Serum total periostin is an independent marker of overall survival in bone metastases of lung adenocarcinoma

Objective: To evaluate clinical and demographic characteristics and the results of cytotoxic treatments of KRASG12C, KRASother, and next-generation sequencing (NGS) panel negative patients. Methods: NGS data of 1264 patients with non-small cell lung cancer were retrospectively evaluated. Among these patients, the mutation distributions of 1081 patients with metastatic lung adenocarcinoma were analyzed. A total of 150 patients with negative NGS panel or mutant KRAS followed up in our clinic were included. Clinical features, overall survival, first-line chemotherapy responses, and progression-free survival of NGS panel negative, KRASG12C, and KRASother groups were compared. Results: In 1081 patients who underwent NGS from tumor tissue with the diagnosis of metastatic lung adenocarcinoma, 296 (27%) NGS panel negative and 276 (26%) KRAS mutant patients were detected. Among these patients, 150 patients whose data were available were 71 (47.3%) NGS panel negative, 54 (36%) KRASother, and 25 (16.7%) KRASG12C. Clinical features, brain metastasis, and first-line chemotherapy response were similar among groups. Bone metastases were detected more often in the NGS panel negative group ( p = 0.03). The median follow-up was 8.4 months. Overall, 107 deaths had occurred at the time of analysis. There was no difference in overall survival ( p = 0.56) or progression-free survival ( p = 0.71) among NGS panel negative, KRASother, and KRASG12C patients. Conclusion: There is no difference in overall survival, first-line chemotherapy response, or progression-free survival among patients with NGS panel negative, KRASG12C, or KRASother metastatic lung adenocarcinoma. Bone metastases were observed more frequently in the NGS panel negative group.

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Dynamic nomograms combining N classification with ratio-based nodal classifications to predict long-term survival for patients with lung adenocarcinoma after surgery: a SEER population-based study

BMC Cancer ◽

10.1186/s12885-021-08410-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Suyu Wang ◽

Yue Yu ◽

Wenting Xu ◽

Xin Lv ◽

Yufeng Zhang ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

External Validation ◽

Predictive Performance ◽

Information Criterion ◽

Curve Analysis ◽

Tnm Stage ◽

Concordance Index ◽

Cancer Specific Survival ◽

Decision Curve Analysis

Abstract Background The prognostic roles of three lymph node classifications, number of positive lymph nodes (NPLN), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) in lung adenocarcinoma are unclear. We aim to find the classification with the strongest predictive power and combine it with the American Joint Committee on Cancer (AJCC) 8th TNM stage to establish an optimal prognostic nomogram. Methods 25,005 patients with T1-4N0–2M0 lung adenocarcinoma after surgery between 2004 to 2016 from the Surveillance, Epidemiology, and End Results database were included. The study cohort was divided into training cohort (13,551 patients) and external validation cohort (11,454 patients) according to different geographic region. Univariate and multivariate Cox regression analyses were performed on the training cohort to evaluate the predictive performance of NPLN (Model 1), LODDS (Model 2), LNR (Model 3) or LODDS+LNR (Model 4) respectively for cancer-specific survival and overall survival. Likelihood-ratio χ2 test, Akaike Information Criterion, Harrell concordance index, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to evaluate the predictive performance of the models. Nomograms were established according to the optimal models. They’re put into internal validation using bootstrapping technique and external validation using calibration curves. Nomograms were compared with AJCC 8th TNM stage using decision curve analysis. Results NPLN, LODDS and LNR were independent prognostic factors for cancer-specific survival and overall survival. LODDS+LNR (Model 4) demonstrated the highest Likelihood-ratio χ2 test, highest Harrell concordance index, and lowest Akaike Information Criterion, and IDI and NRI values suggested Model 4 had better prediction accuracy than other models. Internal and external validations showed that the nomograms combining TNM stage with LODDS+LNR were convincingly precise. Decision curve analysis suggested the nomograms performed better than AJCC 8th TNM stage in clinical practicability. Conclusions We constructed online nomograms for cancer-specific survival and overall survival of lung adenocarcinoma patients after surgery, which may facilitate doctors to provide highly individualized therapy.

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Functions and clinical significance of KLRG1 in the development of lung adenocarcinoma and immunotherapy

BMC Cancer ◽

10.1186/s12885-021-08510-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaodong Yang ◽

Yuexin Zheng ◽

Zhihai Han ◽

Xiliang Zhang

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Killer Cell ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Normal Lung ◽

Using Data ◽

Low Expression

Abstract Background As a marker of differentiation, Killer cell lectin like receptor G1 (KLRG1) plays an inhibitory role in human NK cells and T cells. However, its clinical role remains inexplicit. This work intended to investigate the predictive ability of KLRG1 on the efficacy of immune-checkpoint inhibitor in the treatment of lung adenocarcinoma (LUAD), as well as contribute to the possible molecular mechanisms of KLRG1 on LUAD development. Methods Using data from the Gene Expression Omnibus, the Cancer Genome Atlas and the Genotype-Tissue Expression, we compared the expression of KLRG1 and its related genes Bruton tyrosine kinase (BTK), C-C motif chemokine receptor 2 (CCR2), Scm polycomb group protein like 4 (SCML4) in LUAD and normal lung tissues. We also established stable LUAD cell lines with KLRG1 gene knockdown and investigated the effect of KLRG1 knockdown on tumor cell proliferation. We further studied the prognostic value of the four factors in terms of overall survival (OS) in LUAD. Using data from the Gene Expression Omnibus, we further investigated the expression of KLRG1 in the patients with different responses after immunotherapy. Results The expression of KLRG1, BTK, CCR2 and SCML4 was significantly downregulated in LUAD tissues compared to normal controls. Knockdown of KLRG1 promoted the proliferation of A549 and H1299 tumor cells. And low expression of these four factors was associated with unfavorable overall survival in patients with LUAD. Furthermore, low expression of KLRG1 also correlated with poor responses to immunotherapy in LUAD patients. Conclusion Based on these findings, we inferred that KLRG1 had significant correlation with immunotherapy response. Meanwhile, KLRG1, BTK, CCR2 and SCML4 might serve as valuable prognostic biomarkers in LUAD.

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Development of an immune-related gene pairs signature for predicting clinical outcome in lung adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-83120-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chunlei Wu ◽

Quanteng Hu ◽

Dehua Ma

Keyword(s):

Overall Survival ◽

Regression Analysis ◽

Lung Adenocarcinoma ◽

Risk Score ◽

Cox Regression ◽

Related Gene ◽

Cox Regression Analysis ◽

Gene Pairs ◽

Immune Related Gene ◽

Pathological Subtype

AbstractLung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. We downloaded the gene expression profile and immune-related gene set from the TCGA and ImmPort database, respectively, to establish immune-related gene pairs (IRGPs). Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis, and multivariable Cox regression analysis to screen and develop an IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from the GEO set was used to validate this signature. The relationship of 22 tumor-infiltrating immune cells (TIICs) to the immune risk score was also investigated. An IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in the TCGA set was 0.867 and 0.870, respectively. Similar results were observed in the AUCs of GEO set 1, 2 and 3 (GEO set 1 [1-year: 0.819; 3-year: 0.803]; GEO set 2 [1-year: 0.834; 3-year: 0.870]; GEO set 3 [1-year: 0.955; 3-year: 0.827]). Survival analysis demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that the risk score was an independent prognostic factor. The immune risk score was highly associated with several TIICs (Plasma cells, memory B cells, resting memory CD4 T cells, and activated NK cells). We developed a novel IRGPs signature for predicting 1- and 3- year overall survival in LUAD, which would be helpful for prognosis assessment of LUAD.

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Alkaline phosphatase flare with hyperostosis of bone metastases in lung adenocarcinoma treated with gefitinib

Journal of Cancer Metastasis and Treatment ◽

10.20517/2394-4722.2016.70 ◽

2017 ◽

Vol 3 (2) ◽

pp. 34

Author(s):

Hiroto Kaneko ◽

Kazuho Shimura ◽

Yosuke Matsumoto ◽

Mihoko Yoshida ◽

Masafumi Taniwaki ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Lung Adenocarcinoma ◽

Bone Metastases

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p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy

Frontiers in Oncology ◽

10.3389/fonc.2021.609548 ◽

2021 ◽

Vol 11 ◽

Author(s):

Dongqi Li ◽

Chuanchun He ◽

Fan Ye ◽

En Ye ◽

Hao He ◽

...

Keyword(s):

Cell Proliferation ◽

Overall Survival ◽

Bone Metastasis ◽

Lung Adenocarcinoma ◽

Survival Rates ◽

A549 Cells ◽

Adaptor Protein ◽

Beclin 1 ◽

Cox Regression Analysis

p62 protein has been implicated in bone metastasis and is a multifunctional adaptor protein usually correlated with autophagy. Herein, we investigated p62 expression and its prognostic significance in bone metastasis of lung adenocarcinoma, and analyzed whether the mechanism involved depends on autophagy. mRNA and protein expression of p62, LC3B and Beclin 1 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in fresh bone metastasis tissues (n=6 cases) and normal cancellous bone tissues (n=3 cases). The association between p62 and LC3B expression and patient prognosis was subsequently analyzed in 62 paraffin-embedded bone metastasis specimens by immunohistochemistry assay. Small interfering RNA (siRNA) was employed to downregulate p62 expression in SPC-A-1 and A549 cells. Cell proliferation and migration ability were tested by CCK8, CCF and Transwell assays respectively. Autophagy was induced by Rapamycin or inhibited by Atg 7 knockout/Chloroquine in A549 cells and p62 and LC3II/I expression were analyzed. After subcutaneous inoculation or intracardial injection of A549 cells into nude mice, the effect of p62 downregulation in vivo was analyzed by histopathological examination. The results showed that p62, LC3B and Beclin 1 mRNA and protein were all overexpressed in bone metastasis tissues (all P<0.01). Patient samples with high p62 expression levels were significantly associated with more bone lesions (>3), shorter overall survival rates and shorter progression free survival rates compared with patients having lower p62 expression (P=0.014, P=0.003, P=0.048, respectively). Cox regression analysis identified p62 expression as an independent prognostic indicator of overall survival of patients with bone metastasis (P=0.007). In vitro p62 downregulation inhibited SPC-A-1 and A549 cells migration but had no effect on cell proliferation. After autophagy induction or inhibition, p62 expression involved in autophagy flux and changed inconsistently according to the switch of LC3I to LC3II in different autophagy conditions. In vivo p62 downregulation had no effect on growth of subcutaneous tumor. Lung or bone metastasis lesion was not found in all mice model. These findings suggested that p62 overexpression promotes tumor cell invasion out of LC3-dependent autophagy, which could be used a potential prognostic biomarker and therapeutic target for bone metastasis of lung adenocarcinoma.

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Increased GOLM1 Expression Independently Predicts Unfavorable Overall Survival and Recurrence-Free Survival in Lung Adenocarcinoma

Cancer Control ◽

10.1177/1073274818778001 ◽

2018 ◽

Vol 25 (1) ◽

pp. 107327481877800 ◽

Cited By ~ 4

Author(s):

Xi Liu ◽

Lei Chen ◽

Tao Zhang

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Survival Data ◽

Methylation Status ◽

Lung Squamous Cell Carcinoma ◽

Prognostic Indicator ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Recurrence Free Survival ◽

Free Survival

Golgi membrane protein 1 (GOLM1) is a transmembrane glycoprotein of the Golgi cisternae, which is implicated in carcinogenesis of multiple types of cancer. In this study, using data from the Gene Expression Omnibus and The Cancer Genome Atlas, we compared the expression of GOLM1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and studied its prognostic value in terms of overall survival (OS) and recurrence-free survival (RFS) in these 2 subtypes of non-small cell lung cancer (NSCLC). Results showed that GOLM1 was significantly upregulated in both LUAD and LUSC tissues compared to the normal controls. However, GOLM1 expression was higher in LUAD tissues than in LUSC tissues. More importantly, using over 10 years’ survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC. The following univariate and multivariate analyses confirmed that increased GOLM1 expression was an independent prognostic indicator of poor OS (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.11-1.54, P = .002) and RFS (HR: 1.37, 95% CI: 1.14-1.64, P = .001) in patients with LUAD. Of 511 cases with LUAD, 248 (48.5%) had heterozygous loss (−1), while 28 (5.5%) of 511 cases with LUAD had low-level copy gain (+1). In addition, we also found that the methylation status of 1 CpG site (chr9: 88,694,942-88,694,944) showed a weak negative correlation with GOLM1 expression (Pearson r = −0.25). Based on these findings, we infer that GOLM1 might serve as a valuable prognostic biomarker in LUAD, but not in LUSC. In addition, DNA copy number alterations and methylation might be 2 important mechanisms of dysregulated GOLM1 in LUAD.

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Prognostic phenotypes of early-stage lung adenocarcinoma

European Respiratory Journal ◽

10.1183/13993003.01674-2021 ◽

2021 ◽

pp. 2101674

Author(s):

Anne-Sophie Lamort ◽

Jan Christian Kaiser ◽

Mario A.A. Pepe ◽

Ioannis Lilis ◽

Giannoula Ntaliarda ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Early Stage ◽

Machine Learning Algorithms ◽

Prognostic Information ◽

Tissue Samples ◽

Cancer Hallmarks ◽

Patient Subgroups ◽

Prognostic Power

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL, and FVIII, and were followed for median (95%CI)=2.34 (1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathologic features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45, and PCNA expression had 50% 5-year overall survival while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival [HR95%CI=2.23 (1.33–3.80); p=0.0069]. Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in TCGA and KMplotter data and showed prognostic power supplementary to IASLC TNM stage and WHO histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.

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Elevated expression of ASF1B correlates with poor prognosis in human lung adenocarcinoma

Personalized Medicine ◽

10.2217/pme-2020-0112 ◽

2021 ◽

Vol 18 (2) ◽

pp. 115-127

Author(s):

Zhenxing Feng ◽

Jiao Zhang ◽

Yafang Zheng ◽

Qingzhang Wang ◽

Xiaochuan Min ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Tumor Development ◽

Tumor Stage ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Advanced Tumor Stage ◽

Aberrant Expression ◽

Free Survival ◽

Advanced Tumor

Aim: ASF1 is involved in tumorigenesis. However, its possible role in lung adenocarcinoma (LUAD) is unclear. This study thus explored the role of ASF1A and ASF1B in LUAD. Materials & methods: Data from The Cancer Genome Atlas and Gene Expression Omnibus were employed to investigate ASF1A and ASF1B expression and its roles in LUAD prognosis. Immunohistochemistry was applied to determine the protein expression of ASF1B of 30 LUAD patients. Results: The upregulation of ASF1B in tumor tissues is associated with worse overall survival and progress-free survival and is correlated with advanced tumor stage and tumor development. However, aberrant expression of ASF1A was not found in LUAD and ASF1A was not related to patients’ overall survival and progress-free survival. Conclusion: ASF1B could be a promising prognostic and therapeutic biomarker in LUAD.

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