Outcome In Lung Adenocarcinoma Research Articles

Additional value of metabolic parameters to PET/CT-based radiomics nomogram in predicting lymphovascular invasion and outcome in lung adenocarcinoma.

Lymphovascular invasion (LVI) impairs surgical outcomes in lung adenocarcinoma (LAC) patients. Preoperative prediction of LVI is challenging by using traditional clinical and imaging parameters. The purpose of this study was to investigate the value of the radiomics nomogram integrating clinical factors, CT features, and maximum standardized uptake value (SUVmax) to predict LVI and outcome in LAC and to evaluate the additional value of the SUVmax to the PET/CT-based radiomics nomogram. A total of 272 LAC patients (87 LVI-present LACs and 185 LVI-absent LACs) with PET/CT scans were retrospectively enrolled, and 160 patients with SUVmax ≥ 2.5 of them were used for PET radiomics analysis. Clinical data and CT features were analyzed to select independent LVI predictors. The performance of the independent LVI predictors and SUVmax was evaluated. Two-dimensional (2D) and three-dimensional (3D) CT radiomics signatures (RSs) and PET-RS were constructed with the least absolute shrinkage and selection operator algorithm and radiomics scores (Rad-scores) were calculated. The radiomics nomograms, incorporating Rad-score and independent clinical and CT factors, with SUVmax (RNWS) or without SUVmax (RNWOS) were built. The performance of the models was assessed with respect to calibration, discrimination, and clinical usefulness. All the clinical, PET/CT, pathologic, therapeutic, and radiomics parameters were assessed to identify independent predictors of progression-free survival (PFS). CT morphology was the independent LVI predictor. SUVmax provided better discrimination capability compared with CT morphology in the training set (P < 0.001) and test set (P = 0.042). A total of 1409 CT and PET radiomics features were extracted and reduced to 8, 8, and 10 features to build the 2D CT-RS, 3D CT-RS, and the PET-RS, respectively. There was no significant difference in AUC between the 2D-RS and 3D-RS (P > 0.05), and 2D CT-RS showed a relatively higher AUC than 3D CT-RS. The CT-RS, the CT-RNWOS, and the CT-RNWS showed good discrimination in the training set (AUC [area under the curve], 0.799, 0.796, and 0.851, respectively) and the test set (AUC, 0.818, 0.822, and 0.838, respectively). There was significant difference in AUC between the CT-RNWS and CT-RNWOS (P = 0.044) in the training set. Decision curve analysis (DCA) demonstrated the CT-RNWS outperformed the CT-RS and the CT-RNWOS in terms of clinical usefulness. Furthermore, DCA showed the PETCT-RNWS provided the highest net benefit compared with the PET-RNWS and CT-RNWS. PFS was significantly different between the pathologic and RNWS-predicted LVI-present and LVI-absent patients (P < 0.001). Carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), pathologic LVI, histologic subtype, and SUVmax were independent predictors of PFS in the 244 CT-RNWS-predicted cohort; and CA125, NSE, pathologic LVI, and SUVmax were the independent predictors of PFS in the 141 PETCT-RNWS-predicted cohort. The radiomics nomogram, incorporating Rad-score, clinical and PET/CT parameters, shows favorable predictive efficacy for LVI status in LAC. Pathologic LVI and SUVmax are associated with LAC prognosis.

Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD).

Lung cancer is one of the most common malignant tumors in the world, with a high rate of malignancy and mortality. Seeking new biomarkers and potential drug targets is urgent for effective treatment of the disease. Deubiquitinase UCHL5/UCH37, as an important component of the 26S proteasome, plays critical roles in ubiquitinated substrate degradation. Although previous studies have shown that UCHL5 promotes tumorigenesis, its role in lung cancer remains largely unknown. In this study, we evaluated the expression and clinical significance of UCHL5 in non-small cell lung cancer (NSCLC). The results demonstrated that the UCHL5 expression level was significantly upregulated in NSCLC tissues compared with the adjacent noncancerous tissues. The level of UCHL5 was associated with tumor size, lymph node invasion, TNM stage and malignant tumor history in patients with lung adenocarcinoma (LUAD). Importantly, high UCHL5 expression predicted a poor overall survival (OS) and a poor disease-free survival (DFS) in patients with LUAD. Univariate regression analysis showed that tumor size, lymph node invasion, TNM stage and UCHL5 expression were associated with OS and DFS in patients with LUAD. The multivariate analysis indicated that the UCHL5 expression level was an independent prognostic factor for OS (HR=1.171, 95% CI=1.052-1.303) and DFS (HR=1.143, 95% CI=1.031-1.267) in these patients. UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins. These findings indicate that UCHL5 may serve as a potential prognostic marker and a new therapeutic target for patients with LUAD.

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer.

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer-related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.

Overexpression of GSDMC is a prognostic factor for predicting a poor outcome in lung adenocarcinoma.

The gasdermin (GSDM) superfamily has been demonstrated to consist of several important molecules that modulate multifunctional signal processes, such as cell pyroptosis. In this research, the roles of the GSDM superfamily on the occurrence and prognosis of lung adenocarcinoma (LUAD) were evaluated using integrative bioinformatic analyses and in vitro methods. Here, data from several bioinformatic platforms revealed that GSDMC is significantly upregulated in LUAD tissues and cell lines. Real-time fluorescence quantitative PCR (qPCR) demonstrated that GSDMC was obviously upregulated in radio-resistant LUAD cells, compared with their parental cells. Moreover, upregulated GSDMC expression was confirmed to be an independent indicator of poor first progression (FP) and overall survival (OS) in LUAD patients. DNA methylation analysis showed an evidently negative correlation between GSDMC expression and methylation status of one CpG site (cg05316065) in its DNA sequence. Patients with high methylation values had significantly higher Karnofsky performance scores (KPSs) and prolonged OS rates. Together, we confirmed that overexpression of GSDMC acts as a promising predictive factor for the poor prognosis of LUAD patients.

Elevated FAM83A expression predicts poorer clincal outcome in lung adenocarcinoma.

Family with sequence similarity 83 member A (FAM83A) can promote tumor cell proliferation and facilitate epidermal growth factor tyrosine kinase inhibitor resistance in some malignant tumors, but its role in lung cancer has not been directly explored. We investigated FAM83A expression in lung adenocarcinoma (LUAD) and its significance in clinicopathologic characteristics and prognosis of the disease. We analyzed the mRNA expression of FAM83A in LUAD and normal (or adjacent) lung tissues from Oncomine database firstly. Then, we detected FAM83A protein expression in five paired fresh LUAD and adjacent lung tissue specimens from patients in our hospital by Western blotting. In addtion, FAM83A expression in 86 paraffin-embedded archived LUAD samples was evaluated by Immunohistochemistry, and the correlations between FAM83A expression and clinicopathologic characteristics and prognosis of the patients were analyzed. Oncomine data analysis manifested that FAM83A mRNA expression was increased in LUAD. Western blotting revealed higher FAM83A expression in fresh LUAD tissues than in the adjacent lung tissues (P= 0.036). Immunohistochemistry analysis on 86 paraffin samples further demonstrated that the LUAD tissue had higher FAM83A expression than adjacent lung tissue (P< 0.001). The correlation analysis revealed that advanced stage tumors (stage III-IV) had higher FAM83A expression than early stage tumors (stage I-II) (P= 0.004). High FAM83A expression was significantly associated with lymphnode involvement and clinical staging (P= 0.008 and 0.008 respectively). Univariate and multivariate Cox regression analysis manifested that FAM83A expression was an independent predictive factor for poor survival. Kaplan-Meier survival curves showed that patients with higher FAM83A expression had shorter overall survival than those with lower FAM83A expressions (P= 0.002). FAM83A is upregulated in advanced LUAD and is related to unfavorible prognosis. FAM83A might be a novel diagnostic and prognositic biomarker for LUAD.

Presence of mEGFR ctDNA predicts a poor clinical outcome in lung adenocarcinoma.

BackgroundCirculating tumor DNA (ctDNA) is a biomarker for the selection of target agents in various malignancies. In this study, we examined the effect of ctDNA presence on the response to EGFR‐tyrosine kinase inhibitor (TKI) and on the prognosis in lung adenocarcinoma.MethodsctDNA of EGFR‐TKI sensitizing mutations (mEGFR), L858R substitution and Exon 19 deletion (E19d) mutation, was evaluated using droplet digital PCR (ddPCR) in 81 patients with lung adenocarcinoma which harbored mEGFR in the corresponding tumor tissues.ResultsThe study recruited lung cancer patients at various stages, and the sensitivity, specificity, and area under the curve (AUC) of mEGFR ctDNA detection by ddPCR were 40.0%, 88.5%, and 0.68, respectively. It showed higher sensitivity (75.0% vs. 10.0%) and AUC (0.83 vs. 0.49) in the advanced stages of lung adenocarcinoma compared with the early stages and the number of metastases and the fractional abundance of mEGFR ctDNA showed a strong correlation (σ = 0.516; P < 0.001, Spearman correlation test). There was a significantly shorter progression‐free survival and duration of disease control by EGFR‐TKIs in the ctDNA‐positive group than the negative group (14.0 vs. 41.0 months, P = 0.02 and 12.0 vs. 23.0 months, P = 0.02, log‐rank test, respectively). There was a trend for overall survival time to be shorter in patients with mEGFR ctDNA than for patients without mEGFR ctDNA (35.6 vs. 67.1 months, P = 0.06, log‐rank test).ConclusionsThese data showed that mEGFR ctDNA detection using ddPCR is useful in the advanced stages and its presence predicted distant metastasis and poor clinical outcome in lung adenocarcinoma.

Expression of SUMO1P3 Compared with SUMO1 is an Independent Predictor of Patient Outcome in Lung Adenocarcinoma.

BackgroundThe small ubiquitin-like modifier 1 (SUMO1) and small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) are long noncoding RNAs (lncRNAs). The prognostic significance of SUMO1 and SUMO1P3 expression in non-small cell lung cancer (NSCLC) remains unclear. This study aimed to use clinical, genetic, and survival data from the Cancer Genome Atlas (TCGA), to analyze the prognostic significance of SUMO1 and SUMO1P3 expression in the two main subtypes of NSCLC, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).Material/MethodsData were acquired from TCGA and in silico survival analysis was performed. SUMO1 and SUMO1P3 expression were compared between patients with LUAD and LUSC. Patient outcome was assessed as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). Recurrence-free survival (RFS) was defined as the survival time from primary surgery to the time of locoregional or distant recurrence of lung cancer.ResultsSUMO1P3 was significantly increased in LUSC and LUAD tissues compared with adjacent normal lung tissue and was significantly co-expressed with SUMO1. SUMO1P3 expression was significantly increased in patients with LUAD but not LUSC with reduced RFS after primary or follow-up treatment. Although patients with LUAD who had high SUMO1 or SUMO1P3 expression had reduced RFS compared with low expression groups, univariate and multivariate analysis showed that only SUMO1P3 expression was independently associated reduced RFS (HR, 1.418; 95% CI, 1.041–1.930; p=0.027).ConclusionsSUMO1P3 expression was an independent indicator of reduced RFS in patients with LUAD.

KIF18B as a regulator in microtubule movement accelerates tumor progression and triggers poor outcome in lung adenocarcinoma

KIF18B is involved in several tumor progression and exerts critical effects on microtubule growth during mitosis, but its role in lung adenocarcinoma still remains rare. Hence, we attempted to explore the biological function of KIF18B in lung adenocarcinoma. We first analyzed the expressional pattern of KIF18B in lung adenocarcinoma, and detected the correlation between KIF18B expression and clinical characteristics in lung adenocarcinoma based on The Cancer Genome Atlas (TCGA) database and Oncomine dataset. Subsequently, cell counting kit-8 (CCK-8) assay, wound-healing analysis, and transwell method were performed to assess the effects of KIF18B in lung adenocarcinoma cells. Quantitative real-time reverse transcription-PCR (qRT-PCR) and western blotting were utilized to measure the mRNA and protein expression levels. Our results illustrated that KIF18B expression was significantly up-regulated in lung adenocarcinoma samples compared to normal specimens. High levels of KIF18B were associated with unfavorable prognosis of lung adenocarcinoma patients. Down-regulation of KIF18B in lung adenocarcinoma cells inhibited cell prolifartion, migration, and invasion. Western blot assay demonstrated that KIF18B knockdown markedly decreased Rac1-GTP expression, an important marker of migration and invasion in tumors. Moreover, the phosphorylation of AKT and mTOR expression levels were attenuated after KIF18B knockdown. Taken together, these data enhanced the point that KIF18B might promote lung adenocarcinoma cell proliferation, migration, and invasion by activating Rac1 and mediating the AKT/mTOR signaling pathway.

The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells.

Inhibitors of BET proteins (BETi) are anti-cancer drugs that have shown efficacy in pre-clinical settings and are currently in clinical trials for different types of cancer, including non-small cell lung cancer (NSCLC). Currently, no predictive biomarker is available to identify patients that may benefit from this treatment. To uncover the mechanisms of resistance to BETi, we performed a genome-scale CRISPR/Cas9 screening in lung cancer cells. We identified three Hippo pathway genes, LATS2, TAOK1, and NF2, as key determinants for sensitivity to BETi. The knockout of these genes induces resistance to BETi, by promoting TAZ nuclear localization and transcriptional activity. Conversely, TAZ expression promotes resistance to these drugs. We also showed that TAZ, YAP, and their partner TEAD are direct targets of BRD4 and that treatment with BETi downregulates their expression. Noticeably, molecular alterations in one or more of these genes are present in a large fraction of NSCLC patients and TAZ amplification or overexpression correlates with a worse outcome in lung adenocarcinoma. Our data define the central role of Hippo pathway in mediating resistance to BETi and provide a rationale for using BETi to counter-act YAP/TAZ-mediated pro-oncogenic activity.

Molecular features of lung adenocarcinoma in young patients

BackgroundLung cancer in young patients is rare and has unique clinicopathological features. However, the molecular features of lung cancer in these patients are unclear. In this study, we aimed to describe the molecular features and outcomes of lung adenocarcinoma in patients aged ≤35 years.MethodsA total of 89 patients aged ≤35 years with pathologically diagnosed lung adenocarcinoma were retrospectively evaluated. Mutations in 59 cancer-associated genes and fusions of ALK and ROS1 were analyzed to understand the molecular features of young patients with lung adenocarcinoma. The clinicopathological characteristics and prognosis of each patient were reviewed.ResultsOf the 89 young patients, 25 (28.1%) were male, 9 (10.1%) were smokers, and the median age was 32 years (range, 18–35 years). The authors analyzed 59 genes and a total of 6 mutations and 2 fusion genes were detected. These genes were distributed among 60 patients, 12 of which had two or more mutations. ERBB2 mutations were most common (24.7%), followed by EGFR mutation (21.3%), ALK fusion (16.9%), TP53 mutation (9.0%), BRAF mutation (3.4%), PIK3CA mutation (1.1%), CTNNB1 mutation (1.1%), and ROS1 fusion (1.1%). EGFR, ERBB2, and TP53 mutations, gene abnormalities, and ALK fusions all had significant correlations with histopathological differentiation (P < 0.01). ALK fusions and EGFR mutations conferred a significantly worse prognosis than did ERBB2 mutations and tumors that contained no mutations or fusions (P < 0.01).ConclusionsThe molecular features of lung adenocarcinoma in young patients are different from those of common adenocarcinoma, and the main driver genes are closely correlated with tumor differentiation and prognosis.

Acetylated HOXB9 at lysine 27 is of differential diagnostic value in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China. AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well. However, the role of AcK27-HOXB9 in PDAC is unclear. The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC. Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay, respectively. HOXB9 was upregulated (P < 0.0001), and AcK27-HOXB9 (P =0.0023) was downregulated in patients with PDAC. HOXB9 promoted (P = 0.0115), while AcK27-HOXB9 (P = 0.0279) inhibited PDAC progression. AcK27-HOXB9 predicted favorable outcome in patients with PDAC (P = 0.0412). AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay. The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression. The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.

Abstract 3138: SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: A multi-cohort analysis

Abstract KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 was co-mutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in 4 independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received non-immunotherapy treatment from 1) The Cancer Genome Atlas (TCGA) and 2) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from 3) the MSK-IMPACT (MSK-IO) and 4) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving non-immunotherapy treatment, in the TCGA cohort (n=155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome (P=6e-04 for disease-free survival (DFS) and .031 for overall survival (OS), respectively), compared to KRAS-TP53 co-mutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n=314), KS patients also exhibited shorter OS than KP (P=.03) or K (P=.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P=.0091) in the MSK-IO (n=77), and the shortest PFS (P=.0026) and OS (P=0.0014) in the WFBCCC (n=18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor that lead to adverse clinical outcome in lung adenocarcinoma treated by either non-immunotherapy or immunotherapy. Citation Format: LIANG LIU, Tamjeed Ahmed, Willam Jeffrey Petty, Stefan Grant, Jimmy Ruiz, Thomas W. Lycan, Umit Topaloglu, Ping-Chieh Chou, Lance D. Miller, Gregory A. Hawkins, Martha A. Alexander-Miller, Stacey S. O’Neill, Bayard L. Powell, Ralph B. D’Agostino, Reginald F. Munden, Boris Pasche, Wei Zhang. SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: A multi-cohort analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3138.

Overexpression of Family with Sequence Similarity 83, Member A (FAM83A) Predicts Poor Clinical Outcomes in Lung Adenocarcinoma.

BackgroundThe aim of this study was to explore the expression levels of family with sequence similarity 83, member A (FAM83A) in lung adenocarcinoma (LUAD) and investigate its clinical prognostic value.Material/MethodsBioinformatics mining methods were used to predict the differential expression levels of FAM83A mRNA in LUAD and normal lung tissues based on the TCGA and Oncomine databases. Immunohistochemical staining was performed to demonstrate the FAM83A protein expression levels in 83 cases of LUAD combined with paired normal lung tissues. The correlation between clinicopathologic factors and FAM83A differential expression levels in LUAD was explored by the chi-square test. Kaplan-Meier univariate and Cox multivariate survival analyses were performed to investigate the clinical prognostic value of FAM83A expression in LUAD patients.ResultsResults from TCGA and Oncomine databases revealed that FAM83A mRNA expression level was significantly higher in LUAD than that in normal lung tissues (both P<0.05). Immunohistochemical findings demonstrated that the high positive rate of FAM83A in LUAD was 73.49% (61/83), while that of matched normal lung tissues was only 22.89% (19/83). Moreover, LUAD patients with FAM83A mRNA or high protein levels had dramatically lower OS times than those with FAM83A mRNA or low protein levels (All P<0.05). Lastly, Cox multivariate survival analysis showed that FAM83A differential expression level (low vs. high) was the only independent factor predicting the prognosis of LUAD patients (P=0.001).ConclusionsFAM83A was overexpressed in LUAD, and FAM83A overexpression could be used as an independent factor of poor prognosis in LUAD patients.

PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma

Serine proteases have been implicated as key drivers and facilitators of lung cancer malignancy, and while these proteins represent straightforward targets for therapeutic inhibitors, identification of optimal points for intervention has been complicated by the complex networks in which these enzymes function. Here we implicate a signaling pathway consisting of PRSS3/mesotrypsin and kallikrein-related peptidase 5 (KLK5) in lung adenocarcinoma malignancy. We show that elevated PRSS3/mesotrypsin expression is prognostic for poor outcome for patients with lung adenocarcinoma, and that genetic or pharmacologic targeting of PRSS3/mesotrypsin reduces lung adenocarcinoma cell invasiveness and proliferation. We further show that genetic targeting of KLK5, a known target of PRSS3/mesotrypsin, phenocopies the effect of PRSS3/mesotrypsin knockdown, and also that elevated expression of KLK5 is similarly prognostic for outcome in lung adenocarcinoma. Finally, we use transcriptional profiling experiments to show that PRSS3/mesotrypsin and KLK5 control a common malignancy-promoting pathway. These experiments implicate a potential PRSS3/mesotrypsin-KLK5 signaling module in lung adenocarcinoma and reveal the potential therapeutic benefit of selectively targeting these pathways.

Elevated PHD2 expression might serve as a valuable biomarker of poor prognosis in lung adenocarcinoma, but no lung squamous cell carcinoma.

Using data from The Cancer Genome Atlas (TCGA), we aimed to explore the association between Egl nine homolog 1 (EGLN1/PHD2) expression and survival outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. A retrospective study was conducted based on the level-3 data in the Cancer Genome Atlas (TCGA)-LUAD and TCGA-LUSC and data from the Human Protein Atlas (HPA). Both LUAD and LUSC had elevated PHD2 expression compared to their respective adjacent normal tissues. However, Kaplan-Meier survival curves showed that the high PHD2 expression LUAD patients had a significantly shorter overall survival (OS) and recurrence-free survival (RFS) (p=0.001 and p<0.001) compared to the low expression group. However, these differences were not observed in LUSC patients. Univariate and multivariate analysis showed that high PHD2 expression was an independent indicator of unfavorable OS (HR: 1.685, 95%CI: 1.251-2.269, p=0.001) and unfavorable RFS (HR: 2.008, 95%CI: 1.430-2.818, p<0.001) in LUAD patients. The methylation status of two CpG sites (cg07040244 and cg21875980) in PHD2 was at least moderately and negatively correlated with PHD2 expression. High methylation level of these two CpG sites was associated with better OS in LUAD patients. Elevated PHD2 expression might only serve as a valuable biomarker of poor prognosis in LUAD, but no in LUSC. Cg07040244 and cg21875980 might be two CpG sites modulating PHD2 expression in LUAD.

The Expression of Adipophilin Is Frequently Found in Solid Subtype Adenocarcinoma and Is Associated with Adverse Outcomes in Lung Adenocarcinoma.

BackgroundThe up-regulation of the lipogenic pathway has been reported in many types of malignant tumors. However, its pathogenic role or clinical significance is not fully understood. The objective of this study was to examine the expression levels of adipophilin and related hypoxic signaling proteins and to determine their prognostic impacts and associations with the pathologic characteristics of lung adenocarcinoma.MethodsExpression levels of adipophilin, heat shock protein 27 (HSP27), carbonic anhydrase IX, and hypoxia-inducible factor 1α were examined by immunohistochemical staining using tissue microarray blocks. Correlations between protein expression levels and various clinicopathologic features were analyzed.ResultsA total of 230 cases of primary adenocarcinoma of the lung were enrolled in this study. Adipophilin expression was more frequent in males and with the solid histologic type. It was correlated with HSP27 expression. Patients with adipophilin-positive adenocarcinoma showed a shorter progression-free survival (PFS) (median PFS, 17.2 months vs 18.4 months) in a univariable survival analysis, whereas HSP27 positivity correlated with favorable overall survival (OS) and PFS. In a multivariable analysis, adipophilin and HSP27 were independent prognostic markers of both OS and PFS.ConclusionsActivated lipid metabolism and the hypoxic signaling pathway might play a major role in the progression of lung adenocarcinoma, especially in the solid histologic type.

Abstract 1447: Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma

Abstract Low tryptophan levels promote tumor immune evasion by suppressing immune function. Elucidation of the immunomodulatory effects of altered tryptophan catabolism has relevance to cancer immunotherapy. Previous studies have largely focused on the role of the rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan depletion in the microenvironment. However, IDO1 levels are highly heterogeneous in different cancers, and numerous other downstream tryptophan catabolites have also been shown to have immunomodulatory activity. We surveyed the proteomes of 123 cancer cell lines for regulators of tryptophan metabolism which revealed overexpression of kynureninase (KYNU) in KEAP1 mutant lung adenocarcinomas. Functional analysis indicated that KYNU expression is regulated through nuclear factor, erythroid 2-like (Nrf2) activation. KYNU-high cell lines exhibited increased secretion of KYNU-derived anthranilate/3-hydroxyanthranilate. Ex-vivo studies using isolated PBMCs demonstrated that 3-hydroxyanthranilate reduced CD8+ T-cell viability. KYNU mRNA expression in three independent datasets of lung adenocarcinomas and additionally KYNU protein expression in lung adenocarcinoma tissue microarrays revealed that high KYNU expression predicts poor survival and disease recurrence. Our findings indicate that KYNU promotes immune suppression and is an independent prognostic marker for lung adenocarcinoma. Citation Format: Edwin J. Ostrin, Johannes F. Fahrmann, Ichidai Tanaka, Muge Celiktas, Clemente Aguilar, Mitzi Aguilar, Jennifer B. Dennison, Eunice Murage, Satyendra C. Tripathi, Oliver Delgado, Hong Wang, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio I. Wistuba, Ayumu Taguchi, Samir M. Hanash. Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1447.

Long non-coding RNA MUC5B-AS1 promotes metastasis through mutually regulating MUC5B expression in lung adenocarcinoma

Long non-coding RNAs (lncRNAs) have been involved in the process of cancer occurrence, progression, and treatment. Lung cancer-related lncRNAs are still an emerging field, thus we sought to identify novel functional lncRNAs as candidate targets in lung cancer. Here, we identified one novel lncRNA, MUC5B-AS1 (Ensembl: ENST00000532061.2). MUC5B-AS1 was upregulated in lung adenocarcinoma tissues compared with normal lung tissues. Moreover, MUC5B-AS1 promoted lung cancer cell migration and invasion in vitro and promoted lung cancer cell metastasis in vivo. MUC5B-AS1 and its cognate sense transcript MUC5B were highly co-expressed and mutually regulated in lung adenocarcinoma. Mechanistically, MUC5B-AS1 promoted cell migration and invasion by forming an RNA–RNA duplex with MUC5B, thereby increasing MUC5B expression levels in lung adenocarcinoma. The high expression of MUC5B was significantly associated with poor outcomes in lung adenocarcinoma. Our findings highlight MUC5B-AS1 functions as an oncogenic lncRNA in tumor metastasis and implicate MUC5B-AS1 as an attractive candidate target for lung adenocarcinoma treatment.

Low SOX2 expression marks a distinct subset of adenoid cystic carcinoma of the head and neck and is associated with an advanced tumor stage.

IntroductionThe transcription factor SOX2 has been identified as a lineage survival oncogene in squamous cell carcinoma and copy number gain is a common event in several human malignancies including head and neck cancer. However, the regulation and function of SOX2 during carcinogenesis as well as its prognostic value appears to be highly context dependent. As an example, high SOX2 expression in lung squamous cell carcinoma (SCC) is related to a favorable prognosis, while it is associated with poor outcome in lung adenocarcinoma. More recently, higher SOX2 levels and improved survival was also reported for head and neck SCC (HNSCC), and silencing of SOX2 expression in HNSCC cell lines revealed a mesenchymal-like phenotype with prominent vimentin expression. So far, SOX2 expression and its clinical relevance for other head and neck cancers, such as adenoid cystic carcinoma (HNACC) have not been sufficiently investigated.Material and methodsSOX2, vimentin and E-cadherin expression was assessed by immunohistochemical staining on serial sections from formalin fixed and paraffin embedded tissue samples of a patient cohort (n = 45) with primary ACC and correlated with patient and tumor characteristics as well as survival.ResultsHigh SOX2 expression was found in 14 (31%) primary tumor specimens and was significantly correlated with a N0 lymph node status (p = 0.04), while low SOX2 expression was correlated with a solid growth pattern (p = 0.031). Of the 45 patients, 27 tumor samples resembled an EMT-like phenotype, as assessed by high vimentin and low E-cadherin levels. However, in HNACC SOX2 levels were neither correlated with vimentin nor with E-cadherin expression, further supporting a context dependent regulation and function of SOX2 in distinct tumor entities.ConclusionThe absence of SOX2 was predominantly found in solid HNACC, which are characterized by a more aggressive phenotype in ACC. However, the underlying molecular mechanisms of SOX2 regulation and function in distinct HNACC subgroups remain to be fully elucidated.

P3-132 - High expression of IRE1 in lung adenocarcinoma is associated with a lower rate of recurrence

Recent reports have shown that endoplasmic reticulum (ER) stress is associated with cancer. However, the impacts of ER stress on the prognosis of lung cancer are unknown. Therefore, in this study, we sought to reveal the relationship between the expression of ER stress-related genes (ERO1L, PERK, ATF6 and IRE1) and the outcome of lung adenocarcinoma. One hundred and twenty-six patients with surgically resected lung adenocarcinomas were subjected to an ER stress-related mRNA expression analysis using quantitative RT-PCR. The following parameters were analyzed for all the study patients: age, sex, disease stage, smoking status, lymph node invasion (ly), vascular invasion (v), and EGFR mutation status. We assigned patients to either a high expression group (H group) or a low expression group (L group) according to the expression levels of ER stress-related genes. High expressions of ER stress-related genes were observed in patients with lower stages of lung adenocarcinoma and minimal vascular invasion. A Kaplan-Meier analysis showed significant differences in recurrence-free survival (RFS) and overall survival between H group and L group. High IRE1 expression was an independent predictor of RFS among patients with lung adenocarcinoma (hazard ratio, 0.396; 95%confidence interval, 0.188 - 0.834; P = 0.015). IRE1 may be a useful biomarker to predict recurrence in surgically resected lung adenocarcinoma patients.