A somatic mutation-derived LncRNA signatures of genomic instability predicts the prognosis and tumor microenvironment immune characters in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive carcinoma with genome instability. Long non-coding RNAs (LncRNAs) have been functionally associated with genomic instability in cancers. However, the identification and prognostic value of lncRNAs related to genome instability have not been explored in hepatocellular carcinoma. In this study, we aim to identify a genomic instability-related lncRNA signature for predicting prognosis and the efficacy of immunotherapy in HCC patients. METHODS: According to the somatic mutation and transcript data of 364 patients with HCC, we determined differentially expressed genome instability-related lncRNAs (GInLncRNAs). Gene ontology (GO) enrichment analyses and Kyoto Encyclopedia of genes and genomes enrichment analyses revealed the potential functions of genes co-expressed with those lncRNAs involved in cancer development and immune function. We further determined a genome instability-related lncRNA signature (GInLncSig) through Cox regression analysis and LASSO regression analysis. Thereafter, we performed correlation analyses with mutations, clinical stratification analyses, and survival analyses to evaluate GInLncSig predictive function. Subsequently, we construct a nomogram model for prognostic assessments of patients with HCC. Finally, we performed Immunocytes infiltration analysis, gene set enrichment analysis (ssGSEA) of immunity circle-associated pathways, and T cell-inflamed score to explore GInLncSig's potential value in guiding immunotherapy. RESULTS: We identified 11 independent prognosis-associated GInLncRNAs (AC002511.2, LINC00501, LINC02055, LINC02714, LINC01508, LOC105371967, RP11_96A15.1, RP11_305F18.1, RP11_342M1.3, RP11_432J24.3, U95743.1) to construct a GInLncSig. According to the risk score calculated by GInLncSig, the high-risk group was characterized by a higher somatic mutation count, significantly poorer clinical prognosis, higher T cell-inflamed score, and specific tumor immune infiltration status compared to the low-risk group. Furthermore, we constructed a nomogram model to improve the reliability and clinical utility of predicting the prognosis of patients with HCC. CONCLUSION: Our study established a reliable prognostic prediction signature that could be a tool for prognosis prediction and a promising predictive biomarker of immunotherapy in hepatocellular carcinoma.

Increased MCL-1 synthesis promotes irradiation-induced nasopharyngeal carcinoma radioresistance via regulation of the ROS/AKT loop.

Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.

Urokinase plasminogen activator predicts poor prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its prognosis remains dismal. Hence, it is important to identify the diagnostic and prognostic biomarkers for HCC. Urokinase plasminogen activator (uPA), an extracellular matrix (ECM)-degrading protease, plays a pivotal role in the invasion and metastasis of HCC. METHODS: To confirm the clinical significance of uPA in HCC, we explored uPA expression in HCC in The Cancer Genome Atlas (TCGA) database. The expression level of uPA was further verified by quantitative reverse transcription polymerized chain reaction (qRT-PCR) in 133 pairs of primary HCC samples. A survival analysis was conducted with the Kaplan-Meier method in the HCC samples and TCGA database. RESULTS: Our results showed that uPA was overexpressed in HCC and was significantly associated with HCC tumor size (P=0.015), differentiation grade (P=0.028), and absence of tumor encapsulation (P=0.010). Patients with high uPA expression levels had a poor outcome (P=0.026). TCGA database analysis was also consistent with our experimental results. CONCLUSIONS: In conclusion, our findings revealed that uPA was overexpressed in HCC and was related to HCC malignant features including tumor size, differentiation grade and absence of tumor encapsulation. High uPA expression had a shorter survival time. It is a potential prognostic biomarker of HCC.

A Higher Proportion of the EGFR T790M Mutation May Contribute to the Better Survival of Patients with Exon 19 Deletions Compared with Those with L858R.

INTRODUCTION: Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. METHODS: Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR tyrosine kinase inhibitors and underwent postprogression biopsy were enrolled. Mechanisms including T790M mutation, mesenchymal-epithelial transition proto-oncogene (MET) amplification, and histological transformation, as well as KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation, and anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion, were analyzed. RESULTS: The prevalence of T790M mutation was significantly higher in the Del19 subgroup than that in L858R subgroup (50.4% versus 36.5%, p = 0.043). Apart from this, there was no difference in other mechanisms including MET amplification and histological transformation. The median overall survival (OS) of patients with T790M mutation was 36.0 months (95% confidence interval [CI]: 30.9-41.2), which was significantly longer than the 26.5 months (95% CI: 24.0-29.0) in MET-positive patients, 19.7 months (95% CI: 18.2-21.2) in patients with histological transformation, and 23.0 months (95% CI: 17.4-28.6) in the KRAS/PIK3CA/ALK-altered population (p = 0.021). The hazard ratios of the MET-amplification subgroup and subgroup with histological transformation were 1.809-fold and 2.370-fold higher than that in T790M-positive subgroup. The median OS times were months 33.3 (95% CI: 28.9-37.7) in the Del19 subgroup and 26.4 months (95% CI: 23.2-29.6) in the L858R subgroup (p = 0.028). However, in multivariable analysis adjusted for T790M genotype, the EGFR mutation subtype was no longer found to be significant. CONCLUSIONS: Significant OS benefit was observed in patients with T790M mutation, suggesting that a larger proportion of T790M mutation might contribute to the better survival of patients with Del19.

Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study.

BACKGROUND: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression. RESULTS: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS. CONCLUSIONS: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.

Distribution and prognosis of uncommon metastases from non-small cell lung cancer.

BACKGROUND: According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC. METHODS: We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies. RESULTS: Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 [95% confidence interval (CI) 1.09-1.52, P < 0.01]. Those patients who received systemic therapy plus local treatment had a better survival rate than did those who received systemic therapy only (P < 0.01); all patients received best supportive care. CONCLUSIONS: Metastases to the above mentioned sites are infrequent. The presentation of uncommon metastases tends to indicate a poor outcome, and selected patients may benefit from local treatment.

Multiple primary malignancies involving lung cancer.

BACKGROUND: The incidence of multiple primary malignancies (MPM) has increased sharply in recent decades. However, the clinical characteristics and prognosis of MPM patients involving lung cancer were not fully elucidated. This retrospective study was designed to explore the clinical characteristics and prognosis of MPM patients involving lung cancer in the People's Republic of China. METHODS: Of 5405 lung cancer cases diagnosed at the Guangdong Lung Cancer Institute between 2005 and 2013, we analyzed 185 patients (3.4 %) with MPM involving lung cancer. RESULTS: Among 185 patients with MPM involving lung cancer, 10 (5.4 %)had three malignancies and 175 (94.6 %) had two malignancies. 10 patients with three malignancies were excluded from the analysis to avoid misunderstanding. Of 175 accompanying malignancies, 64 (36.6 %) were synchronous MPM patients and 111 (63.4 %) were metachronous MPM patients; 49 (28.0 %) were lung cancer first MPM patients and 126 (72.0 %) were other cancer first MPM patients. The most frequent accompanying malignancy was colon cancer (25/175), followed by rectal cancer (18/175), esophageal cancer (17/175), and thyroid cancer (13/175). Metachronous MPM patients showed significantly better overall survival (OS) than synchronous MPM, with a median OS of 72.8 (range 12.2-391.0) and 12.9 (range 0.8-86.3)months, respectively (P < 0.001). Cox regression analysis revealed that time of occurrence and stage were independent factors for OS. CONCLUSIONS: Colorectal cancer, esophageal cancer, and thyroid cancer were the tumors that most frequently accompanying lung cancer. Metachronous MPM patients showed significantly better OS compared with synchronous MPM patients.

Differences in driver genes between smoking-related and non-smoking-related lung cancer in the Chinese population.

Recently, non-smoking-related lung cancer was classified as an independent disease entity because it is different from tobacco-associated lung cancer. Non-smoking-related lung cancer occurs more often in women than men, and the predominant histological type is adenocarcinoma (ADC) rather than squamous cell carcinoma. Most of the driver gene alterations that have been identified in ADC in never-smokers include epidermal growth factor receptor mutations, KRAS mutations, echinoderm microtubule-associated protein like 4/anaplastic lymphoma kinase fusion, and ROS1 fusion, among others. Meanwhile, significant progress has been made in the treatment of ADC. However, in comparison with ADC, no such available molecular targets exist for smoking-associated lung cancer, for which treatment strategies are limited. Next-generation sequencing has been widely applied to the discovery of more genetic profiles of lung cancers. This review summarizes the differences between smoking-related and non-smoking-related lung cancer as follows: different somatic mutation burdens, C:G→A:T transversions, common and novel driver genes, and treatment strategies. Overall, smoking-related lung cancer is more complicated than non-smoking-related lung cancer. Furthermore, we review the prevalence of driver genes in smoking-associated and non-smoking-associated lung cancers in the Chinese population.

Personalized treatment strategies for non-small-cell lung cancer in Chinese patients: the role of crizotinib.

Anaplastic lymphoma kinase (ALK) rearrangement is an oncogene targeted with approved drugs second to epidermal growth factor receptor (EGFR) in lung cancer. Crizotinib was developed and introduced into clinical practice rapidly and successfully after the discovery of ALK rearrangement in non-small-cell lung cancer. Chinese and other Asian patients treated with crizotinib seem to have lower toxicity and higher efficacy compared with other ethnicities. Crizotinib showed potent antitumor activity and manageable toxicity in mesenchymal-epithelial transition factor (c-Met)/ROS1-positive non-small-cell lung cancer patients, but prospective clinical trials are still needed to confirm its efficacy and safety. Crizotinib appears to be effective against tumors originating from various organs that harbor ALK abnormalities. In the near future, we would classify the tumors by their genetic information beyond organs, such as ALKoma, EGFRoma, and RAFoma, and a single compound could be used for many different types of cancer in different organs. The major challenge of the widespread use of crizotinib in clinical practice is establishing convenient diagnostic techniques for the detection of ALK/c-Met/ROS1. In the present study, we reviewed the application of crizotinib in Chinese patients.

Predictive and prognostic value of de novo MET expression in patients with advanced non-small-cell lung cancer.

BACKGROUND: Cellular-mesenchymal-epithelial transition (MET) protein has recently been identified as a novel target that shows promise for the treatment of non-small-cell lung cancer (NSCLC). However, the relationship between de novo MET expression and patient outcomes remains unclear. METHODS: We reviewed the data of patients who had been diagnosed with NSCLC between December 2013 and October 2014. All the patients were evaluated for MET expression status. MET-positive was defined as having an H-score ≥ 60 by immunohistochemistry analysis. MET expression was analyzed in 158 patients who were negative for the common driver genes, including EGFR, ALK, KRAS and ROS1. A chi-squared test was used to assess the clinicopathological parameters. Multivariate analyses were performed using the Cox proportional hazards model. RESULTS: MET data were available for analysis in 158 advanced NSCLC patients. Of these, based on the MET H-score criteria, the IHC-positive rate was 48.1% (76/158). There were more patients with adenocarcinoma in the MET-positive group compared with the MET-negative group (P=0.01). Nine patients with lymphoepithelioma-like carcinoma had no MET expression. There was no significant difference in overall survival (OS) between MET-positive and -negative patients. There was also no significant difference in the efficacy (Z=-0.44, P=0.66) or progression free survival (PFS) of first-line chemotherapy between the MET-positive and -negative patients (mPFS 6.8 months [95% CI: 5.4-8.2] vs. 5.9 months [5.5-6.3], P=0.92). In the cell model, the MET-positive cell showed no difference in chemotherapy but with a increase in percentage of growth inhibition upon treatment with MET inhibitor INC280 compared to MET-negative cell. CONCLUSION: Our data showed that de novo MET expression was not rare. It was not a predictive or prognostic factor for stage IV NSCLC patients, but this should be confirmed in larger population cohort.

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor.

OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls. MATERIALS AND METHODS: This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P=0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P<0.001), while the RR (76.5% vs. 68.9%, P=0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR)=3.06; 95% CI=2.12-4.42, P<0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P<0.001). The adjusted HR for death in the study group was 1.91 (95% CI=1.33-2.76; P<0.001). CONCLUSION: In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials.

Prognostic significance of genotype and number of metastatic sites in advanced non-small-cell lung cancer.

BACKGROUND: TNM stage remains the most important prognostic factor in clinical practice. The 7th edition lung cancer staging system has not considered some important prognostic factors, such as the number of metastatic organ sites and the molecular biologic characterization. PATIENTS AND METHODS: Using driver gene alternation and tumor burden, advanced NSCLC cases were divided into 3 groups: M1-I group, epidermal growth factor (EGFR)-positive and/or anaplastic lymphoma kinase (ALK)-positive; MI-II, wild-type EGFR and ALK with intrathoracic metastasis or 1 distant metastatic organ with ≤ 3 metastasis lesions; and MI-III, wild-type EGFR and ALK with 1 distant metastatic organ with > 3 metastasis lesions or multiple metastatic organs. Overall survival was comparable between the 7th edition staging system and our category of M descriptors. RESULTS: A total of 627 patients with stage IV NSCLC newly diagnosed at Guangdong Lung Cancer Institute between January 2009 and July 2012 were enrolled in the present study. The median overall survival (OS) was 22.2 (95% CI, 19.590-24.810), 15.5 (95% CI, 13.176-17.824), and 10.0 (95% CI, 8.033-11.967) months for M1-I, M1-II, and M1-III, respectively (P < .001). According to the 7th edition of the TNM staging system, the median OS of the M1a and M1b groups was 22.8 (95% CI, 19.484-26.116) and 13.7 (95% CI, 11.793-15.607) months, respectively (P < .001). The maximum of the absolute values of the M1 category for our study and the 7th TNM staging system was 5.881 and 5.089, respectively. CONCLUSION: Advanced NSCLC could potentially be further divided into 3 subgroups according to the genotype and number of metastatic organ sites and metastasis lesions.

Novel agents and strategies for overcoming EGFR TKIs resistance.

Since the recognition of epidermal growth factor receptor (EGFR) as a therapeutic target, EGFR tyrosine kinase inhibitors (TKIs) have been used in lung cancer patients with EGFR mutations, which has been a major breakthrough for lung cancer treatment.. The progression-free survival (PFS) of patients with EGFR mutations treated with EGFR TKIs is significantly prolonged compared with that of patients who underwent standard chemotherapy. However, all patients who initially respond to EGFR TKIs eventually develop acquired resistance (AR). Many small molecule agents and monoclonal antibodies (McAb) targeting signaling pathways are potential therapeutic regimens for overcoming resistance, and various therapeutic strategies are used in clinical practice. Here we review the novel agents and therapeutic strategies for overcoming AR to EGFR TKIs.

Clinical trials for lung cancer in China.

Lots of international multi-center clinical trials have been conducted in China over the past 10 years. We also have more and more clinical trials designed and launched by qualified Chinese investigators in recent years, especially after the establishment of the Chinese Thoracic Oncology Group (CTONG) in 2007. These trials are mainly about targeted drugs. The finished ones provided more evidence for the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the first-line/maintenance/second-line settings in Chinese patients. The ongoing ones will diversify the use of EGFR-TKIs in 1(st)/2(nd)/3(rd) line settings and help to answer the questions whether patients will benefit from (neo)adjuvant EGFR-TKIs and chemotherapy intercalating and maintenance use of EGFR-TKIs. Here, we introduce far-reaching clinical trials conducted, ongoing and will be launched soon in China.