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      Molecular sputum analysis for the diagnosis of lung cancer

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          Abstract

          Lung cancer is the leading cause of cancer mortality rate worldwide, mainly because of the presence of metastatic disease at the time of diagnosis. Early detection of lung cancer improves prognosis, and towards this end, large screening trials in high-risk individuals have been conducted since the past century. Despite all efforts, the need for novel (complementary) lung cancer diagnostic and screening methods still exists. In this review, we focus on the assessment of lung cancer-related biomarkers in sputum in the past decennium. Besides cytology, mutation and microRNA analysis, special attention has been paid to DNA promoter hypermethylation, of which all available literature is summarised without time restriction. A model is proposed to aid in the distinction between diagnostic and risk markers. Research on the use of sputum for non-invasive detection of early-stage lung cancer has brought new insights and advanced molecular techniques. The sputum shows a promising potential for routine diagnostic and possibly screening purposes.

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          Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

          Hisayuki Shigematsu, Li. Lin, Takao Takahashi … (2005)
          Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.
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            Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.

            M Greenblatt, W Bennett, M Hollstein … (1994)
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              Quantification of free circulating DNA as a diagnostic marker in lung cancer.

              Rosalia Ciricione, Davide Conte, Gabriella Sozzi … (2003)
              Analysis of circulating DNA in plasma can provide a useful marker for earlier lung cancer detection. This study was designed to assess the sensitivity and specificity of a quantitative molecular assay of circulating DNA to identify patients with lung cancer and monitor their disease. The amount of plasma DNA was determined through the use of real-time quantitative polymerase chain reaction (PCR) amplification of the human telomerase reverse transcriptase gene (hTERT) in 100 non-small-cell lung cancer patients and 100 age-, sex-, and smoking-matched controls. Screening performance of the assay was calculated through the receiver operating characteristic (ROC) curve. Odds ratios were calculated using conditional logistic regression analysis. Median concentration of circulating plasma DNA in patients was almost eight times the value detected in controls (24.3 v 3.1 ng/mL). The area under the ROC curve was 0.94 (95% CI, 0.907 to 0.973). Plasma DNA was a strong risk factor for lung cancer; concentrations in the upper tertile were associated with an 85-fold higher risk than were those in the lowest tertile. This study shows that higher levels of free circulating DNA can be detected in patients with lung cancer compared with disease-free heavy smokers by a PCR assay, and suggests a new, noninvasive approach for early detection of lung cancer. Levels of plasma DNA could also identify higher-risk individuals for lung cancer screening and chemoprevention trials.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 06 August 2013
                Publication date (Electronic): 18 July 2013
                Publication date PMC-release: 6 August 2013
                Volume: 109
                Issue: 3
                Pages: 530-537
                Affiliations
                [1 ]Department of Pathology, VU University Medical Center , De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                [2 ]Department of Pathology, Canisius-Wilhelmina Hospital , Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands
                [3 ]Tumor Genomics Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori , Via Venezian 1, 20133 Milan, Italy
                [4 ]Department of Epidemiology and Biostatistics, VU University Medical Center , De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                Author notes
                Article
                Publisher Item ID: bjc2013393
                DOI: 10.1038/bjc.2013.393
                PMC ID: 3738145
                PubMed ID: 23868001
                SO-VID: 9a84e6cd-05c7-402c-8379-8a69032f3d70
                Copyright © Copyright © 2013 Cancer Research UK
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                Date received : 22 January 2013
                Date revision received : 08 May 2013
                Date accepted : 21 June 2013
                Categories
                Subject: Minireview

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: biomarkers,dna methylation,early detection lung cancer,lung cancer screening,molecular diagnostics,non-small-cell lung cancer
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: biomarkers, dna methylation, early detection lung cancer, lung cancer screening, molecular diagnostics, non-small-cell lung cancer

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