013] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1-3 gene polymorphisms on outcomes of patients was examined. METHODS Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay. RESULTS Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036). CONCLUSION This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.
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Affiliation(s)
- M Tiseo
- Oncology Unit, University Hospital, Via Gramsci 14, 43126 Parma, Italy.
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Ahmed H, Salama A, Salem SE, Bahnassy AA. A case of synchronous double primary breast carcinoma and osteosarcoma: Mismatch repair genes mutations as a possible cause for multiple early onset malignant tumors. AMERICAN JOURNAL OF CASE REPORTS 2012; 13:218-23. [PMID: 23569533 PMCID: PMC3616025 DOI: 10.12659/ajcr.883382] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 07/23/2012] [Indexed: 12/23/2022]
Abstract
Background: Simultaneous or consequent development of multiple solid tumors might be faced in some patients, especially the young. These tumors might be related to certain hereditary cancer syndromes or certain genetic predispositions. Case Report: We present the case of a 19-year-old woman with metastatic breast cancer to the contralateral axillary lymph node, associated with simultaneous osteosarcoma of the left lower femur. As she did not fit into any of the familial cancer syndromes, genetic predisposition was suspected. We detected MLH1 and MSH2 promotor methylation (PM), microsatellite instability (MSI), and different mutational events in both tumors. BRCA1 gene mutations were detected in the breast tumor, with reduced mRNA expression of BRCA1&2. ERCC1, MLH1 and MSH2, especially in OS, and RRM1 was overexpressed in both tumors. Conclusions: Aberrations in MMR genes could explain simultaneous or consequent development of multiple solid tumors, especially in a young patient. We recommend detecting these defects, close follow-up for those patients, and genetic counseling for their family members. Further studies in a larger population are essential to support our results.
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Affiliation(s)
- Hytham Ahmed
- Department of Surgical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
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Stecklein SR, Jensen RA. Identifying and exploiting defects in the Fanconi anemia/BRCA pathway in oncology. Transl Res 2012; 160:178-97. [PMID: 22683426 DOI: 10.1016/j.trsl.2012.01.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 01/18/2012] [Accepted: 01/19/2012] [Indexed: 01/07/2023]
Abstract
Defects in components of DNA repair pathways are responsible for numerous hereditary cancer syndromes and are also common in many sporadic malignancies. Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 or components of the Fanconi anemia (FA) complex incite genomic instability and predispose to malignancy. The products of the BRCA and FA genes participate in a conserved DNA damage repair pathway that is responsible for repairing interstrand crosslinks and double-strand DNA breaks by homologous recombination. While the genetic instability resulting from FA/BRCA dysfunction contributes to cancer pathogenesis, deficiency of these genes also lends to therapeutic exploitation. Crosslinking agents and ionizing radiation induce damage in cancer cells that requires the FA/BRCA pathway to be resolved; thus cancers that are deficient in BRCA1, BRCA2, or any other component of the FA/BRCA pathway are hypersensitive to these agents. Moreover, emerging synthetic lethal strategies offer opportunities to selectively target cancer cells with defects in homologous recombination. Conversely, enhanced activity of the FA/BRCA pathway is responsible for acquired resistance to specific therapeutic agents, suggesting that both dysfunction and hyperfunction of the FA/BRCA repair machinery are rational targets for cancer therapy. Selection of specific cytotoxic agents based on repair capacity may improve responses and enable personalized cytotoxic chemotherapy. This article reviews the FA/BRCA pathway and current approaches to identify deficiencies within it, discusses synthetic lethality and enhanced repair capacity as causes of therapeutic hypersensitivity and resistance, respectively, and highlights recent studies that have linked FA/BRCA pathway function with therapeutic efficacy.
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Affiliation(s)
- Shane R Stecklein
- Department of Pathology and Laboratory Medicine and The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA
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Zhu ML, Shi TY, Hu HC, He J, Wang M, Jin L, Yang YJ, Wang JC, Sun MH, Chen H, Zhao KL, Zhang Z, Chen HQ, Xiang JQ, Wei QY. Polymorphisms in the ERCC5 gene and risk of esophageal squamous cell carcinoma (ESCC) in Eastern Chinese populations. PLoS One 2012; 7:e41500. [PMID: 22848513 PMCID: PMC3406052 DOI: 10.1371/journal.pone.0041500] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 06/21/2012] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR = 0.76, 95% CI = 0.63-0.93, CT/CC: adjusted OR = 0.80, 95% CI = 0.67-0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis. CONCLUSIONS/SIGNIFICANCES These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.
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Affiliation(s)
- Mei-Ling Zhu
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ting-Yan Shi
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hai-Chuan Hu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing He
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Mengyun Wang
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Li Jin
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ya-Jun Yang
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiu-Cun Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Meng-Hong Sun
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Huan Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Kuai-Le Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhen Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hai-Quan Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jia-Qing Xiang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qing-Yi Wei
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America (JX)
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Xiao X, Meng Q, Xu J, Jiao Y, Rosen EM, Fan S. [EGFR-dependent impact of indol-3-carbinol on radiosensitivity of lung cancer cells]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2012; 15:391-8. [PMID: 22814257 PMCID: PMC6000072 DOI: 10.3779/j.issn.1009-3419.2012.07.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
背景与目的 吲哚-3-甲醇（indole-3-carbinol, I3C）是十字花科蔬菜中一种主要的有效植物化学物质，且具有防癌和抗癌作用。本研究旨在观察I3C是否影响表皮生长因子受体（epidermal growth factor receptor, EGFR）表达水平不同的肺癌细胞放射敏感性。 方法 采用MTT和克隆形成实验方法分别检测肺癌细胞的生长和存活率；siRNA转染方法降低细胞中EGFR蛋白表达水平；Western blot和RT-PCR法分别测定EGFR蛋白和mRNA的表达。 结果 采用无明显毒副作用的5 μmol/L剂量的I3C预处理明显降低了EGFR表达阳性的人肺腺癌H1975和人肺鳞癌H226细胞对γ-射线照射的放射敏感性，而I3C对EGFR表达阴性的人肺鳞癌NIH-H520细胞的放射敏感性则影响非常小。Western blot结果显示I3C可以增加H1975和H226细胞中EGFR蛋白的表达水平和Y845位点磷酸化水平。EGFR siRNA降低了NIH-H1975细胞中EGFR蛋白的表达，增加了细胞的放射敏感性，并有效地降低和抑制了I3C导致的细胞耐辐射效应。 结论 我们的研究结果首次证实I3C可以通过调节EGFR表达和磷酸化水平从而影响肺癌细胞的放射治疗敏感性，提示EGFR可能是I3C影响肺癌放射治疗敏感性的重要靶蛋白。
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Affiliation(s)
- Xiao Xiao
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China
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Zhu ML, Wang M, Cao ZG, He J, Shi TY, Xia KQ, Qiu LX, Wei QY. Association between the ERCC5 Asp1104His polymorphism and cancer risk: a meta-analysis. PLoS One 2012; 7:e36293. [PMID: 22815677 PMCID: PMC3399856 DOI: 10.1371/journal.pone.0036293] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 03/29/2012] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results. METHODOLOGY/PRINCIPAL FINDINGS To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92-1.06, P = 0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93-1.03, P = 0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression. CONCLUSIONS/SIGNIFICANCE This meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.
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Affiliation(s)
- Mei-Ling Zhu
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Mengyun Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhi-Gang Cao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Breast Surgery, Cancer Center and Cancer Institute, Fudan University, Shanghai, China
| | - Jing He
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ting-Yan Shi
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Kai-Qin Xia
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Li-Xin Qiu
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qing-Yi Wei
- Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
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Bonanno L, Favaretto A, Rugge M, Taron M, Rosell R. Role of genotyping in non-small cell lung cancer treatment: current status. Drugs 2012; 71:2231-46. [PMID: 22085382 DOI: 10.2165/11597700-000000000-00000] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Non-small cell lung cancer (NSCLC) is a common malignant disease with an extremely poor prognosis. Chemotherapeutic treatment for advanced disease is currently based on histological subtyping, but recent discoveries of genetic alterations in subsets of NSCLC have already changed clinical practice with regard to Egfr mutations as predictive markers of response to gefitinib and erlotinib. This has also paved the way for the integration of molecular analyses into early phase clinical trials, as demonstrated by the clinical development of crizotinib, effective in lung cancer harbouring Alk rearrangements. Similarly, other subgroups of NSCLC carry potentially targetable molecular alterations and their study has the potential to change the diagnostic and therapeutic approach to lung cancer in the near future. In contrast to a wealth of knowledge surrounding genomic alterations in lung adenocarcinomas, fewer data are available concerning squamous cell lung cancer (SCC), although recent data demonstrate that genotyping can provide new therapeutic perspectives in SCC treatment. Moreover, the study of molecular predictive markers of response to chemotherapy aims to improve chemotherapeutic treatment, increasing efficacy and limiting toxicity.
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Affiliation(s)
- Laura Bonanno
- Medical Oncology 2, Instituto Oncologico Veneto-IRCCS, Padua, Italy
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Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck. Pharmacogenet Genomics 2012; 22:50-7. [PMID: 22108238 DOI: 10.1097/fpc.0b013e32834e3cf6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of SCCHN. METHODS We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1059 non-Hispanic white patients with SCCHN and 1066 cancer-free age- and sex-matched controls, and evaluated their associations with the risk of SCCHN. RESULTS Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted odds ratio=0.76, 95% confidence interval=0.62-0.92 for AC vs. AA; adjusted odds ratio=0.81, 95% confidence interval=0.67-0.98 for AC/CC vs. AA), but this association was nonsignificant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 patients with SCCHN, we found that rs4150351 AC/CC was associated with a statistically significant increase in the XPG/ERCC5 mRNA expression. CONCLUSION These findings suggest that genetic variation in XPG/ERCC5 may not affect the risk of SCCHN, although rs4150351 C variant genotypes were associated with an increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.
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Leng XF, Chen MW, Xian L, Dai L, Ma GY, Li MH. Combined analysis of mRNA expression of ERCC1, BAG-1, BRCA1, RRM1 and TUBB3 to predict prognosis in patients with non-small cell lung cancer who received adjuvant chemotherapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:25. [PMID: 22439756 PMCID: PMC3338093 DOI: 10.1186/1756-9966-31-25] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 03/23/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND The aim of this study was to investigate prognostic value of excision repair cross-complementing 1 (ERCC1), BCL2-associated athanogene (BAG-1), the breast and ovarian cancer susceptibility gene 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and class III β-tubulin (TUBB3) in patients with non-small cell lung cancer (NSCLC) who received platinum- based adjuvant chemotherapy. METHODS Messenger RNA expressions of these genes were examined in 85 tumor tissues and 34 adjacent tissue samples using semi-quantitative RT-PCR. The expressions of these five genes were analyzed in relation to chemotherapy and progression-free survival (PFS) and overall survival (OS). Seventy-four patients were enrolled into chemotherapy. RESULTS Patients with ERCC1 or BAG-1 negative expression had a significantly longer PFS (P = 0.001 and P = 0.001) and OS (P = 0.001 and P = 0.001) than those with positive expression. Patients with negative ERCC1 and BAG-1 expression benefited more from platinum regimen (P = 0.001 and P = 0.002). Patients with BRCA1 negative expression might have a longer OS (P = 0.052), but not PFS (P = 0.088) than those with BRCA1 positive expression. A significant relationship was observed between the mRNA expression of ERCC1 and BAG-1 (P = 0.042). In multivariate analysis, ERCC1 and BAG-1 were significantly favorable factors for PFS (P = 0.018 and P = 0.017) and OS (P = 0.027 and P = 0.022). CONCLUSIONS ERCC1 and BAG-1 are determinants of survival after surgical treatment of NSCLC, and its mRNA expression in tumor tissues could be used to predict the prognosis of NSCLC treated by platinum.
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Affiliation(s)
- Xue-Feng Leng
- Department of Cardiothoracic Surgery, The First Afflicted Hospital of Guangxi Medical University, 22# Shuangyong Road, Qingxiu Region 530021 Nanning, China
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Postel-Vinay S, Vanhecke E, Olaussen KA, Lord CJ, Ashworth A, Soria JC. The potential of exploiting DNA-repair defects for optimizing lung cancer treatment. Nat Rev Clin Oncol 2012; 9:144-55. [PMID: 22330686 DOI: 10.1038/nrclinonc.2012.3] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The tumor genome is commonly aberrant as a consequence of mutagenic insult and incomplete DNA repair. DNA repair as a therapeutic target has recently received considerable attention owing to the promise of drugs that target tumor-specific DNA-repair enzymes and potentiate conventional cytotoxic therapy through mechanism-based approaches, such as synthetic lethality. Treatment for non-small-cell lung cancer (NSCLC) consists mainly of platinum-based chemotherapy regimens and improvements are urgently needed. Optimizing treatment according to tumor status for DNA-repair biomarkers, such as ERCC1, BRCA1 or RRM1, could predict response to platinum, taxanes and gemcitabine-based therapies, respectively, and might improve substantially the response of individual patients' tumors. Finally, recent data on germline variation in DNA-repair genes may also be informative. Here, we discuss how a molecular and functional DNA-repair classification of NSCLC may aid clinical decision making and improve patient outcome.
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Affiliation(s)
- Sophie Postel-Vinay
- INSERM U981, Department of Medicine, Université Paris-Sud XI-Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France
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Zhang YQ, Bianco A, Malkinson AM, Leoni VP, Frau G, De Rosa N, André PA, Versace R, Boulvain M, Laurent GJ, Atzori L, Irminger-Finger I. BARD1: an independent predictor of survival in non-small cell lung cancer. Int J Cancer 2011; 131:83-94. [PMID: 21815143 DOI: 10.1002/ijc.26346] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 07/12/2011] [Indexed: 12/21/2022]
Abstract
BRCA1 mRNA overexpression is correlated with poor survival in NSCLC. However, BRCA1 functions depend on the interaction with BARD1 for its stability, nuclear localization and ubiquitin ligase activity. Expression of alternatively spliced BARD1 isoforms that lack the BRCA1-interaction domain was found upregulated and correlated with poor prognosis in breast and ovarian cancer. These BARD1 isoforms are essential for proliferation of cancer cells in vitro. We investigated whether BARD1 isoforms are expressed in NSCLC. While in lung tissues from healthy controls BARD1 expression was undetectable on the mRNA level and protein level, we found two novel isoforms in addition to previously identified mRNAs expressed in all NSCLC samples tested. Furthermore, the pattern of BARD1 isoform expression was similar in tumor and morphologically normal peri-tumor tissues, and only one novel isoform π was specifically upregulated in tumors. Immunohistochemistry revealed that all 100 NSCLC cases tested expressed isoform-specific BARD1 epitopes, while BARD1 expression was undetectable in biopsies from healthy controls. Statistical analysis showed that the expression of epitopes PVC and WFS, present on isoform π, or epitope WFS alone, expressed on isoforms π, κ and β, were significantly correlated with decreased patient survival. These findings were corroborated in a mouse model of chemically induced lung cancer. Immunostaining of mouse tumors showed that BARD1 epitopes PVC and WFS were specifically upregulated in invasive, but not in confined lung tumors. Thus, BARD1 isoforms might be involved in tumor initiation and invasive progression and might represent a novel prognostic marker for NSCLC.
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Affiliation(s)
- Yong-Qiang Zhang
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, University Hospitals Geneva, Geneva, Switzerland
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Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: a meta-analysis of published studies and recommendations. PLoS One 2011; 6:e25164. [PMID: 22022380 PMCID: PMC3194810 DOI: 10.1371/journal.pone.0025164] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 08/26/2011] [Indexed: 12/19/2022] Open
Abstract
Purpose Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis. Methods Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately. Results 23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I2 always >30%), partly due to variability in thresholds defining ‘low’ and ‘high’ ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23–2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51–1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Egger's p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64–0.99). SCLC data were inadequate to draw firm conclusions. Conclusions Current evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials.
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Ioannidis G, Georgoulias V, Souglakos J. How close are we to customizing chemotherapy in early non-small cell lung cancer? Ther Adv Med Oncol 2011; 3:185-205. [PMID: 21904580 PMCID: PMC3150068 DOI: 10.1177/1758834011409973] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Although surgery is the only potentially curative treatment for early-stage non-small cell lung cancer (NSCLC), 5-year survival rates range from 77% for stage IA tumors to 23% in stage IIIA disease. Adjuvant chemotherapy has recently been established as a standard of care for resected stage II-III NSCLC, on the basis of large-scale clinical trials employing third-generation platinum-based regimens. As the overall absolute 5-year survival benefit from this approach does not exceed 5% and potential long-term complications are an issue of concern, the aim of customized adjuvant systemic treatment is to optimize the toxicity/benefit ratio, so that low-risk individuals are spared from unnecessary intervention, while avoiding undertreatment of high-risk patients, including those with stage I disease. Therefore, the application of reliable prognostic and predictive biomarkers would enable to identify appropriate patients for the most effective treatment.This is an overview of the data available on the most promising clinicopathological and molecular biomarkers that could affect adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine practice. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information warranting further validation. On the other hand, real-time quantitative polymerase-chain reaction strategy involving relatively small number of genes offers a practical alternative, with high cross-platform performance. Although data extrapolation from the metastatic setting should be cautious, the concept of personalized, pharmacogenomics-guided chemotherapy for early NSCLC seems feasible, and is currently being evaluated in randomized phase 2 and 3 trials. The mRNA and/or protein expression levels of excision repair cross-complementation group 1, ribonucleotide reductase M1 and breast cancer susceptibility gene 1 are among the most potential biomarkers for early disease, with stage-independent prognostic and predictive values, the clinical utility of which is being validated prospectively. Inter-assay discordance in determining the biomarker status and association with clinical outcomes is noteworthing.
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Abstract
The role of DNA repair pathways is to maintain cellular integrity. However, genetic instability is a driving force in the development of tumor cells and many tumors are characterized by the loss of functionality in one or several DNA repair pathways. However, if genetic instability trespasses a certain point, it will induce cell death. Therefore, the dysfunctionality of several DNA repair pathways could represent an Achille's heel for the tumor, if such pathways could be pharmacologically targeted. For instance, the inhibition of PARP1, a protein in the base excision repair pathway (BER) is sufficient to induce cell death in cancer cells bearing BRCA1 or BRCA2 mutations, which are essential proteins in the homologous recombination repair pathway (HR). This phenomenon called "synthetic letality" constitutes recent knowledge and we discuss here the possibility that this strategy might be applied to innovative treatment options in lung cancer. Further, several DNA repair proteins could be used in lung cancer as prognostic and/or predictive biomarkers of response to chemotherapy or radiation. Indeed, specific biomarkers of each DNA repair pathway do exist and could guide oncologists in therapeutic decisions (e.g. ERCC1 and cisplatin). Finally, pharmacologic modulation of DNA repair proteins might also be interesting as it might increase therapeutic efficacy of anticancer strategies (DNA-interacting chemotherapy and radiotherapy). Here, we will present the principal DNA repair pathways and associated biomarkers (ERCC1, MSH2, PARP1 and BRCA1/2), and discuss their status in non-small call lung cancer (NSCLC).
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Fifth Educational Symposium of the Spanish Lung Cancer Group: report on the Molecular Biology Workshop. Lung Cancer 2011; 74:535-43. [PMID: 21616552 DOI: 10.1016/j.lungcan.2011.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Revised: 04/19/2011] [Accepted: 04/25/2011] [Indexed: 01/07/2023]
Abstract
The majority of non-small-cell lung cancer (NSCLC) patients present with locally advanced (35%) or metastatic disease (40%); in this setting, it is of the utmost importance to balance efficacy with toxicity. However, with platinum combinations, survival has reached a "plateau", with median overall survival times of a mere 10-12 months, making it mandatory to search for new strategies and to identify more effective treatment. Molecular characteristics can be more informative than clinical features in predicting clinical benefit, and the identification of molecular markers can help define subgroups of patients who are likely to respond to different treatments, thus avoiding unnecessary toxicities and costs and providing the maximum benefit to each patient. Here we review research on biomarker assessment that was presented during the Molecular Biology Workshop held in Palma de Mallorca on 25 November 2010, during the Fifth Educational Symposium of the Spanish Lung Cancer Group.
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Sudhindra A, Ochoa R, Santos ES. Biomarkers, prediction, and prognosis in non-small-cell lung cancer: a platform for personalized treatment. Clin Lung Cancer 2011; 12:360-8. [PMID: 21729648 DOI: 10.1016/j.cllc.2011.02.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Revised: 12/29/2010] [Accepted: 02/22/2011] [Indexed: 01/24/2023]
Abstract
In lung cancer, the introduction of targeted agents in those patients who carry a genetic abnormality has resulted in better clinical outcomes with better quality of life. These molecular abnormalities have also become predictive biomarkers. It is imperative that we continue searching for these biomarkers in different tumorigenesis pathways, so we can provide the most appropriate therapy to each individual in the near future. Since the 1980s, chemotherapy for patients with advanced non-small-cell lung cancer has been shown to provide a small improvement in survival. In the early 1990s, platinum-based regimens became the backbone of treatment for this disease. In 2002, the Eastern Cooperative Oncology Group 1594 clinical trial showed that there was no overall survival difference among four common chemotherapy regimens used in non-small-cell lung cancer. It was not until 2006 when the introduction of biologic agents into the field of lung cancer improved, for the first time ever, median overall survival beyond 1 year. To date, we recognize that there are differences between all histologic subtypes of non-small-cell lung cancer in terms of their response to specific agents. All these plus the introduction of molecular medicine have resulted in the identification of markers for prognosis and prediction in lung cancer. In this review, we describe the actual and ongoing clinical efforts to validate the prognostic and predictive value of these potential markers in lung cancer. We hope that the clinical use of biomarkers will help us to deliver personalized medicine to our lung cancer patients by improving their quality of response which may translate into further survival advantage.
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Affiliation(s)
- Akshay Sudhindra
- Sylvester Comprehensive Cancer Center/University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
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Suzuki M, Ishikawa H, Tanaka A, Mataga I. Heterogeneity of anticancer drug sensitivity in squamous cell carcinoma of the tongue. Hum Cell 2010; 24:21-9. [PMID: 21547692 DOI: 10.1007/s13577-010-0004-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Accepted: 10/22/2010] [Indexed: 11/28/2022]
Abstract
Heterogeneity is known to be present to varying degrees in cancer cell groups. There have been no reports, however, of studies in which a single cell clone was prepared from a cancer cell group to examine heterogeneity with respect to anticancer drug sensitivity. Thus, the authors herein report an investigation into the heterogeneity of cancer cells within the same tumor with respect to anticancer drug sensitivity. Anticancer drug sensitivity was investigated in primary tumors, metastatic lymph node tumors, recurrent tumors and established cell lines obtained from four cases of tongue cancer using an oxygen electrode apparatus. As differences were observed in anticancer drug sensitivity from one case to another, even though all four were of the same pathological tissue type, the individual differences were apparently significant. Moreover, primary tumors and recurrent tumors demonstrated different sensitivities to the anticancer drugs even in the same patient. When single cell clones were prepared from primary tumors and anticancer drug sensitivity testing was carried out, sensitivity to anticancer drugs that was not seen in the primary tumors was observed. We performed RT-PCR on cell groups derived from this single cell using MDR1, MRP1, MRP2 and ERCC1, which are primary genes that are resistant to anticancer drugs. Expression of MDR and ERCC1 was not observed in single cell clones nos. 1-10. MRP1 and MRP2, on the other hand, were expressed in all of these single cell clones. Because cells with different sensitivity levels were initially present in the cancer cell groups, even when large numbers of cancer cells died in response to anticancer drug therapy, the results suggest the possibility that recurrence and metastasis occur based on cells with differing sensitivities. After examining anticancer drug sensitivity at the single cell level, we believe that anticancer drug-resistant genes may be involved in the heterogeneity of anticancer drug sensitivity with respect to cancer cell groups.
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Affiliation(s)
- Minako Suzuki
- Oral and Maxillofacial Surgery and Systemic Medicine, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan.
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Jordheim LP, Sève P, Trédan O, Dumontet C. The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol 2010; 12:693-702. [PMID: 21163702 DOI: 10.1016/s1470-2045(10)70244-8] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The large subunit of human ribonucleotide reductase, RRM1, is involved in the regulation of cell proliferation, cell migration, tumour and metastasis development, and the synthesis of deoxyribonucleotides for DNA synthesis. It is also a cellular target for the chemotherapeutic agent, gemcitabine. RRM1 has been studied in a large number of patients with different types of cancer, such as non-small-cell lung cancer, pancreatic cancer, breast cancer, and biliary tract cancer, to establish its prognostic or predictive value when patients were treated with gemcitabine, and mRNA expression and genetic variants as determined by genotyping have in some cases been associated with clinical outcome of patients with cancer. Here, we review preclinical and clinical studies of RRM1 assessment and discuss the further steps in the development of this clinically pertinent biomarker.
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Affiliation(s)
- Lars Petter Jordheim
- INSERM U590, Laboratoire de Cytologie Analytique, Faculte de Medecine Rockefeller, Universite Claude Bernard Lyon I, 69008 Lyon, France.
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Papadaki C, Tsaroucha E, Kaklamanis L, Lagoudaki E, Trypaki M, Tryfonidis K, Mavroudis D, Stathopoulos E, Georgoulias V, Souglakos J. Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer. Br J Cancer 2010; 104:316-23. [PMID: 21157449 PMCID: PMC3031890 DOI: 10.1038/sj.bjc.6606027] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND We explored the predictive significance of BRCA1, TXR1 and TSP1 expression in non-small-cell lung cancer (NSCLC) patients treated with docetaxel in association with cisplatin or gemcitabine. METHODS To analyse BRCA1, TXR1 and TSP1 mRNA expression from microdissected primary tumours of 131 patients with stage IIIB (wet) and IV NSCLC, RT-qPCR was used. RESULTS The mRNA levels of TXR1/TSP1 were inversely correlated (Spearman's test: -0.37; P=0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; P=0.018), longer median progression-free survival (PFS; P=0.029) and median overall survival (mOS P=0.003), whereas high TSP1 expression was correlated with higher RR (P=0.035), longer PFS (P<0.001) and mOS (P<0.001). Higher BRCA1 mRNA expression was associated with higher RR (P=0.028) and increased PFS (P=0.021), but not mOS (P=0.4). Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent factor for increased PFS (HR 0.49; 95% CI 0.32-0.76; P<0.001) and mOS (HR 0.37; 95% CI 0.2-0.58; P<0.001), whereas high BRCA1 expression was correlated with increased PFS (HR 0.53; 95% CI 0.37-0.78; P=0.001). CONCLUSIONS These data indicate that TXR1/TSP1 and BRCA1 expression could be used for the prediction of taxanes' resistance in the treatment of NSCLC.
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Affiliation(s)
- C Papadaki
- Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece
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Allingham-Hawkins D, Lea A, Levine S. ERCC1 Expression Analysis to Guide Therapy in Non-Small Cell Lung Cancer. PLOS CURRENTS 2010; 2:RRN1202. [PMID: 21152077 PMCID: PMC2998231 DOI: 10.1371/currents.rrn1202] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/07/2010] [Indexed: 11/18/2022]
Abstract
Worldwide, lung cancer accounts for approximately 1 million deaths each year, making it the most common cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often associated with a relatively poor prognosis. The majority of NSCLC patients present with advanced disease and have an average 5-year survival rate of 5%. Currently, the standard of care for NSCLC includes treatment with a platinum-based chemotherapy regimen. However, not all patients benefit equally from such treatment. Therefore, recent pharmacogenomic studies have been performed in order to identify specific biomarkers that may allow for patient-tailored treatment strategies. One such biomarker is expression of the excision repair cross-complementation group 1 protein, ERCC1.
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Sabatino MA, Marabese M, Ganzinelli M, Caiola E, Geroni C, Broggini M. Down-regulation of the nucleotide excision repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells. Mol Cancer 2010; 9:259. [PMID: 20868484 PMCID: PMC2955619 DOI: 10.1186/1476-4598-9-259] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Accepted: 09/24/2010] [Indexed: 12/31/2022] Open
Abstract
Background Drug resistance is one of the major obstacles limiting the activity of anticancer agents. Activation of DNA repair mechanism often accounts for increase resistance to cancer chemotherapy. Results We present evidence that nemorubicin, a doxorubicin derivative currently in clinical evaluation, acts through a mechanism of action different from classical anthracyclines, requiring an intact nucleotide excision repair (NER) system to exert its activity. Cells made resistant to nemorubicin show increased sensitivity to UV damage. We have analysed the mechanism of resistance and discovered a previously unknown mechanism resulting from methylation-dependent silencing of the XPG gene. Restoration of NER activity through XPG gene transfer or treatment with demethylating agents restored sensitivity to nemorubicin. Furthermore, we found that a significant proportion of ovarian tumors present methylation of the XPG promoter. Conclusions Methylation of a NER gene, as described here, is a completely new mechanism of drug resistance and this is the first evidence that XPG gene expression can be influenced by an epigenetic mechanism. The reported methylation of XPG gene could be an important determinant of the response to platinum based therapy. In addition, the mechanism of resistance reported opens up the possibility of reverting the resistant phenotype using combinations with demethylating agents, molecules already employed in the clinical setting.
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Price M, Monteiro ANA. Fine tuning chemotherapy to match BRCA1 status. Biochem Pharmacol 2010; 80:647-53. [PMID: 20510205 DOI: 10.1016/j.bcp.2010.05.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 05/12/2010] [Accepted: 05/14/2010] [Indexed: 02/01/2023]
Abstract
Targeted cancer therapies have been primarily directed at inhibiting oncogenes that are overexpressed or constitutively active in tumors. It is thought that as the cell's circuitry gets re-wired by the constitutive activation of some pathways it becomes exquisitely dependent on this activity. Tumor cell death normally results from inhibiting constitutively active pathways. The dependence of tumor cells on the activity of these pathways has been called oncogene addiction. Approaches that aim to exploit loss of function, rather than gain of function changes have also become a powerful addition to our arsenal of cancer therapies. In particular, when tumors acquire mutations that disrupt pathways in the DNA damage response they rely on alternative pathways that can be targeted pharmacologically. Here we review the use of BRCA1 as a marker of response to therapy with a particular focus on the use of Cisplatin and PARP inhibitors. We also explore the use of BRCA1 as a marker of response to microtubule inhibitors and how all these approaches will bring us closer to the goal of personalized medicine in cancer treatment.
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Affiliation(s)
- Melissa Price
- Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
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Blomquist TM, Crawford EL, Willey JC. Cis-acting genetic variation at an E2F1/YY1 response site and putative p53 site is associated with altered allele-specific expression of ERCC5 (XPG) transcript in normal human bronchial epithelium. Carcinogenesis 2010; 31:1242-50. [PMID: 20233728 DOI: 10.1093/carcin/bgq057] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
ERCC5 (XPG) is a key component of the nucleotide excision DNA repair pathway. In two recent case-control studies, we determined that ERCC5 transcript expression pattern in grossly normal human bronchial epithelial cells (NBEC) was different in individuals diagnosed with lung cancer compared with non-lung cancer controls. In this study, we tested the hypothesis that variation at cis-acting sites contributed to observed variation in ERCC5 transcript expression in NBEC. Allele-specific expression (ASE) was measured at transcribed polymorphic site rs1047768 in exon 2 of ERCC5 in NBEC complementary DNA (cDNA) of 22 individuals using allele-specific competitive polymerase chain reaction. ASE at rs1047768 was then assessed for association with allelotype at polymorphic sites rs751402 (E2F1 and YY1 recognition and response site) and rs2296147 (putative P53 recognition site) in the proximal promoter and 5' untranslated region, respectively, of ERCC5. Interindividual variation in recombination between rs751402, rs2296147 and rs1047768 in poly-heterozygotes was controlled for by allele-specific sequencing. Measured rs1047768 T:C allelic ratio was (i) significantly higher in NBEC cDNA compared with genomic DNA controls (P < 0.001) among samples heterozygous at both rs751402 and rs2296147; (ii) less high (P = 0.02) for samples homozygous at rs751402 but heterozygous at rs2296147 and (iii) not significantly different (P = 0.18) for doubly homozygous individuals. Here, we demonstrate that rs751402 A allele and rs2296147 T allele are associated with higher ASE of ERCC5 T allele transcript at rs1047768 in NBEC.
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Affiliation(s)
- Thomas M Blomquist
- Department of Medicine, University of Toledo Medical Center, Toledo, OH 43614, USA
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Carpagnano GE, Palladino GP, Gramiccioni C, Foschino Barbaro MP, Martinelli D. Exhaled ERCC-1 and ERCC-2 microsatellite alterations in NSCLC patients. Lung Cancer 2010; 68:305-7. [PMID: 20188432 DOI: 10.1016/j.lungcan.2010.01.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/29/2010] [Accepted: 01/30/2010] [Indexed: 11/29/2022]
Abstract
BACKGROUND The excision repair cross-complementation (ERCC) enzyme plays a rate-limiting role in nucleotide excision repair pathway. Microsatellite alterations (MAs) at the long arm of chromosome 19, where are located the ERCC genes, have recently been associated with non-small cell lung cancer (NSCLC) pathogenesis and reduced survival. The aim of the present study was to explore MAs at 19q in DNA from exhaled breath condensate (EBC) of NSCLC patients investigating their possible correlation with the smoking habit, with the biological behaviour of the tumour and their predictive survival power. METHODS 34 NSCLC patients and 33 healthy controls (19 non-smokers and 14 smokers) were enrolled. All the subjects underwent 19q microsatellite analysis of their EBC. A total of 25 patients were either given a follow-up of at least 102 weeks, or were followed up until death. RESULTS No MAs were found in EBC or WB in the healthy non-smokers, while 16% of exhaled MAs were found in healthy smokers and 25% of exhaled MAs in NSCLC patients. The number of MAs resulted related with tobacco consumption and with NSCLC patients' survival. CONCLUSIONS In conclusion, the study of MAs at 19q resulted feasible in EBC-DNA. These genetic alterations are specific for lung cancer and predictive of survival in NSCLC patients. Our results suggest interesting clinical perspectives for the analysis of exhaled MAs at 19q in NSCLC patients.
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