Finding biomarkers for non-small cell lung cancer diagnosis and prognosis

Despite of several decades of efforts,lung cancer remains one of most deadly diseases,with a 5-year survival rate approximately 15％ worldwide.In China,the situation is even worse.Although there is no o...     

DNA Methylation Markers in Lung Cancer

Lung cancer is the most common cancer and the leading cause of cancer-related morbidity and mortality worldwide. As early symptoms of lung cancer are minimal and non-specific, many patients are diagnosed at an advanced stage. Despite a concerted effort to diagnose lung cancer early, no biomarkers that can be used for lung cancer screening and prognosis prediction have been established so far. As global DNA demethylation and gene-specific promoter DNA methylation are present in lung cancer, DNA methylation biomarkers have become a major area of research as potential alternative diagnostic methods to detect lung cancer at an early stage. This review summarizes the emerging DNA methylation changes in lung cancer tumorigenesis, focusing on biomarkers for early detection and their potential clinical applications in lung cancer.     

Lung Cancer: Are we up to the Challenge?

Lung cancer is the leading cause of cancer deaths worldwide among both men and women, with more than 1 million deaths annually. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers.Although recent advances have been made in diagnosis and treatment strategies, the prognosis of NSCLC patients is poor and it is basically due to a lack of early diagnostic tools.However, in the last years genetic and biochemical studies have provided more information about the protein and gene's mutations involved in lung tumors. Additionally, recent proteomic and microRNA's approaches have been introduced to help biomarker discovery.Here we would like to discuss the most recent discoveries in lung cancer pathways, focusing on the genetic and epigenetic factors that play a crucial role in malignant cell proliferation, and how they could be helpful in diagnosis and targeted therapy.     

Association of epidermal growth factor receptor (EGFR) gene polymorphism with lung cancer risk: a systematic review

Abstract

Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a well-documented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. In this review, association of EGFR 181946C?>?T, 8227G?>?A gene polymorphism with lung cancer was found, and EGFR Short genotype of cytosine adenine repeat number polymorphism was significantly associated with an increased risk of lung cancer.     

肺部微生态与肺癌的关系

近年来肿瘤相关微生物的研究已成为热点,主要涉及细菌、免疫细胞和肿瘤细胞之间的相互作用、细菌致癌途径及其在肿瘤诊断及治疗意义等方面。随着微生物检测手段的飞速发展,人们发现,肺部具有独特的微生态,越来越多的研究在求证肺部微生态与呼吸系统疾病之间的联系。肺癌目前仍然是威胁人类健康的最常见、预后极差的恶性肿瘤。寻求早期筛查、干预、诊治手段是目前攻克肺癌的重点和难点。肺癌患者的肺微生态有其特征性改变,微生物可能通过产生细菌毒素和其他炎性因子而影响肺癌的发生及发展。本文对肺微生态与肺癌相关性进行了综述,并对今后的研究提出了展望。     

Heterogeneity of lipidomic profiles among lung cancer subtypes of patients

Lung cancer is a leading cause of cancer‐related deaths with an increasing incidence and poor prognoses. To further understand the regulatory mechanisms of lipidomic profiles in lung cancer subtypes, we measure the profiles of plasma lipidome between health and patients with lung cancer or among patients with squamous cell carcinomas, adenocarcinoma or small cell lung cancer and to correct lipidomic and genomic profiles of lipid‐associated enzymes and proteins by integrating the data of large‐scale genome screening. Our studies demonstrated that circulating levels of PS and lysoPS significantly increased, while lysoPE and PE decreased in patients with lung cancer. Our data indicate that lung cancer‐specific and subtype‐specific lipidomics in the circulation are important to understand mechanisms of systemic metabolisms and identify diagnostic biomarkers and therapeutic targets. The carbon atoms, dual bonds or isomerism in the lipid molecule may play important roles in lung cancer cell differentiations and development. This is the first try to integrate lipidomic data with lipid protein‐associated genomic expression among lung cancer subtypes as the part of clinical trans‐omics. We found that a large number of lipid protein‐associated genes significantly change among cancer subtypes, with correlations with altered species and spatial structures of lipid metabolites.     

The diagnostic and molecular characteristics of malignant mesothelioma and ovarian/peritoneal serous carcinoma

B. Davidson The diagnostic and molecular characteristics of malignant mesothelioma and ovarian/peritoneal serous carcinoma Malignant mesothelioma and ovarian/peritoneal serous carcinoma are two of the most common tumours affecting the serosal cavities. Unlike other malignant tumours diagnosed at this anatomical site, such as lung and breast carcinoma, malignant mesothelioma and serous carcinoma share a common histogenesis, may be difficult to differentiate morphologically, and co‐express many of the diagnostic markers used by cytopathologists in effusion diagnosis. Selected markers have nevertheless shown sufficient sensitivity and specificity to differentiate serous carcinoma from malignant mesothelioma effectively. Recently, our group applied high throughput technology to the identification of new markers that may aid in differentiating these two cancer types and validated several of these markers in follow‐up studies. This review will present current data regarding the diagnostic and biological aspects of malignant mesothelioma and ovarian/peritoneal serous carcinoma.     

Identification of candidate genes for lung cancer somatic mutation test kits

Over the past three decades, mortality from lung cancer has sharply and continuously increased in China, ascending to the first cause of death among all types of cancer. The ability to identify the actual sequence of gene mutations may help doctors determine which mutations lead to precancerous lesions and which produce invasive carcinomas, especially using next-generation sequencing (NGS) technology. In this study, we analyzed the latest lung cancer data in the COSMIC database, in order to find genomic “hotspots” that are frequently mutated in human lung cancer genomes. The results revealed that the most frequently mutated lung cancer genes are EGFR, KRAS and TP53. In recent years, EGFR and KRAS lung cancer test kits have been utilized for detecting lung cancer patients, but they presented many disadvantages, as they proved to be of low sensitivity, labor-intensive and time-consuming. In this study, we constructed a more complete catalogue of lung cancer mutation events including 145 mutated genes. With the genes of this list it may be feasible to develop a NGS kit for lung cancer mutation detection.     

Molecular-genetic markers in lung cancer diagnostics

The major approaches to different lung cancer marker development are outlined in the review, including genetic, epigenetic, protein, transcryptomic, proteomic, metabolic, and miRNA markers. As far as epigenetic changes are among the earliest events in malignant transformation, methylated markers are thoroughly discussed. Special attention is given to minimally invasive tumor markers, which could be detected in easily accessible biological fluids, because they can be useful for screening and early diagnostics of cancer (before its clinical manifestation) as well as for verification of standard methods of diagnostics. Extracellular nucleic acids, circulating in blood (cirNA), are highlighted as the potential source of material for the early lung cancer diagnostics, prediction of antitumor treatment efficiency, post-treatment monitoring and disease prognosis.     

Cancer therapies: basic and clinical perspectives in brain, prostate, and lung tumors: Naples, September, 24-27, 2000.

A continuous flow of theoretical and practical information among basic research, diagnosis, and therapeutic innovation is a crucial process to achieve a timely and effective progress in defeating human cancer. According to this essential concept, the main objective of the Fourth Joint International Cancer Conference "Cancer Therapies: Basic and Clinical Perspectives in Brain, Prostate and Lung Cancer" has been of gathering together basic scientists and clinicians who represent scientific opinion leaders in their field, to present and discuss the most recent scientific achievements in basic and clinical perspectives, advanced diagnostic and therapeutic strategies, and molecular and cellular therapeutic approaches in brain, prostate, and lung cancer.     

Deprivation and emergency admissions for cancers of colorectum,lung, and breast in south east England: ecological study

Objectives: To examine the relation between deprivation and acute emergency admissions for cancers of the colon, rectum, lung, and breast in south east England. Design: Ecological analysis with data from hospital episode statistics and 1991 census. Setting: North and South Thames Regional Health Authorities (population about 14 million), divided into 10 aggregations of 31 470 census enumeration districts (median population 462). Subjects: 146 639 admissions relating to 76 552 patients aged <100 years on admission, resident in the Thames regions, admitted between 1 April 1992 and 31 March 1995. Results: Residents living in deprived areas were more likely to be admitted as emergencies and has ordinary inpatient admissions and less likely to be admitted as day cases. Adjusted odds of ordinary admissions from the most deprived tenth occurring as emergencies (relative to admissions from the most affluent tenth) were 2.29 (95% confidence interval 2.09 to 2.52) for colorectal cancer, 2.20 (1.99 to 2.43) for lung cancer, and 2.41 (2.17 to 2.67) for female breast cancer; adjusted odds of admissions as day cases were 0.70 (0.64 to 0.76), 0.50 (0.44 to 0.56), and 0.56 (0.50 to 0.62), respectively. Patients from deprived areas with lung or breast cancers were less likely to be recorded as having surgical interventions. Adjusted odds of patients from the most deprived tenth receiving surgery were 0.88 (0.78 to 1.00), 0.58 (0.48 to 0.70), and 0.63 (0.56 to 0.71), respectively. Admissions for colorectal cancer from the most deprived areas were less likely to be to hospitals admitting 100 or more new patients a year; the opposite held true for breast cancer admissions. No association was found for lung cancer admissions. Conclusions: Earlier diagnostic and referral procedures in primary care in deprived areas are required if there are to be significant reductions in mortality from these cancers. A national information strategy is required to ensure the continued availability of population based data on NHS patients and to mandate standardised datasets from the private sector. Rationalisation of acute services, hospital mergers, and plans for bed closures must take into account the increased healthcare needs and inequities in access to treatment and care of residents in areas with high levels of deprivation. Health authorities and primary care groups should re-examine their purchasing intentions, service reviews, and monitoring arrangements in the light of these findings.

Key messages

• A major reorganisation of cancer services is under way in England and Wales with the aim of improving access to and quality of treatment
• Residents with cancers of the bowel, lung, or breast in deprived areas in the Thames region were more likely to be admitted as emergencies and ordinary inpatients than their counterparts from more affluent areas, and patients with lung or breast cancers from deprived areas were less likely to receive surgical treatment
• Patients with colorectal cancer from the most deprived areas were less likely to be seen at hospitals with a large caseload than were patients from affluent areas; the opposite held true for patients with breast cancer, but no association was found for admissions for lung cancer
• More effective early diagnostic and referral procedures in primary care in deprived areas are required if reductions in mortality are to be achieved
• Hospital mergers and plans for service reconfiguration and bed closures must take into account inequities in access to treatment among residents in deprived areas

     

Cancer patterns in Canada.

Cancer is diagnosed in about 70 000 Canadians each year and is the leading cause of the loss of potential years of life before age 75 among women. Life-threatening forms of cancer will develop in at least one of every three Canadian newborns during their lifetimes if current cancer risks are not reduced. Lung and breast cancers are, respectively, the leading causes of premature death due to cancer among men and women. Compared with other countries Canada has low death rates for stomach cancer but high rates for certain smoking-related cancers (those of the lung and of the mouth and throat), leukemia and cancers of the colon, breast and lymphatic tissues. Newfoundland has the highest rates of death from stomach cancer and the lowest rates of death from prostatic cancer, whereas the western provinces have the opposite pattern. The rates of death from lung cancer among men are highest in Quebec, the province with the highest prevalence of smoking. In Canada the overall rates of death from cancer increased by 32% among men from 1951 to 1983. However, among women they declined by 12% from 1951 to 1976 and increased from 1976 to 1983, particularly among those aged 55 to 74. The rising rates of death due to lung cancer were primarily responsible for these increases. Lung cancer will likely displace breast cancer as the leading cancer killer of Canadian women by 1990. Given the relatively low survival rates for cancers caused by smoking and the lack of substantial improvement in rates for the most frequent types of cancer, preventive strategies that include effective measures to reduce tobacco consumption are urgently required.     

Lumican Is Overexpressed in Lung Adenocarcinoma Pleural Effusions

Adenocarcinoma (AdC) is the most common lung cancer subtype and is often associated with pleural effusion (PE). Its poor prognosis is attributable to diagnostic delay and lack of effective treatments and there is a pressing need in discovering new biomarkers for early diagnosis or targeted therapies. To date, little is known about lung AdC proteome. We investigated protein expression of lung AdC in PE using the isobaric Tags for Relative and Absolute Quantification (iTRAQ) approach to identify possible novel diagnostic/prognostic biomarkers. This provided the identification of 109 of lung AdC-related proteins. We further analyzed lumican, one of the overexpressed proteins, in 88 resected lung AdCs and in 23 malignant PE cell-blocks (13 lung AdCs and 10 non-lung cancers) using immunohistochemistry. In AdC surgical samples, lumican expression was low in cancer cells, whereas it was strong and diffuse in the stroma surrounding the tumor. However, lumican expression was not associated with tumor grade, stage, and vascular/pleural invasion. None of the lung cancer cell-blocks showed lumican immunoreaction, whereas those of all the other tumors were strongly positive. Finally, immunoblotting analysis showed lumican expression in both cell lysate and conditioned medium of a fibroblast culture but not in those of A549 lung cancer cell line. PE is a valid source of information for proteomic analysis without many of the restrictions of plasma. The high lumican levels characterizing AdC PEs are probably due to its release by the fibroblasts surrounding the tumor. Despite the role of lumican in lung AdC is still elusive, it could be of diagnostic value.     

Markers of small cell lung cancer

Lung cancer is the number one cause of cancer death; however, no specific serum biomarker is available till date for detection of early lung cancer. Despite good initial response to chemotherapy, small-cell lung cancer (SCLC) has a poor prognosis. Therefore, it is important to identify molecular markers that might influence survival and may serve as potential therapeutic targets. The review aims to summarize the current knowledge of serum biomarkers in SCLC to improve diagnostic efficiency in the detection of tumor progression in lung cancer. The current knowledge on the known serum cytokines and tumor biomarkers of SCLC is emphasized. Recent findings in the search for novel diagnostic and therapeutic molecular markers using the emerging genomic technology for detecting lung cancer are also described. It is believed that implementing these new research techniques will facilitate and improve early detection, prognostication and better treatment of SCLC.     

Differential magnetic resonance diagnosis of central lung cancer and acute pneumonia

The paper analyzes the authors' own data of chest magnetic resonance imaging (MRI) in 86 patients with verified central lung cancer and acute pneumonia. The MRI signs of lung cancer are systematized in exo-, endo-, and peribronchial forms of growth. The additional capacities of contrast enhancement are analyzed. The MRI semiotics of acute pneumonia has been developed. The differential diagnostic criteria for recognizing central lung cancer and acute pneumonia have been also elaborated.     

Buccal Spectral Markers for Lung Cancer Risk Stratification

Lung cancer remains the leading cause of cancer deaths in the US with >150,000 deaths per year. In order to more effectively reduce lung cancer mortality, more sophisticated screening paradigms are needed. Previously, our group demonstrated the use of low-coherence enhanced backscattering (LEBS) spectroscopy to detect and quantify the micro/nano-architectural correlates of colorectal and pancreatic field carcinogenesis. In the lung, the buccal (cheek) mucosa has been suggested as an excellent surrogate site in the “field of injury”. We, therefore, wanted to assess whether LEBS could similarly sense the presence of lung. To this end, we applied a fiber-optic LEBS probe to a dataset of 27 smokers without diagnosed lung cancer (controls) and 46 with lung cancer (cases), which was divided into a training and a blinded validation set (32 and 41 subjects, respectively). LEBS readings of the buccal mucosa were taken from the oral cavity applying gentle contact. The diagnostic LEBS marker was notably altered in patients harboring lung cancer compared to smoking controls. The prediction rule developed on training set data provided excellent diagnostics with 94% sensitivity, 80% specificity, and 95% accuracy. Applying the same threshold to the blinded validation set yielded 79% sensitivity and 83% specificity. These results were not confounded by patient demographics or impacted by cancer type or location. Moreover, the prediction rule was robust across all stages of cancer including stage I. We envision the use of LEBS as the first part of a two-step paradigm shift in lung cancer screening in which patients with high LEBS risk markers are funnelled into more invasive screening for confirmation.     

Potentialities of MRI in the differential diagnosis of peripheral lung cancer and inflammatory changes

The paper analyzes the authors' own data of chest magnetic resonance imaging (MRI) in 62 patients with verified peripheral lung cancer and different inflammatory changes (round pneumonic focuses, abscesses, etc.). The MRI signs of peripheral lung cancer are systematized. The additional capacities of contrast enhancement are analyzed. The MRI semiotics of different inflammatory changes has been developed. The differential diagnostic criteria for recognizing peripheral lung cancer and inflammatory changes have been also elaborated.     

Reducing the risk of overdiagnosis in lung cancer: a support from molecular biology

Early detection and swift treatment, when achievable, may significantly affect prognosis in lung cancer patients. Therefore, individuals with a high risk for lung cancer are invited to participate into international screening programs, such as the International Early Lung Cancer Action Program (I-ELCAP). An undesirable consequence of such massive enterprises is the detection of pulmonary nodules also in subjects who are unlikely to ultimately die from lung cancer. Nevertheless, the individuals with pulmonary nodule undergo stringent diagnostic procedures to assess the nature of the lesion. This implies a noticeable (physical and emotional) stress for our patients and the likelihood of overdiagnosis and, potentially, consequent overtreatment. Molecular markers, more specifically, microRNAs, might significantly add value to the workup process aiming at the distinction between benign and malignant lesions and, among the malignant ones, those concretely threatening for the patients' survival. We are confident that such a multidisciplinary approach would better suit our patients' diagnostic and/or therapeutic, actual needs.     

miR-137 impairs the proliferative and migratory capacity of human non-small cell lung cancer cells by targeting paxillin

Human lung cancer is the leading cause of cancer motility worldwide, with nearly 1.4 million deaths each year, among which non-small cell lung cancer (NSCLC) accounts for almost 85 % of this disease. The discovery of microRNAs (miRNAs) provides a new avenue for NSCLC diagnostic and treatment regiments. Currently, a large number of miRNAs have been reported to be associated with the progression of NSCLC, among which serum miR-137 has been examined to be down-regulated in NSCLC patients. However, the function of miR-137 on NSCLC cells migration and invasion and the relative mechanisms were less known. Here, we found that ectopic expression of miR-137 could inhibit cell proliferation, induce cell apoptosis, and suppress cell migration and invasion in NSCLC cell line A549. Moreover, we found that paxillin (PXN) was a target gene of miR-137 in NSCLC cells and restored expression of PXN abolished the miR-137-mediated suppression of cell migration and invasion. Taken together, our results showed that miR-137 acted as a tumor suppressor in NSCLC by targeting PXN, and it may provide novel diagnostic and therapeutic options for human NSCLC clinical operation in future.     

Carcinogenicity of chrysotile asbestos: A case control study of textile workers

Chrysotile is the predominant type of asbestos used in the United States and thus represents the most important source of exposure to asbestos already in place. While the steepest exposure-response observed for lung cancer has been in workers exposed to chrysotile in textile operations, some argue that chrysotile is less carcinogenic than amphibole asbestos types. Mineral oil exposures have been hypothesized to be responsible for the highly elevated lung cancer risk seen in textile workers. A lung cancer case-control analysis among a cohort of South Carolina chrysotile asbestos textile workers was conducted. Only a modest reduction in the slope of the lung cancer exposure-response relationship was observed after controlling for mineral oil exposures. These data do not support mineral oil exposure as a plausible explanation for the elevated lung cancer risk seen in chrysotile asbestos textile workers. The possible role of longer, thinner, more carcinogenic fibers in textiles is one plausible hypothesis needing further investigation.