Prognostic value of Transglutaminase 2 in non-small cell lung cancer patients.
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ABSTRACT:
SUBMITTER: Chihong Z
PROVIDER: S-EPMC5542209 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients develop distant metastases following pulmonary resection. Currently, there are no reliable factors allowing for individual selection of high-risk patients for adjuvant systemic therapies. METHODS: We assessed by quantitative reverse transcription PCR microRNA (miRNA) expression in 273 stage I-IIIA NSCLC samples. Expression of 677 miRNAs was evaluated in fresh-frozen tumour samples in the training cohort of 50 squamous cell carcinoma (SCC) patients who underwent curative surgery. Of those, 20 patients developed distant metastases, and 30 were free of recurrence for >4 years. In the second step, miRNAs with highest predictive value for distant relapse were re-evaluated in formalin-fixed paraffin-embedded material in an independent group of 134 stage I-IIIA SCC patients. Additionally, the same miRNAs were investigated in 89 lung adenocarcinoma (AC) patients and in normal lung parenchyma (NLP). RESULTS: In the training cohort of SCC, six miRNAs were differently expressed in the non-recurrent vs recurrent groups and correlated with distant recurrence-free survival, however none reached the level of significance after correction for multiple testing. Of these six miRNAs, miR-662, -192 and -192* were confirmed as prognostic in the independent SCC cohort. Expression of miR-128, -10b, -502-3p and -192 differed between SCC and AC, and miR-128 and -192 - between NLP and NSCLC. CONCLUSIONS: We identified three new miRNAs predictive of distant relapse in operable SCC. Future miRNA studies should account for differences between NSCLC subtypes.
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Project description:Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels.A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate.Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p.T790M mutant allele frequency; 2.676 and 2.71 respectively; P < 0.05). In the same way, patients with p.T790M-negative or unchanging or decreasing plasma levels of sensitizing EGFR mutation were 12 and 4.8 times more likely to maintain response or stable disease, respectively, than patients in which the opposite occurred (P < 0.05).On average, the p.T790M mutation was detected in plasma 51 days before the assessment of progression disease by CT-scan. Finally, ctDNA outperformed CTCs for assessing tumor progression (P = 0.021).The appearance or increase in a unit of the p.T790M allele frequency almost triples the risk of death and progression. This information can be used to design clinical trials aiming to estimate whether T790M positive patients should start second line treatment based on molecular data rather than imaging data.
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Project description:The role of the different circulating regulatory T-cells (Treg) subsets, as well as their correlation with clinical outcome of non-small cell lung cancer (NSCLC) patients is poorly understood. Peripheral blood from 156 stage III/IV chemotherapy-naive NSCLC patients and 31 healthy donors (HD) was analyzed with flow cytometry for the presence and functionality of CD4+ Treg subsets (naive, effector and terminal effector). Their frequencies were correlated with the clinical outcome. All CD4+ Treg subsets exhibited highly suppressive activity by TGF-? and IL-10 production. The percentages of naive Treg were found elevated in NSCLC patients compared to HD and were associated with poor clinical outcome, whereas the percentage of terminal effector Treg was lower compared to HD and higher levels were correlated with improved clinical response. At baseline, normal levels of naive and effector Treg were associated with longer overall survival (OS) compared to high levels, while the high frequency of the terminal effector Treg was correlated with longer Progression-Free Survival and OS. It is demonstrated, for first time, that particular CD4+ Treg subtypes are elevated in NSCLC patients and their levels are associated to the clinical outcome. The blocking of their migration to the tumor site may be an effective therapeutic strategy.
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Project description:BackgroundExpression of transglutaminase 2 (TGase 2) is related to invasion and resistance to chemotherapeutic agents in several cancer cells. However, there has been only limited clinical validation of TGase 2 as an independent prognostic marker in cancer.MethodsThe significance of TGase 2 expression as an invasive/migratory factor was addressed by in vitro assays employing down-regulation of TGase 2. TGase 2 expression as a prognostic indicator was assessed in 429 Korean patients with early-stage non-small cell lung cancer (NSCLC) by immunohistochemical staining.ResultsTGase 2 expression increased the invasive and migratory properties of NSCLC cells in vitro, which might be related to the induction of MMP-9. In the analysis of the immunohistochemical staining, TGase 2 expression in tumors was significantly correlated with recurrence in NSCLC (p = 0.005) or in the non-adenocarcinoma subtype (p = 0.031). Additionally, a multivariate analysis also showed a significant correlation between strong TGase 2 expression and shorter disease-free survival (DFS) in NSCLC (p = 0.029 and HR = 1.554) and in the non-adenocarcinoma subtype (p = 0.030 and HR = 2.184). However, the correlation in the adenocarcinoma subtype was not significant.ConclusionsTGase 2 expression was significantly correlated with recurrence and shorter DFS in NSCLC, especially in the non-adenocarcinoma subtype including squamous cell carcinoma.
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Project description:This study was designed to explore the association between elevated platelet to lymphocyte ratio (PLR) and prognosis of patients with non-small cell lung cancer (NSCLC) by meta-analysis. A total of 11 studies with 3,430 subjects were included and the combined hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated. The data showed that elevated PLR predicted poor overall survival (OS) (HR = 1.42; 95% CI: 1.25-1.61, p < 0.001; I(2) = 63.6, Ph = 0.002) and poor disease-free survival (DFS)/progression-free survival (PFS) (HR = 1.19; 95%CI: 1.02-1.4, p = 0.027; I(2) = 46.8, Ph = 0.111). Subgroup analysis showed elevated PLR did not predict poor OS in patients included in large sample studies (HR = 1.44; 95% CI: 0.94-2.21, p = 0.098) whereas patients with Caucasian ethnicity (HR = 1.59; 95%CI: 1.27-1.98, p < 0.001) and PLR cut-off value > 180 (HR = 1.61; 95%CI: 1.3-1.99, p < 0.001) had enhanced prognostic efficiency for OS. Subgroup analysis also demonstrated that high PLR did not predict poor DFS/PFS in Asian patients. In conclusion, our meta-analysis suggested that elevated PLR was associated with poor OS and DFS/PFS in NSCLC. In addition, high PLR especially predicted poor OS in Caucasians but had no association with poor DFS/PFS in Asians.
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Project description:IntroductionChemo-radiation is standard treatment in locally advanced non-small cell lung cancers (NSCLC). The prognostic value of mutations has been poorly explored in this population.ResultsClinical data were collected from 190 patients and mutational profiles were obtained in 78 of them; 58 (74%) were males, 31 (40%) current smokers, 47/31 stage IIIA/IIIB and 40 (51%) adenocarcinoma. The following mutations were identified: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/65), PI3KCA 2% (1/57), NRAS 3% (1/32), and ALK+ (FISH) 4% (2/51). HER2 was not detected. Median follow-up was 3.1 years. Overall survival was evaluated by group; no significant differences were identified in median overall survival (p = 0.21), with 29.4 months for the EGFR/ALK group (n = 11), 12.8 months for other mutations (n = 17), and 23.4 months for wild-type (n = 50). The EGFR/ALK and other mutations groups had poorer median progression-free survival (9.6 and 6.0 months) compared to the wild-type group (12.0 months; multivariate hazard ratio 2.0 [95% CI, 0.9-4.2] and 2.8 [95% CI, 1.5-5.2] respectively, p = 0.003).Materials and methodsWe retrospectively reviewed all patients receiving radical treatment for locally advanced NSCLC in a single institution between January 2002 and June 2013. Next generation sequencing was performed on DNA from paraffin-embedded tissue. ALK rearrangements were detected by immunohistochemistry and/or FISH. Mutational prognostic value for Kaplan-Meier survival parameters was determined by log-rank tests and Cox proportional hazards models.ConclusionsSelected gene alterations may be associated with poorer progression-free survival in locally advanced radically treated NSCLC and their prognostic and/or predictive value merits further evaluation in a larger population.
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Project description:Introduction: Accumulating evidence showed that a large number of microRNAs (miRNAs) are abnormally expressed in lung cancer tissues and play critical roles in cancer development and progression. The aim of this study is to identify the differentially expressed miRNAs (DEMs) between non-small cell lung cancer (NSCLC) and normal lung tissues, and evaluate the prognostic value and potential target gene functional enrichment of the DEMs. Materials and Methods: We first downloaded the high-throughput miRNA data from The Cancer Genome Atlas Project (TCGA) database, and subsequently analyzed the data using bioinformatics analysis including limma package in R, Kaplan-Meier curve and Log-rank method, and several online analysis tools. Results: A total of 125 DEMs and 138 DEMs were respectively identified in lung adenocarcinoma (LUAD) tissues and lung squamous cell carcinoma (LUSC) tissues compared with their matched normal tissues. Moreover, we found that the prognostic function of the eight miRNAs (miR-375, miR-148a, miR-29b-1 and miR-584 for LUAD; miR-4746, miR-326, miR-93 and miR-671 for LUSC). Furthermore, the two four-miRNA signatures were constructed and found to be an independent prognostic factor for LUAD and LUSC patients, respectively. Additionally, our results indicated that the target genes of eight miRNAs may be involved in various pathways related to NSCLC, including PI3K-Akt, TGF-beta, FoxO, Ras, GPI-anchor biosynthesis and metabolic, Rap1, HIF-1 and proteasome. Conclusion: Overall, eight miRNAs were closely correlated with survival of NSCLC patients, and the constructed two four-miRNA signatures could be respectively used as prognostic markers in LUAD and LUSC patients.
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Project description:Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients.
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Project description:An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P<0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage.
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Project description:This study evaluated the prognostic value of positron emission tomography/computed tomography (PET/CT) using (18) F-fluoroazomycin arabinoside (FAZA) in patients with advanced non-small-cell lung cancer (NSCLC) compared with (18) F-fluorodeoxyglucose (FDG). Thirty-eight patients with advanced NSCLC (stage III, 23 patients; stage IV, 15 patients) underwent FAZA and FDG PET/CT before treatment. The PET parameters (tumor-to-muscle ratio [T/M] at 1 and 2 h for FAZA, maximum standardized uptake value for FDG) in the primary lesion and lymph node (LN) metastasis and clinical parameters were compared concerning their effects on progression-free survival (PFS) and overall survival (OS). In our univariate analysis of all patients, clinical stage and FAZA T/M in LNs at 1 and 2 h were predictive of PFS (P = 0.021, 0.028, and 0.002, respectively). Multivariate analysis also indicated that clinical stage and FAZA T/M in LNs at 1 and 2 h were independent predictors of PFS. Subgroup analysis of chemoradiotherapy-treated stage III patients revealed that only FAZA T/M in LNs at 2 h was predictive of PFS (P = 0.025). The FDG PET/CT parameters were not predictive of PFS. No parameter was a significant predictor of OS. In patients with advanced NSCLC, FAZA uptake in LNs, but not in primary lesions, was predictive of treatment outcome. These results suggest the importance of characterization of LN metastases in advanced NSCLC patients.
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