Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non-small-cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer-specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer-specific survival (P < 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760-766) N on-small-cell lung cancer (NSCLC), which comprises mainly adenocarcinoma and squamous cell carcinoma, is one of the most common human cancers.(1) Despite rigorous endeavors to develop anticancer therapies, the prognosis of lung cancer patients still remains poor. To predict recurrence after surgery and to judge indications of additional therapies appropriately, clinical and biological markers have long been sought.The Keap1-Nrf2 system plays a central role in protecting cells from electrophilic and oxidative stresses.(2) Under unstressed conditions, Keap1 ubiquitinates Nrf2, and Nrf2 is degraded by the proteasome. Upon exposure to the stimuli, Keap1 is inactivated, and stabilized Nrf2 induces the transcription of many cytoprotective genes. Somatic mutations in the NRF2 or KEAP1 gene that cause constitutive stabilization of NRF2 have been found in many human cancers.(3-9) Reduced expression of KEAP1 due to KEAP1 methylation has been suggested as another mechanism for NRF2 stabilization.(10,11) NRF2 stabilization and subsequent accumulation contribute to the poor prognosis of NSCLC patients. (6,7) This is because NRF2 confers resistance to anticancer therapies and an aggressive proliferative tendency on cancer cells. (10,12) Recently, still another cause for the constitutive stabilization of NRF2 in cancer cells was reported. One of the selective substrates for autophagy, (13,1...

DNA methylation in the promoter region of a gene is associated with a loss of that gene's expression and plays an important role in gene silencing. The inactivation of tumor-suppressor genes by aberrant methylation in the promoter region is well recognized in carcinogenesis. However, there has been little study in this area when it comes to genome-wide profiling of the promoter methylation. Here, we developed a genome-wide profiling method called Microarray-based Integrated Analysis of Methylation by Isoschizomers to analyse the DNA methylation of promoter regions of 8091 human genes. With this method, resistance to both the methylation-sensitive restriction enzyme HpaII and the methylation-insensitive isoschizomer MspI was compared between samples by using a microarray with promoter regions of the 8091 genes. The reliability of the difference in HpaII resistance was judged using the difference in MspI resistance. We demonstrated the utility of this method by finding epigenetic mutations in cancer. Aberrant hypermethylation is known to inactivate tumour suppressor genes. Using this method, we found that frequency of the aberrant promoter hypermethylation in cancer is higher than previously hypothesized. Aberrant hypomethylation is known to induce activation of oncogenes in cancer. Genome-wide analysis of hypomethylated promoter sequences in cancer demonstrated low CG/GC ratio of these sequences, suggesting that CpG-poor genes are sensitive to demethylation activity in cancer

Background. Relationships between tumor doubling time (DT) and other prognostic factors and the risk of death related to these factors are not yet fully understood. Methods. Tumor doubling time of primary lung carcinomas of 174 patients, detected in a limited number of local municipalities during a limited period, was calculated using the Schwartz formula. Survival rate of the 174 patients was compared with reference to categories of prognostic factors (univariate analyses) and significant factors affecting survival were identified by multivariate analyses using the Cox proportional hazard model. Results. Tumor doubling time had a log normal distribution. There was a significant difference in mean DT in relation to sex, smoking history, presence of symptoms, cell type, primary tumor factor, and stage. Univariate analyses showed a significant difference in survival in relation to DT, age, sex, method of tumor detection, smoking history, symptoms, therapy, cell type, primary tumor (T) factor, regional lymph node (N) factor, distant metastasis (M) factor, and stage. Multivariate analyses using the Cox's proportional hazard model in a stepwise fashion identified a final set of five significant variables: N factor (P = 0.0001); therapy (P = 0.0016); M factor (P = 0.0017); T factor (P = 0.0018), and DT (P = 0.0152). Conclusions. Tumor doubling time was an independent and significant prognostic factor for lung cancer patients.

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Aberrant DNA methylation is an important event in carcinogenesis. Of the various regions of a gene that can be methylated in cancers, the promoter is the most important for the regulation of gene expression. Here, we describe a microarray analysis of DNA methylation in the promoter regions of genes using a newly developed promoter-associated methylated DNA amplification DNA chip (PMAD). For each sample, methylated Hpa II-resistant DNA fragments and Msp Icleaved (unmethylated + methylated) DNA fragments were amplified and labeled with Cy3 and Cy5 respectively, then hybridized to a microarray containing the promoters of 288 cancer-related genes. Signals from Hpa II-resistant (methylated) DNA (Cy3) were normalized to signals from Msp I-cleaved (unmethylated + methylated) DNA fragments (Cy5). Normalized signals from lung cancer cell lines were compared to signals from normal lung cells. About 10.9% of the cancer-related genes were hypermethylated in lung cancer cell lines. Notably, HIC1, IRF7, ASC, RIPK3, RASSF1A, FABP3, PRKCDBP, and PAX3 genes were hypermethylated in most lung cancer cell lines examined. The expression profiles of these genes correlated to the methylation profiles of the genes, indicating that the microarray analysis of DNA methylation in the promoter region of the genes is convenient for epigenetic study. Further analysis of primary tumors indicated that the frequency of hypermethylation was high for ASC (82%) and PAX3 (86%) in all tumor types, and high for RIPK3 in small cell carcinoma (57%). This demonstrates that our PMAD method is effective at finding epigenetic changes during cancer.