NECTIN2 is a prognostic biomarker and potential therapeutic target in lung adenocarcinoma.

INTRODUCTION: NECTINs are transmembrane proteins mediating cell-to-cell adhesion. NECTINs interact with integrins or other membrane receptors to trigger multiple cellular functions. Aberrant NECTIN expression is associated with cancer progression and poor outcomes. While NECTIN2 is overexpressed in various cancer types, its role in lung cancer is not well understood. MATERIAL AND METHODS: We investigated the function of NECTIN2 in lung adenocarcinoma (LUAD) using the Cancer Genome Atlas (TCGA) dataset and clinical samples of 105 LUAD patients who had undergone surgical resection. Cell proliferation, apoptosis, migration and invasion were investigated using human lung adenocarcinoma cell lines. RESULTS: We found that high NECTIN2 expression correlated with reduced overall survival in LUAD in TCGA database. In clinical samples, high NECTIN2 expression was associated with lower recurrence-free survival in all patients (P < 0.001) and in stage I patients (P = 0.001). Functional analyses demonstrated that NECTIN2 knockout promoted cell apoptosis and diminished cell proliferation and migration capacity. NECTIN2 overexpression did not significantly affect cellular functions. DISCUSSION: Our results suggest that NECTIN2 plays a significant role in cell apoptosis and cancer cell migration, leading to increased postoperative recurrence. Furthermore, NECTIN2 serves as a prognostic indicator and a potential therapeutic target in LUAD. CONCLUSIONS: High NECTIN2 expression in LUAD was found to be associated with postoperative recurrence, and was observed to play an important role in cell apoptosis and migration.

Analysis of quality metrics in comprehensive cancer genomic profiling using a dual DNA-RNA panel.

Background: The nucleic acid quality from formalin-fixed paraffin-embedded (FFPE) tumor vary among samples, resulting in substantial variability in the quality of comprehensive cancer genomic profiling tests. The objective of the study is to investigate how nucleic acid quality affects sequencing quality. We also examined the variations in nucleic acid quality among different hospitals or cancer types. Methods: Three nucleic acid quality metrics (ddCq, Q-value, and DV200) and five sequencing quality metrics (on-target rate, mean depth, coverage uniformity, target exon coverage, and coverage of the housekeeping gene) were examined using 585 samples from the Todai OncoPanel, a dual DNA-RNA panel. Results: In the DNA panel, ddCq served as an indicator of sequencing depth and Q-value reflected the uniformity of sequencing across different regions. It was essential to have favorable values not only for ddCq but also for Q-value to obtain ideal sequencing results. For the RNA panel, DV200 proved to be a valuable metric for assessing the coverage of the housekeeping genes. Significant inter-hospital differences were observed for DNA quality (ddCq and Q-value), but not for RNA quality (DV200). Differences were also observed among cancer types, with Q-value being the lowest in lung and the highest in cervix, while DV200 was the highest in lung and the lowest in bowel. Conclusions: We demonstrated distinct characteristics and high predictive performances of ddCq, Q-value, and DV200. Variations were observed in the nucleic acid quality across hospitals and cancer types. Further study is warranted on preanalytical factors in comprehensive cancer genomic profiling tests.

Correlation between variant call accuracy and quality parameters in comprehensive cancer genomic profiling tests.

Background: Comprehensive genomic profiling (CGP) tests have been widely utilized in clinical practice. In this test, the variant list automatically output from the data analysis pipeline often contains false-positive variants, although the correlation between the quality parameters and prevalence of false-positive variants remains unclear. Methods: We analyzed 125 CGP tests performed in our laboratory. False-positive variants were manually detected via visual inspection. The quality parameters of both wet and dry processes were also analyzed. Results: Among the 125 tests, 52 (41.6%) required more than one correction of the called variants, and 21 (16.8%) required multiple corrections. A significant correlation was detected between somatic false-positive variants and quality parameters in the wet (ΔΔCq, pre-capture library peak size, pre-capture library DNA amount, capture library peak size, and capture library concentration) and dry processes (total reads, mapping rates, duplication rates, mean depth, and depth coverage). Capture library concentration and mean depth were strong independent predictors of somatic false-positive variants. Conclusions: We demonstrated a correlation between somatic false-positive variants and quality parameters in the CGP test. This study facilitates gaining a better understanding of CGP test quality management.

Clinical utility of Todai OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

Integrin alpha 2 is associated with tumor progression and postoperative recurrence in non-small cell lung cancer.

BACKGROUND: Integrins are transmembrane proteins that mediate cell adhesion to extracellular matrix. Whereas expression of integrin alpha 2 is associated with motility, invasiveness and cellular differentiation in various tumors, the role of integrin alpha 2 in lung cancer has not been studied in detail. The aim of this study was to determine whether and how aberrant integrin alpha 2 expression in non-small cell lung cancer leads to different outcomes. METHODS: We measured expression of integrin alpha 2 by quantitative polymerase chain reaction in 100 samples collected from non-small cell lung cancer patients who had undergone surgical resection. We assigned patients to high and low expression groups and analyzed survival. Cellular morphology, adhesion, proliferation, migration and invasion were examined in human lung cancer cell lines. RESULTS: Among 100 cases, 41 were female, with a median age of 71 years. High expression of integrin alpha 2 in non-small cell lung cancer was associated with lower recurrence-free survival (P = 0.004). Overexpression of integrin alpha 2 in cell lines had no effect on cell proliferation or invasion but resulted in increased cell size (1416 µm2 versus 470 µm2 in H522 cells, P < 0.001; 1822 µm2 versus 1029 µm2 in H661 cells, P = 0.02), adhesion (P < 0.001 in H522 and H661 cells) and migration (gap area filled was 71% versus 36% in H522 cells, P < 0.001; 57% versus 26% in H661 cells, P = 0.001). These changes were suppressed by E7820, an inhibitor of integrin alpha 2. CONCLUSIONS: Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence.

Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan.

Importance: Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine. Objective: To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases. Design, Setting, and Participants: This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study's central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021. Exposures: Simulated cases of cancer. Main Outcomes and Measures: The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation. Results: The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance. Conclusions and Relevance: The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

Brief, manualised and semistructured individual psychotherapy programme for patients with advanced cancer in Japan: study protocol for Managing Cancer and Living Meaningfully (CALM) phase 2 trial.

INTRODUCTION: Managing Cancer and Living Meaningfully (CALM) is a novel, brief and manualised psychotherapeutic intervention intended to treat and prevent depression and end-of-life distress in patients with advanced cancer. This phase 2 trial aims to assess the feasibility and preliminary efficacy of CALM in Japanese patients with cancer. METHODS AND ANALYSIS: This study is a single-arm clinical trial. All patients involved in the study are ≥18 years of age, have been diagnosed with advanced or metastatic solid-tumour cancer, and their expected survival is at least 6 months. CALM comprises three to six individual therapy sessions, each lasting approximately 45-60 min, provided over 3- 6 months. The participants will be asked to complete questionnaires at baseline (t0), 3 months (t1) and 6 months (t2). The primary outcomes are rates of completion of the intervention and of the outcome measures and improvement of depressive symptoms measured using the Patient Health Questionnaire-9 between t0 and t2. The criteria for the successful rate of completion is that at least 70% participants who participate in at least three sessions will complete measures at t2. The secondary outcomes are the improvement in scores on: (1) the Quality of Life at the End of Life-Cancer Scale, (2) the Experiences in Close Relationships scale, (3) the Death and Dying Distress Scale and (4) the Clinical Evaluation Questionnaire. ETHICS AND DISSEMINATION: This study was approved by the Research Ethics Committee of The University of Tokyo, Cancer Institute Hospital of Japanese Foundation for Cancer Research and Yamaguchi University. We will conduct the study in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The results of this study will be submitted for peer-reviewed publication and presentation at local, national and international scientific meetings and conferences. TRAIL REGISTRATION NUMBER: UMIN000040032; Pre-results.

Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency.

Immune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade malignancy, and treatment strategies have not changed for decades. In this study, we searched for novel targets for antibody-drug conjugate (ADC) therapy for SCLC. We identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1 (NRXN1). The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines (SHP77 and NCI-H526). The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines. Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy. Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

Dual EGFR and ABL Tyrosine Kinase Inhibitor Treatment in a Patient with Concomitant EGFR-Mutated Lung Adenocarcinoma and BCR-ABL1-Positive CML.

Tyrosine kinase inhibitor (TKI) combination is expected to increase in the era of precision medicine. TKI combination may be required to treat double primary cancers, each having a targetable gene, or to treat a single malignancy with multiple targetable genes. Here, we demonstrate the first report of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). A 60-year-old man with an 8-year history of CML was diagnosed as advanced EGFR-mutated lung adenocarcinoma. Complete molecular response of CML had been achieved by imatinib, and ABL-TKI had been switched to nilotinib four years previously due to muscle cramps. We discontinued nilotinib and started afatinib. Although partial response of lung adenocarcinoma was achieved, cytogenetic relapse of CML was observed following nilotinib discontinuation. We applied the previously described framework of cytochrome P450 3A4-mediated oral drug-drug interactions and selected gefitinib and nilotinib to treat both malignancies. We effectively and safely administered this combination for seven months. The present report is the first to demonstrate the safety and efficacy of dual EGFR and ABL TKI treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and CML.

Integrin α11 in non-small cell lung cancer is associated with tumor progression and postoperative recurrence.

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11ß1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT-PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.

Rapid temporal improvement of pembrolizumab-induced pneumonitis using the anti-TNF-α antibody infliximab.

Immune checkpoint inhibitors are associated with a wide spectrum of immune-related adverse events (irAEs) that are typically transient but are sometimes severe or even fatal. No consensus exists for the treatment of severe immune-mediated pneumonitis that is refractory to corticosteroids. Here, we report an autopsy case of pembrolizumab-induced pneumonitis that was transiently improved using infliximab. A 67-year-old male with advanced lung adenocarcinoma developed pneumonitis two weeks after a single dose of first-line pembrolizumab. The pneumonitis was refractory to corticosteroids, and the patient required mechanical ventilation. Addition of a single dose of infliximab rapidly improved the respiratory status and chest CT showed resolution of ground-glass opacities in the right upper and middle lobes. However, the patient died from re-exacerbation of pneumonitis 17 days after infliximab administration. The autopsy confirmed organizing phase diffuse alveolar damage in the right lower lobe, while the right upper lobe remained almost intact consistent with the CT findings, which is suggestive of the therapeutic effect of infliximab. The half-life of infliximab is 7-12 days, and a second dose of infliximab two weeks after the first dose is sometimes required for the treatment of gastrointestinal toxicity induced by anti-CTLA4 antibodies. Although the current guidelines do not recommend repeated administration of infliximab for immune-mediated pneumonitis, the present case suggests that repeated infliximab therapy may be beneficial in the treatment of immune-mediated pneumonitis.

Identification of a metastatic lung adenocarcinoma of the palate mucosa through genetic and histopathological analysis: a rare case report and literature review.

BACKGROUND: Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. CASE PRESENTATION: A 76-year old male with an adenocarcinoma of unknown primary origin in the lung presented with another tumor of the palate mucosa. The tumor cells in the pleural effusion were all negative for immunohistochemical markers (TTF-1 and Napsin A) and lung-specific oncogenic driver alterations (EGFR mutation and ALK translocation). The tumor of the palate mucosa was likewise identified as an adenocarcinoma, and the cells showed cytological similarities with the tumor cells in the pleural effusion; TTF-1, Napsin A, EGFR mutation and ALK translocation were all negative. This result suggested that origins of the tumors of the palate mucosa and in the lung were the same, even though the origin had not yet been determined. Next, we addressed whether the tumor of the palate mucosa was a primary tumor or not. Secretory carcinoma (SC), which is a common type of minor salivary gland tumor (MSGT), was suspected; however, mammaglobin was negative and ETV6-NTRK3 (EN) fusion was not observed. Other MSGTs were excluded based on histological and immunohistochemical findings. Furthermore, an additional examination demonstrated an oncogenic KRAS mutation at codon 12 (p.G12D) in both palate tumor and in pleural effusion. KRAS mutation is known to exist in one-third of lung adenocarcinomas (LUADs), but quite rare in MSGTs. The possibility of metastasis from other organs was considered unlikely from the results of endoscopic and imaging studies. This result indicated that the primary site of the CUP was indeed the lung, and that the tumor of the palate mucosa was a metastasis of the LUAD. CONCLUSIONS: A tumor of the palate mucosa that showed diagnostic difficulties was determined to be a metastatic LUAD by genomic alterations and histopathological findings.

Mean platelet volume and lymphocyte-to-monocyte ratio are associated with shorter progression-free survival in EGFR-mutant lung adenocarcinoma treated by EGFR tyrosine kinase inhibitor.

BACKGROUND: A growing body of evidence supports the role of platelets in cancer metastasis, escape from immune surveillance, and angiogenesis. Mean platelet volume (MPV), which reflects platelet turnover, is reported routinely as part of automated complete blood count. Accumulating evidence suggests that MPV is a useful biomarker in several diseases including cancer. However, its role in cancer patients receiving molecular targeted therapy has not been described in the literature. MATERIALS AND METHODS: We retrospectively analysed the prognostic impact of MPV in advanced or recurrent EGFR mutant lung adenocarcinoma treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Lymphocyte-to-monocyte ratio (LMR) has been previously reported to be a poor prognostic factor in EGFR mutant non-small cell lung cancer and was also included as a covariate. RESULTS: Using the previously described Cutoff Finder algorithm, the cut-off points for MPV and LMR that best predicted progression free survival (PFS) of EGFR-TKI were determined as 10.3 and 2.8, respectively. The median PFS was 14.7 and 8.2 months in MPV low and high groups (p = 0.013, log-rank test). The median PFS was 13.5 and 6.2 months in LMR high and low groups (p < 0.001, log-rank test). MPV and LMR were independently distributed (chi square test) and the multivariate analysis using Cox's proportional hazards regression model revealed that high MPV, low LMR, and pleural effusion were significant predictors for shorter PFS. CONCLUSION: MPV and LMR, measured as part of routine complete blood count, can be utilized to predict the outcome of EGFR-TKI therapy with no additional costs. Our results suggest a mechanism of EGFR-TKI resistance which is associated with the functional status of the platelets.

Altered editing level of microRNAs is a potential biomarker in lung adenocarcinoma.

Adenosine-to-inosine (A-to-I) microRNA editing is associated with tumor phenotypes in various cancer types. Recent analyses of The Cancer Genome Atlas (TCGA) dataset have shown several microRNAs that undergo A-to-I editing in human cancers, some of which have been reported to be associated with prognosis. Herein, we examined published small RNA deep sequencing data of 74 cases of lung adenocarcinoma (AD) and the corresponding normal counterpart (NC) specimen in silico in order to identify A-to-I microRNA editing events. Editing levels of miR-379-5p, miR-99a-5p, and miR-497-5p were lower in AD than in NC and, in a large number of cases, the editing level of miR-200b-3p was higher in AD than in NC. Difference in the editing level between AD and NC was largest for miR-99a-5p. Then, we examined the editing level of miR-99a-5p in 50 surgically resected lung adenocarcinoma cases at our institution by a conventional sequence-based method, and its association with clinical outcomes. The editing level of miR-99a-5p was significantly lower in 19 cases of AD (38%) than in corresponding NC. These cases showed a shorter overall survival as assessed using the log-rank test (P = .047). This trend was consistent with previous analyses of TCGA dataset. The altered editing level of microRNAs in lung adenocarcinoma could serve as a potential biomarker.

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

BACKGROUND: Cisplatin is a key drug for treating lung adenocarcinoma, and its sensitivity to cisplatin is directly related to prognosis. We aimed to reveal the roles of genes related to glutathione synthesis (glutamate-cysteine ligase catalytic subunit, GCLC) and cystine uptake (cystine/glutamate transporter, xCT and CD44v8-10) in cisplatin resistance and prognosis in lung adenocarcinoma. METHODS: We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and CD44v8-10, and investigated their sensitivities to cisplatin. We also measured mRNA expression levels of these genes in the tumor tissues from 92 lung adenocarcinoma patients. Patients were divided into high-expression (upper quartile, N = 23) and low-expression groups (remaining patients, N = 69). Recurrence-free survival, overall survival (N = 92), and post-recurrence survival (N = 22) were selected as endpoints. RESULTS: Compared with the control green fluorescent protein-expressing cell line (inhibitory concentration 50:6.9 µM), all the stable cell lines were more resistant to cisplatin (12.9 µM, P = 0.025; 13.9 µM, P = 0.028; 26.7 µM, P = 0.001; 17.7 µM, P = 0.008, respectively). In contrast, there was no significant difference in recurrence-free or overall survival between the high- and low-expression groups for any of the genes. However, high expression of GCLC was a risk factor for poorer post-recurrence survival (hazard ratio, 6.26; 95% confidence interval, 1.37-28.7; P = 0.018). CONCLUSION: High expression levels of genes related to glutathione synthesis and cystine uptake promote cisplatin resistance in lung adenocarcinoma cell lines. High expression of GCLC in tumor tissue may be a potential predictor of treatment failure.

High expression of IRE1 in lung adenocarcinoma is associated with a lower rate of recurrence.

OBJECTIVE: Recent reports have shown that endoplasmic reticulum stress is associated with cancer. However, the impacts of endoplasmic reticulum stress on the prognosis of lung cancer are unknown. Therefore, in this study, we sought to reveal the relationship between the expression of endoplasmic reticulum stress-related genes (endoplasmic reticulum oxidoreductase 1L, protein kinase RNA-like endoplasmic reticulum kinase, activating transcription factor 6 and inositol-requiring kinase 1) and the outcome of lung adenocarcinoma. METHODS: One hundred and twenty-six patients with surgically resected lung adenocarcinomas were subjected to an endoplasmic reticulum 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 or a low-expression group according to the expression levels of endoplasmic reticulum stress-related genes. RESULTS: High expressions of endoplasmic reticulum 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 and overall survival between high-expression group and low-expression group. High inositol-requiring kinase 1 expression was an independent predictor of recurrence-free survival among patients with lung adenocarcinoma (hazard ratio, 0.396; 95% confidence interval, 0.188-0.834; P = 0.015). CONCLUSIONS: Inositol-requiring kinase 1 may be a useful biomarker to predict recurrence in surgically resected lung adenocarcinoma patients.

The chimeric transcript RUNX1-GLRX5: a biomarker for good postoperative prognosis in Stage IA non-small-cell lung cancer.

Stage IA non-small-cell lung cancer cases have been recognized as having a low risk of relapse; however, occasionally, relapse may occur. To predict clinical outcome in Stage IA non-small-cell lung cancer patients, we searched for chimeric transcripts that can be used as biomarkers and identified a novel chimeric transcript, RUNX1-GLRX5, comprising RUNX1, a transcription factor, and GLRX5. This chimera was detected in approximately half of the investigated Stage IA non-small-cell lung cancer patients (44/104 cases, 42.3%). Although there was no significant difference in the overall survival rate between RUNX1-GLRX5-positive and -negative cases (P = 0.088), a significantly lower relapse rate was observed in the RUNX1-GLRX5-positive cases (P = 0.039), indicating that this chimera can be used as a biomarker for good prognosis in Stage IA patients. Detection of the RUNX1-GLRX5 chimeric transcript may therefore be useful for the determination of a postoperative treatment plan for Stage IA non-small-cell lung cancer patients.