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Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study  [cached]
Niu Nifang,Schaid Daniel J,Abo Ryan P,Kalari Krishna
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-422
Abstract: Background Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. Methods GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines. Results 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10-4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468. Conclusions GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.
Current Status for Anaplastic Lymphoma Kinase in Non-small Cell Lung Cancer  [PDF]
Peng SONG, Li ZHANG, Congcong SHANG
- , 2018, DOI: : 10.3779/j.issn.1009-3419.2018.09.10
Abstract: The incidence of ALK gene rearrangement in non-small cell lung cancer (NSCLC) was about 3% to 5%. ALK gene inhibitors have made great breakthrough in recent years, significantly extending the survival period of patients with ALK(+) advanced NSCLC. But the majority of patients will be acquired drug resistance after treatment. This article has been explained separately from the ALK genetic background, the detection method, the treatment of the three generations of ALK inhibitors and the strategy after drug resistance. It is desire to have reference value and reference meaning for clinical work.?
MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment
Monica Spinola, Felicia S Falvella, Francesca Colombo, James P Sullivan, David S Shames, Luc Girard, Paola Spessotto, John D Minna, Tommaso A Dragani
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-62
Abstract: Here we show that MFSD2A expression is strongly downregulated in non-small cell lung cancer cell lines of different histotypes and in primary lung adenocarcinomas. Experimental modulation of MFSD2A in lung cancer cells is associated with alteration of mRNA levels of genes involved in cell cycle control and interaction with the extracellular matrix. Exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and significantly reduced tumor colony number in vitro (4- to 27-fold, P < 0.0001) and tumor volume in vivo (~3-fold, P < 0.0001). siRNA knockdown studies in normal human bronchial epithelial cells confirmed the role of MFSD2A in G1 regulation.Together these data suggest that MFSD2A is a novel lung cancer tumor suppressor gene that regulates cell cycle progression and matrix attachment.Cancer progression is defined as the stepwise process through which cells evolve towards a more malignant and aggressive phenotype [1]. This process results from the accumulation of somatic genetic and epigenetic changes occurring within neoplastic cells [2]. However, a growing body of evidence also points to the role of genetic background in cancer susceptibility, progression, and prognosis [3-5]. We previously identified a 106 kb linkage disequilibrium block containing genetic elements associated with survival in lung adenocarcinoma (ADCA) patients [6]. The refined region maps to chromosome 1p34 and includes MYCL1, TRIT1 (tRNA isopentenyltransferase 1), and MFSD2A (major facilitator superfamily domain containing 2). While the role of MYCL1 and TRIT1 in lung tumor growth and development has been studied [6,7], no information is available on MFSD2A. Thus, we addressed the functional role of MFSD2A in lung tumorigenesis.Based on our previous finding of MFSD2A downregulation in a pool of lung tumor specimens [7], we extended the analysis to 18 individual samples of lung ADCA tumors and corresponding benign adjacent tissue. MFSD2A
ERCC1 Expression as a Predictor of Survival After Operation in Stage I Non-small Cell Lung Cancer Patients  [PDF]
Zhengping DING,Jie ZHANG,Jinchen SHAO
Chinese Journal of Lung Cancer , 2010,
Abstract: Background and objective Proteins of the nucleotide excision repair pathway can repair DNA damage. The excision repair cross-complementing (ERCC) gene family reduce damagement of DNA by nucleotide excision and repair. The aim of this study is to investigate the expressions of ERCC1 (members of DNA repair gene family) in patients with non-small cell lung cancer (NSCLC) as well as their clinical prognostic significance. Methods Expression levels of ERCC1 were detected by IHC in 118 stage I NSCLC patients. Kaplan-Meier survival curve, and Cox multivariate regression analysis were used for statistical analysis. Results The patients with high expression of ERCC1 had significantly longer survival time than those with low expression of ERCC1, and Cox multivariate regression analysis showed that expression of RRM1 was an independent prognostic factor for NSCLC patients. Conclusion NSCLC patients with high ERCC1 expression have a better survival when compared to patients with low ERCC1 expression. Therefore, an intact DNA repair mechanism may reduce the accumulation of genetic aberrations that are thought to contribute to a tumor malignant potential and therefore the risk of relapse after definitive treatment.
Important prognostic factors for the long-term survival of lung cancer subjects in Taiwan
Tai-An Chiang, Ping-Ho Chen, Pei-Fen Wu, Tsu-Nai Wang, Po-Ya Chang, Albert Ko, Ming-Shyan Huang, Ying-Chin Ko
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-324
Abstract: Total of 24,910 subjects diagnosed with lung cancer was analysed. Survival estimates by Kaplan-Meier methods. Cox proportional-hazards model estimated the death risk (hazard ratio (HR)) for various prognostic factors.The prognostic indicators associated with a higher risk of lung cancer deaths are male gender (males versus females; HR = 1.07, 95% confidence intervals (CI): 1.03–1.11), males diagnosed in later periods (shown in 1991–1994 versus 1987–1990; HR = 1.13), older age at diagnosis, large cell carcinoma (LCC)/small cell carcinoma (SCC), and supportive care therapy over chemotherapy. The overall 5-year survival rate for lung cancer death was significantly poorer for males (21.3%) than females (23.6%). Subjects with squamous cell carcinoma (SQCC) and treatment by surgical resection alone had better prognosis. We find surgical resections to markedly increase 5-year survival rate from LCC, decreased risk of death from LCC, and no improved survival from SCC.Gender and clinical characteristics (i.e. diagnostic period, diagnostic age, histological type and treatment modality) play important roles in determining lung cancer survival.Lung cancer is the leading cause of cancer deaths worldwide with geographic and demographic distinctions. Age-standardized incidence rate adjusted by world population (ASRW) for lung cancer is 35.5 per 100,000 males and 12.1 per 100,000 females in 2002, in the world [1]. The highest ASRW for males is in central-Eastern Europe and Northern America with 60 per 100,000, for females is in Northern America with 35.6 per 100,000, and most differences between genders in central-Eastern Europe (M: F = 7.55: 1). Lung cancer is a highly malignant neoplasm with poor prognosis when diagnosed at an advanced stage, and prognostication is crucial for clinicians. Many factors may influence lung cancer survival, including gender [2,3], diagnostic age [4,5], histological type [6,7], and treatment modality [8-10].For the Taiwanese in 2002, age-adjusted inci
Analysis of Survival Predictors in Patients with Lung Cancer and Brain Metastases  [PDF]
Shaohua CUI, Hao BAI, Lili DONG, Yizhuo ZHAO, Aiqin GU, Wei ZHANG, Yuqing LOU, Liyan JIANG
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.07.08
Abstract: Background and objective The prognosis for patients with lung cancer and brain metastases remains poor, with approximately 6 months of survival, despite active measures after treatment. In this study, we determined and analyzed clinical parameters that affect the survival of patients with lung cancer and brain metastases to provide clinical guidance. Methods Lung cancer cases with brain metastases were retrospectively collected during 2002 and 2008 from Shanghai Chest Hospital, Shanghai Jiao Tong University. Kaplan-Meier method and Cox regression were performed for univariate and multivariate analyses, respectively, to explore independent predictors influencing the survival of patients with lung cancer and brain metastases. Results Age, Eastern Cooperative Oncology Group performance status (ECOG PS), metastasis interval, number of metastasis, treatment method, treatment period, symptoms of brain metastases, extracranial metastasis, and brain metastasis order were factors that affect the survival of patients with brain metastases as confirmed through the Kaplan-Meier method. Treatment periods and extracranial metastasis were independent survival predictors in patients with lung cancer and brain metastasis as indicated by Cox proportional hazard model. Conclusion Treatment periods and extracranial metastasis were independent predictors of survival of patients with lung cancer and brain metastasis. Treatment periods and extracranial metastasis were independent predictors of survival of patients with lung cancer and brain metastasis.
Automatic Detection of 2D and 3D Lung Nodules in Chest Spiral CT Scans  [PDF]
Ayman El-Baz,Ahmed Elnakib,Mohamed Abou El-Ghar,Georgy Gimel'farb,Robert Falk,Aly Farag
International Journal of Biomedical Imaging , 2013, DOI: 10.1155/2013/517632
Abstract: Automatic detection of lung nodules is an important problem in computer analysis of chest radiographs. In this paper, we propose a novel algorithm for isolating lung abnormalities (nodules) from spiral chest low-dose CT (LDCT) scans. The proposed algorithm consists of three main steps. The first step isolates the lung nodules, arteries, veins, bronchi, and bronchioles from the surrounding anatomical structures. The second step detects lung nodules using deformable 3D and 2D templates describing typical geometry and gray-level distribution within the nodules of the same type. The detection combines the normalized cross-correlation template matching and a genetic optimization algorithm. The final step eliminates the false positive nodules (FPNs) using three features that robustly define the true lung nodules. Experiments with 200?CT data sets show that the proposed approach provided comparable results with respect to the experts. 1. Introduction Lung cancer remains the leading cause of cancer-related deaths in the US. In 2012, there were approximately 229,447 new cases of lung cancer and 159,124 related deaths [1]. Early detection of lung tumors (visible on chest film as nodules) may increase the patient’s chance of survival, but detecting nodules is a complicated task. Nodules show up as relatively low-contrast white circular objects within the lung fields. The difficulty for computer-aided detection (CADe) schemes is distinguishing true nodules from (overlapping) shadows, vessels, and ribs. CADe systems for detection of lung nodules in thoracic CT generally consist of two major stages: (1) selection of the initial candidate nodules and then (2) elimination of the false positive nodules (FPNs) with preservation of the true positive nodules (TPNs). At the first stage, conformal nodule filtering or unsharp masking can enhance nodules and suppress other structures to separate the candidates from the background by simple thresholding or a multiple gray-level thresholding technique [2, 3]. To improve the separation, background trend is corrected in [4, 5] within image regions of interest. Then, a series of 3D cylindrical and spherical filters are used to detect small lung nodules from high-resolution CT images [6, 7]. Circular and semicircular nodule candidates can be detected by template matching [8–11]. However, these spherical, cylindrical, or circular assumptions are not adequate for describing the general geometry of the lesions. This is because their shape can be irregular due to the speculation or the attachments to the pleural surface (i.e.,
Genetic Variations in the Regulator of G-Protein Signaling Genes Are Associated with Survival in Late-Stage Non-Small Cell Lung Cancer  [PDF]
Jingyao Dai, Jian Gu, Charles Lu, Jie Lin, David Stewart, David Chang, Jack A. Roth, Xifeng Wu
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021120
Abstract: The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients.
Interstitial lung disease in children – genetic background and associated phenotypes
Dominik Hartl, Matthias Griese
Respiratory Research , 2005, DOI: 10.1186/1465-9921-6-32
Abstract: Interstitial lung disease (ILD) in children represents a heterogeneous group of rare respiratory disorders characterised by restrictive lung disease and diffuse pulmonary infiltrates. Affected children usually present with dry cough, dyspnoea and tachypnoea. Physical findings show elevated resting respiratory rate and rales (or crackles) mostly more pronounced in the basal segments of the lungs. In children suffering from severe ILD, chronic hypoxemia, cyanosis, finger clubbing and growth failure occur [1,2]. High-resolution computed tomography provides detailed diagnostic information about the extent and distribution of the lung pathology and has become the most relevant imaging technique for ILD in children [3]. However, the diagnostic gold standard is still the lung biopsy where the characteristic histological findings of inflammation in the pulmonary interstitium with wall thickening by inflammatory cells and/or fibrosis can be found. At present, no pathognomonic laboratory criteria for the diagnosis of ILD in children are available [4]. ILD is associated with pulmonary inflammation which can resolve completely, partially or can progress to fibrosis. The factors determining the progression of ILD are not well understood but an interaction between genetic background and environmental modifiers is suggested [1,5-7].In children, ILD is less frequent and comprises a broader spectrum of disorders with a more variable clinical course compared to adults. In addition, there are special disease entities which predominantly occur in children, like the recently described pulmonary interstitial glycogenosis [8], the neuro-endocrine cell hyperplasia of infancy [9] and the genetic disorders of surfactant metabolism [10]. Most of the information on ILD in childhood is based on studies performed in adults. In the recent years, however, there is increasing evidence that ILD in children differs substantially from adult ILD [2]. PediatricILD occur in the context of lung developmen
Frequency and Spectrum of KRAS Mutations in Moroccan Patients with Lung Adenocarcinoma  [PDF]
Ibrahim Elghissassi,Hanane Inrhaoun,Anwar Boukir,Fouad Kettani,Lamia Gamra,Amina Mestari,Lamia Jabri,Youssef Bensouda,Hind Mrabti,Hassan Errihani
ISRN Oncology , 2014, DOI: 10.1155/2014/192493
Abstract: Background. In lung adenocarcinoma, the frequency of KRAS mutations is ethnicity dependent with a higher proportion in African Americans and white Caucasians than in Asians. The prevalence of these mutations among North Africans patients is unknown. The objective of this study was to report the frequency and spectrum of KRAS mutations in a group of Moroccan lung adenocarcinoma patients. Methods. Tumor specimens from 117 Moroccan patients with lung adenocarcinoma were selected to determine frequency and spectrum of KRAS mutations. KRAS mutations in codons 12 and 13 of exon 2 were analyzed using conventional DNA sequencing. Results. The overall frequency of the KRAS mutations was 9% (11/117). In the population with KRAS mutations, there was a trend towards more male ( ) and more smokers ( ) compared to patients with wild type KRAS. KRAS mutations were located at codon 12 in 10 out of 11 patients (91%). The G12C mutation was the most frequent KRAS mutation (73%). Conclusion. This is the first study to date examining the frequency and spectrum of KRAS mutations in lung adenocarcinomas in North African and Arab populations. KRAS mutation frequency in Moroccan patients was comparable with the frequency observed in East-Asian population. KRAS mutations are more likely observed in males and smokers and to be transversions. Further studies, in larger numbers of patients, are needed to confirm these findings. 1. Introduction Lung cancer is one of the most common cancers in Morocco and in the world and is the leading cause of cancer mortality in both males and females [1, 2]. During the last few years, improvement in the knowledge of lung cancer molecular biology led to identification of several biological events crucial for tumor cell survival. In nonsmall-cell lung cancer (NSCLC), one of the most commonly genetic aberrations is conversion of the protooncogene KRAS to its activated oncogenic form. KRAS encodes low molecular weight GTPase binding proteins that regulate cell growth, differentiation, and apoptosis. Mutations of KRAS are associated with impaired GTPase activity, causing increased mitogenic RAS signaling [3]. Mutations in KRAS gene occur more frequently (20–30%) in adenocarcinoma and less frequently (about 7%) in squamous-cell carcinoma and are usually associated with a history of smoking [4]. The incidence of KRAS mutation is ethnicity dependent with a higher proportion in African Americans and white Caucasians (20–30%) than in Asians (5–20%) [5–7]. However, such information is still lacking in some other races, such as North African patients.
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