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Identification of Carboxypeptidase E and -Glutamyl Hydrolase As Identification of Carboxypeptidase E and ␥-Glutamyl Hydrolase as Biomarkers for Pulmonary Neuroendocrine Tumors by cDNA Microarray PING HE, MD, LYUBA VARTICOVSKI, MD, ELISE D. BOWMAN, MS, JUNYA FUKUOKA, MD, JUDITH A. WELSH, BS, KOH MIURA, MD, JIN JEN, PHD, EDWARD GABRIELSON, MD, ELISABETH BRAMBILLA, MD, WILLIAM D. TRAVIS, MD, AND CURTIS C. HARRIS, MD Pulmonary neuroendocrine tumors vary dramatically in their tidase E (CPE) and ␥-glutamyl hydrolase (GGH), was validated by malignant behavior. Their classification, based on histological exam- immunohistochemistry and cross-validated on additional archival ination, is often difficult. In search of molecular and prognostic samples of pulmonary neuroendocrine tumors. Kaplan-Meier survival markers for these tumors, we used cDNA microarray analysis of analysis revealed that immunostaining for CPE was a statistically human transcripts against reference RNA from a well-characterized significant predictor of good prognosis, whereas GGH expression immortalized bronchial epithelial cell line, BEAS-2B. Tumor cells correlated with poor prognosis. Thus, cDNA microarray analysis led were isolated by laser-capture microdissection from primary tumors to the identification of 2 novel biomarkers that should facilitate of 17 typical carcinoids, small cell lung cancers, and large cell neu- molecular diagnosis and further study of pulmonary neuroendocrine roendocrine carcinomas. An unsupervised, hierarchical clustering tumors. HUM PATHOL 35:1196-1209. © 2004 Elsevier Inc. All rights algorithm resulted in a precise classification of each tumor subtype reserved. according to the proposed histological classification. Selection of Key words: atypical carcinoid, biomarkers, carboxypeptidase E, genes, using supervised analysis, resulted in the identification of 198 ␥-glutamyl hydrolase, gene pulmonary neuroendocrine tumors. statistically significant genes (P <.004) that also accurately discrimi- Abbreviations: ABC, avidin-biotin-peroxidase complex; AC, atyp- nated between 3 predefined tumor subtypes. Two-by-two compari- ical carcinoid; CPE, carboxypeptidase E; GGH, ␥-glutamyl hydrolase; sons of these genes identified classifier genes that distinguished each IHC, immunohistochemistry; LCM, laser capture microdissection; tumor subtype from the others. Changes in expression of selected LCNEC, large cell neuroendocrine carcinoma; NE, neuroendocrine; differentially expressed genes for each tumor subtype were internally PBS, phosphate-buffered saline; RT-PCR, reverse-transcription poly- validated by real-time reverse-transcription polymerase chain reac- merase chain reaction; SCLC, small cell lung cancer; TC, typical tion. Expression of 2 potential classifier gene products, carboxypep- carcinoid. Lung cancer continues to be the leading cause of low-grade typical carcinoid (TC), intermediate-grade cancer-related deaths worldwide. The high incidence atypical carcinoid (AC), high-grade large cell neuroen- and mortality reflect continued exposure to cigarette docrine carcinoma (LCNEC), and small cell lung can- smoking, lack of effective methods for early diagnosis, cer (SCLC).1 TC, AC, and LCNEC collectively comprise and inadequate markers of aggressive lung cancer only 3%-5% of all pulmonary malignancies, whereas types. Pulmonary neuroendocrine (NE) tumors ac- SCLC accounts for 15%-25%. The prognostic relevance count for 20% to 30% of lung cancer cases and include of pulmonary NE tumors has changed substantially since the recognition of the LCNEC subtype,2 because pulmonary NE tumors vary significantly in their malig- nant behavior. The 5-year survival rates for TC, AC, From the Laboratory of Human Carcinogenesis, National Can- cer Institute, National Institutes of Health, Bethesda, MD; Depart- LNEC, and SCLC are 87%, 56%, 27%, and 9%, respec- ment of Pulmonary and Mediastinal Pathology, Armed Forces Insti- tively. These tumors have a similar morphological ap- tute of Pathology, Washington, DC, USA; Division of Hematology, pearance, with organoid, trabecular or rosette-like pat- Center for Biologics Evaluation and Research, Food and Drug Ad- terns, and common neuroendocrine markers ministration, Bethesda, MD, USA; Department of Surgery, Tohoku University Postgraduate School of Medicine, Sendai, Japan; Labora- detectable by immunohistochemistry: chromogranin A, tory of Population Genetics, National Cancer Institute, National In- synaptophysin, and neural cell adhesion molecule stitutes of Health, Bethesda, MD, USA; Department of Pathology, (NCAM, CD56). In some cases, electron microscopy Johns Hopkins University, Baltimore, MD USA; and Laboratory of analysis is also required for the detection of neuroen- Cellular Pathology, Grenoble, France. Accepted for publication June docrine granules. The current treatment for patients 18, 2004. with TC and AC is surgical resection, because these Address correspondence and reprint requests to Curtis C. Har- tumors grow relatively slowly and are frequently de- ris, MD, Chief, Laboratory of Human Carcinogenesis, National Can- tected as solitary pulmonary lesions. Surgical resection cer Institute, National Institutes of Health, 37 Convent Drive, Bldg. is feasible in less than 1/3 of LCNEC patients with or 37, Rm. 3068, Bethesda, MD 20892-4255. 3 0046-8177/$—see front matter without neoadjuvant treatment. Unfortunately, at the © 2004 Elsevier Inc. All rights reserved. time of diagnosis, the vast majority of SCLC is dissem- doi:10.1016/j.humpath.2004.06.014 inated, and prognosis is poor. Thus, accurate and 1196 BIOMARKERS FOR PULMONARY NEUROENDOCRINE TUMORS (He et al) timely diagnosis of pulmonary NE tumor subtypes is and gel electrophoresis. Purified RNA was dissolved into 11 essential for the selection of appropriate treatment and ␮L of diethyl polycarbonate–treated water and used for am- prediction of clinical outcome. plification. The amplified RNA was subjected to cDNA mi- DNA microarray technology provides a powerful croarray analysis. tool for analyzing changes in gene expression.4,5 Appli- cation of this technology to human lung cancer facili- Tissue Culture tates the characterization of gene expression pro- files.6-10 However, very few have led to the identification The reference cell line, BEAS-2B, derived from normal human bronchial epithelium, was immortalized by SV40.12 of molecular markers that can aid in the diagnosis and Cells were cultured in a serum-free medium, LHC-9, and prognosis of lung cancer. There are no molecular harvested at passage 30. Total RNA was isolated from cultured markers that distinguish among the subtypes of pulmo- cells using the Micro RNA isolation kit (Stratagene) accord- nary NE tumors. In addition, the generation of a ge- ing to the manufacturer’s instructions. nome-wide expression profile requires a large dataset with multiple samples. This is difficult to obtain for many primary tumors, especially those that rarely un- RNA Amplification dergo an open resection, including SCLC. RNA amplification was performed as described by Luo et Using laser capture microdissection (LCM)11 and al.13 Briefly, oligo (dT) primers with T7 promoter sequence, cDNA microarray from a limited number of pulmonary 5'-TCTAGTCGACGGCCAGTGAATTGTAATACGAC-TCAC- neuroendocrine tumor samples, we have identified 198 TATAGGGCG(T)21-3', were used to synthesize the first strand genes that are differentially expressed in pulmonary NE of cDNA. After the second strand of cDNA synthesis, RNA was amplified using T7 RNA polymerase on the cDNA templates. tumors by comparing tumor gene expression profiles ␮ with a reference RNA from a human immortalized Two rounds of amplification, starting with 1 g of total RNA, generated 40 to 60 ␮g of amplified RNA, which was used for bronchopulmonary cell line with NE features. The RNA microarray analysis. changes of 2 candidate genes, CPE and GGH, were cross-validated by immunohistochemistry (IHC) on 55 cases of pulmonary NE tumors, and their expression Microarray, Hybridization, and Analysis was correlated with clinical outcome. The cDNA microarray contained 9180 cDNA clones based on the Hs Unigene build #131 platform. This total comprised 7102 “named” genes, 1179 expressed sequence tag MATERIALS AND METHODS (EST) clones, and 122 Incyte clones per slide. The slides were Tissue Samples printed by the National Cancer Institute (NCI) Microarray Facility, Advanced Technology Center, Gaithersburg, MD. Fresh-frozen tissues of 17 primary pulmonary NE tumors RNA (8 ␮g), amplified from the BEAS-2B reference cell line, (11 TC, 2 LCNEC, 3 SCLC, and 1 with combined features of was labeled with Cy5-dUTP. Amplified RNA (4 ␮g each) from SCLC and LCNEC) were collected from hospitals in Balti- tumors was labeled with Cy3-dUTP using Superscript II (In- more and Maryland metropolitan areas over an 11-year pe- vitrogen, Carlsbad, CA). Briefly, RNA was incubated with riod. Tissues were flash-frozen after surgery and stored at Cy3-dUTP or Cy5-dUTP (Perkin Elmer Life Sciences, Boston, Ϫ80°C until used. Histopathologic classification of these tu- MA) at 42°C for 1 hour to synthesize the first strand cDNA. mors was based on the 1999 World Health Organization/ The reaction was stopped by the addition of 5 ␮L .5 mmol LASLSC “histological typing of lung and pleural tumors” EDTA, and the RNA was degraded by the addition of 10 ␮L proposed by Travis et al.1,2 Additional samples used for IHC 1N NaOH and then incubated at 65°C for 1 hour. After were obtained from the Laboratory of Cellular Pathology, neutralizing, the samples were purified by Microcon 30 (Mil- Grenoble, France and the Department of Pathology,
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