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A Multiparametric Serum Kallikrein Panel for Diagnosis of Non ^ Small

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A Multiparametric Serum Kallikrein Panel for Diagnosis of Non ^ Small Imaging, Diagnosis, Prognosis A Multiparametric Serum Kallikrein Panel for Diagnosis of Non ^ Small Cell Lung Carcinoma Chris Planque,1, 2 Lin Li,3 Yingye Zheng,3 Antoninus Soosaipillai,1, 2 Karen Reckamp,4 David Chia,5 Eleftherios P. Diamandis,1, 2 and Lee Goodglick5 Abstract Purpose: Human tissue kallikreins are a family of15 secreted serine proteases.We have previous- ly shown that the expression of several tissue kallikreins is significantly altered at the transcription- al level in lung cancer. Here, we examined the clinical value of 11members of the tissue kallikrein family as potential biomarkers for lung cancer diagnosis. Experimental Design: Serum specimens from 51 patients with non ^ small cell lung cancer (NSCLC) and from 50 healthy volunteers were collected. Samples were analyzed for11kallikreins (KLK1, KLK4-8, and KLK10-14) by specific ELISA. Data were statistically compared and receiver operating characteristic curves were constructed for each kallikrein and for various combinations. Results: Compared with sera from normal subjects, sera of patients with NSCLC had lower levels of KLK5, KLK7, KLK8, KLK10, and KLK12, and higher levels of KLK11, KLK13, and KLK14. Expres- sion of KLK11and KLK12 was positively correlated with stage.With the exception of KLK5, expres- sion of kallikreins was independent of smoking status and gender. KLK11, KLK12, KLK13, and KLK14 were associated with higher risk of NSCLC as determined by univariate analysis and con- firmed by multivariate analysis.The receiver operating characteristic curve of KLK4, KLK8, KLK10, KLK11,KLK12, KLK13, and KLK14 combined exhibited an area under the curve of 0.90 (95% con- fidence interval, 0.87-0.97). Conclusions: We propose a multiparametric panel of kallikrein markers for lung cancer diagnosis with relatively good accuracy. This model requires validation with a larger series and may be further improved by addition of other biomarkers. Lung cancer is the leading cause of cancer-related mortality f80% of all cases and, in turn, is composed of three major worldwide in both men and women. According to WHO, two histologic subtypes of adenocarcinoma, squamous cell carci- histologically distinct subtypes of lung cancer, that is, small-cell noma (SCC), and large-cell carcinoma (1). Patient survival (SCLC) and non–small cell lung cancer (NSCLC), are from lung cancer depends mainly on cell type and stage of recognized, depending on cell types. NSCLC accounts for disease at presentation. When lung cancer is diagnosed at a localized stage, the 5-year survival is f50%, whereas this rate drops to f5% when diagnosis is made at the time of lymph Authors’ Affiliations: 1Department of Laboratory Medicine and Pathobiology, node involvement or metastasis (2). University of Toronto and 2Department of Pathology and Laboratory Medicine, To supplement advances in surgical treatment, many studies Mount Sinai Hospital, Toronto, Ontario, Canada; 3Fred Hutchinson Cancer have focused on the development of diagnostic methods, Research Center, Seattle, Washington; 4Divisions of Hematology and Medical including new serum tumor markers. Thus far, a number of Oncology, City of Hope Comprehensive Cancer Center and Beckman Research such biomarkers have been reported for NSCLC, including Institute, Duarte, California; and 5Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of SCC antigen, carcinoembryonic antigen, neuron-specific eno- Medicine, University of California, Los Angeles, Los Angeles, California lase, cytokeratin 19 fragment (CYFRA 21-1), cancer antigen Received 9/5/07; revised 12/12/07; accepted 12/13/07. 125 (CA-125), and tissue polypeptide antigen. However, the Grant support: Natural Sciences and Engineering Research Council of Canada expression of these antigens does not seem to be sufficiently (E.P. Diamandis), and Early Detection Research Network National Cancer Institute CA-86366 (L. Goodglick, E.P. Diamandis, and D. Chia) and the Specialized sensitive and specific to be reliable for the diagnosis of the Programs of Research Excellence in Lung Cancer grant P50-CA90388, National majority of lung malignancies. Cancer Institute (L. Goodglick and K. Reckamp). Proteases may represent good diagnostic/prognostic bio- The costs of publication of this article were defrayed in part by the payment of page markers, as they are involved in cancer progression (3). Human charges. This article must therefore be hereby marked advertisement in accordance tissue kallikreins are a family of 15 highly conserved serine with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research proteases (KLK1-KLK15) encoded by the largest contiguous Online (http://clincancerres.aacrjournals.org/). cluster of protease genes in the human genome. Due to their Requests for reprints: Lee Goodglick, Department of Pathology and Laboratory protease activity and expression in many tissues and cell types, Medicine, David Geffen School of Medicine, University of California, Los Angeles, kallikreins have been implicated in a wide range of physiologic 10833 Le Conte Avenue, Box 951732, CHS, Los Angeles, CA 90095-1747. Phone: 310-825-9134; Fax: 310-267-2104; E-mail: [email protected]. functions, ranging from regulation of cell growth to tissue F 2008 American Association for Cancer Research. remodeling and skin desquamation. Kallikreins may also be doi:10.1158/1078-0432.CCR-07-4117 directly or indirectly involved in cancer pathogenesis by www.aacrjournals.org 13 5 5 Clin Cancer Res 2008;14(5) March 1, 2008 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2008 American Association for Cancer Research. Imaging, Diagnosis, Prognosis promoting angiogenesis and degradation of extracellular matrix vacutainer tubes. Samples were centrifuged at 3,000 rpm for 15 min proteins (4). Accumulating evidence indicates that many within 1 h of collection, separated, and stored in aliquots at -80jC. members of the kallikrein family are differentially expressed Staging was determined by the American Joint Committee on Cancer in cancer, primarily in hormone-related malignancies, at the Guidelines. Distributions of patients by demographic and clinical characteristics are presented in Table 1. mRNA and protein levels. Furthermore, many members of the ELISA for kallikrein measurement in serum. ELISA-type immuno- kallikrein family have been reported to be promising diagnos- fluorometric procedures developed in-house were used to measure tic/prognostic biomarkers for several cancer types, including kallikrein levels in serum. Assays used in the present study were of the breast, prostate, ovarian, and testicular carcinomas. In addition ‘‘sandwich’’ type, with one antibody used for capture and another for to prostate-specific antigen, a prostate cancer biomarker, several detection. Three types of configurations of ELISA were used in this kallikrein proteins, including KLK6 and KLK10, represent study, using either monoclonal-monoclonal (KLK5, KLK6, KLK7, KLK8, promising serum-based markers for diagnosis and prognosis KLK10, and KLK13), monoclonal-polyclonal (KLK4, KLK11, KLK12, of ovarian cancer (4). Likewise, KLK3, KLK5, and KLK14 have and KLK14), or polyclonal-polyclonal (KLK1) combinations. Detailed been proposed as serum markers for diagnosis and prognosis of information on these methods is provided in Supplementary Table S1. breast carcinomas (4). All ELISAs were tested negative for cross-reactivity against other kallikreins. Assay precision within the dynamic range was <10%. These Little is known about the role of kallikreins in lung cancer. assays were standardized with recombinant proteins produced in yeast Thus far, most of the information related to kallikrein or mammalian expression systems. More details about the kallikrein expression in the lung was obtained by microarray analysis ELISA have recently been published (10). and real-time reverse transcription-PCR. For instance, micro- Statistical methods. The relationships between biomarkers and array profiling of human lung adenocarcinoma showed that tumor and patient characteristics were examined with the nonparamet- KLK11 is uniquely overexpressed in a subgroup (cluster C2) of ric Kruskal-Wallis test. Spearman’s rank correlation coefficient was used neuroendocrine tumors with less favorable outcome (5). to assess the correlations among biomarkers. Logistic regression was Another microarray-based study indicated that KLK5 and done to calculate the odds ratio (OR) to define the relation between KLK10 are overexpressed in the squamous cell lung carcinoma biomarkers and cancer status. ORs were calculated on log-transformed subtype (6). In addition, using quantitative real-time reverse biomarkers and were represented with their 95% confidence interval (95% CI) and two-sided P values. transcription-PCR, we previously reported a significant correla- KLK5 To evaluate the markers for disease screening and diagnosis, the tion between overexpression and the SCC histotype, as classification accuracy needs to be assessed. Here, we used receiver KLK7 well as a decrease of expression in lung adenocarcinoma, operating characteristic (ROC) curve, the most commonly used compared with adjacent nonmalignant lung tissues (7). summary of classification accuracy. The ROC curve is a plot of the Similarly, we identified only one transcript of KLK10 in lung true positive fraction versus the false positive fraction for the set of rules tissues
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