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Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors

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Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors Published OnlineFirst February 26, 2013; DOI: 10.1158/1078-0432.CCR-12-3260 Clinical Cancer Human Cancer Biology Research Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors Iacopo Petrini1, Yisong Wang1, Paolo A. Zucali3, Hye Seung Lee1,4, Trung Pham1, Donna Voeller1, Paul S. Meltzer2, and Giuseppe Giaccone1 Abstract Purposes: To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET). Experimental Design: Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients’ outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors. Results: Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors, respectively. Immunohistochemistry on a series of 132 TETs, including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1- negative tumors had a shorter time to progression and a trend for a shorter disease-related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro. Conclusion: Our data support a tumor suppressor role of FOXC1 in TETs. Clin Cancer Res; 19(8); 1– 12. Ó2013 AACR. Introduction myasthenia gravis being the most common (1). Surgery Thymic epithelial tumors (TET) are a group of rare represents the mainstay of treatment for thymic malignan- neoplasms with heterogeneous histologic features and clin- cies, and prognosis is significantly influenced by pathologic ical behavior. Thymic carcinomas are aggressive tumors that stage and by completeness of tumor resection (2). Meta- microscopically remind the features of carcinomas of other static and nonresectable TETs are candidates for systemic organs (1). On the contrary, the histologic appearance of therapy. Although, combination chemotherapy is able to thymomas resembles the structure of normal thymus and induce substantial tumor shrinkage of variable duration, it these tumors are grouped into 5 subcategories (A, AB, B1, is not curative in patients with metastatic disease (2). There B2, B3), depending on their cancer cell shape, degree of is very little understanding of the biology of these neo- atypia, and number of intratumoral thymocytes, according plasms and molecular prognostic markers, and specific to the most recent World Health Organization (WHO) targets for therapy have so far not been identified. classification (1). Thymomas, but not thymic carcinomas, Tumor cells share many stem cell-like properties with are frequently associated with paraneoplastic syndromes: embryonic cells, and the ectopic reactivation of embryo- restricted genes is observed during the neoplastic progres- sion (3). Several cell lineage-specific transcription factors, Authors' Affiliations: 1Medical Oncology Branch; 2Genetics Branch, implicated in organogenesis, have been found to be ectop- National Cancer Institute, NIH, Bethesda, Maryland; 3Department of Med- ically reactivated by copy number aberrations in cancers, ical Oncology, Humanitas Cancer Center, IRCCS, Rozzano, Milan, Italy; and 4Department of Pathology, Seoul National University Bundang Hos- including NKX2-1 (TITF) in lung cancer (4–8), ESR1 in pital, Seongnam-si (Gyeonggi), Republic of Korea breast cancer (9), GATA6 in pancreatic cancer (10), and Note: Supplementary data for this article are available at Clinical Cancer MITF in melanoma (11). Research Online (http://clincancerres.aacrjournals.org/). The role of thymic developmental genes in TETs has not Corresponding Author: Giuseppe Giaccone, Medical Oncology Branch, been explored to date. Thymic epithelial cells originate from National Cancer Institute, 10 Center Drive, Bethesda, MD 20892. Phone: the endoderm of the third pharyngeal pouch (12). Finely 301-402-3415; Fax 301-402-0172; E-mail: [email protected] spatiotemporally regulated waves of proliferation and dif- doi: 10.1158/1078-0432.CCR-12-3260 ferentiation of thymic epithelial cell precursors are neces- Ó2013 American Association for Cancer Research. sary for the normal maturation of the thymus as well as www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst February 26, 2013; DOI: 10.1158/1078-0432.CCR-12-3260 Petrini et al. tion, R1 ¼ microscopic residual disease infiltrating resection Translational Relevance margins, and R2 ¼ macroscopic residual disease (16). An Thymic epithelial tumors (TET) are a group of neo- experienced thoracic tumor pathologist (H.S. Lee; Seoul plasms with heterogeneous histologic features and clin- National University Bundang Hospital, South Korea) ical behavior. The identification of markers useful to reviewed the retrieved material for the amount of tumor predict patient prognosis and molecular targets for ther- content, adequate storage, and classified the TETs according apies is limited by a very little understanding of the to the 2004 WHO classification (1). biology of these neoplasms. We evaluated the copy Confirmation cohort. Frozen TET samples from 27 number aberrations of genes involved in normal thymus patients were collected at National Cancer Institute (NCI; development in TETs, following the intriguing idea that Bethesda, MD). Characteristics of patients are summarized the ectopic deregulation of genes relevant for prolifera- in Table 1. tion and differentiation of embryonic cells, can contrib- ute to tumor growth. Frequent copy number losses of Nucleic acid extraction and array CGH FOXC1 were observed in more aggressive tumors and Because of the heterogeneity of the histologic features and correlated with a reduced protein expression; tumors the presence of non-neoplastic intratumoral thymocytes, negative for FOXC1 expression were associated with a only 59 tumor samples containing at least 80% of tumor shorter time to progression. In addition, FOXC1 showed cells were selected for array CGH, as assessed by hematox- tumor suppressor activity in in vitro models. Our data ylin and eosin (H&E)-stained slides. indicate that FOXC1 loss can identify a group of TETs Frozen tumors were embedded in optimal cutting tem- with poor prognosis, possibly because of its tumor perature and 8 mm slides were cut in a À20C cryostat. Slides suppressor properties. were stained with H&E, and sample regions with more than 80% of tumor cells were macrodissected for nucleic acid extraction. From FFPE samples, DNA was extracted using DNeasy interactions with thymic septum cells of neural crest origin kit (Qiagen Inc.). Both RNA and DNA were extracted and lymphocyte precursors (thymocytes; ref. 13). To effi- from cell lines and frozen tumors using AllPrep DNA/ ciently sustain this process, genes controlling the cell pro- RNA Mini Kit (Qiagen). CGH was conducted using Agi- liferation need to be expressed or repressed at precise lent platform according to Genomic DNA ULS labeling moments of the development of thymic epithelial cells (13). kit protocol (Agilent Technologies Inc.) as previously We conducted array comparative genomic hybridization extensively described elsewhere (17). Twenty samples (CGH) in TETs to determine the copy number status of from FFPE were hybridized on Human Genome CGH genes involved in thymus development. Interestingly, Array 105A (Agilent) and the remaining on SurePrint G3 FOXC1 and PBX1, two transcription factors that regulate Human CGH Array 180K (Agilent). Frequency of copy TBX1 expression, were frequently included in regions of number aberrations was inferred using Nexus Copy Num- copy number loss and copy number gain, respectively. We ber6(BiodiscoveryInc.).Microarraydatahavebeen suggest that FOXC1 presents tumor suppressor-like activity, deposited in gene expression omnibus repository with and loss of FOXC1 expression correlates with poorer time to the number: GSE23540. progression (TET) in patients with TET. Copy number and real-time PCR Materials and Methods Copy number PCR was adopted to confirm CGH results in Our Institution Ethical Review Boards approved this a subset of tumors. Real-time PCR (RT-PCR) was used for research (ClinicalTrials.gov ID: NCT00965627). The study the evaluation of TBX1, PBX1, and FOXC1 gene expression has been conducted in agreement with the Declaration of in TET frozen tumors and cell lines. TaqMan gene expres- Helsinki. sion assay primers were purchased from Applied Biosys- tems. RPLP0 and RPPH1 genes were used as endogenous Patients and samples controls for mRNA expression and gene copy number valid- Cohort 1. Clinical data and formalin-fixed paraffin- ation, respectively. RT-PCRs were operated on ABI 7900HT embedded (FFPE) samples were collected from a series of Fast RT-PCR System (Applied Biosystems). Fold change ÀDC 132 consecutive patients who underwent surgery for TET at of mRNA expression was calculated by 2 t method, and the Istituto Clinico Humanitas (Rozzano-Milan, Italy) in gene copy number was determined by CopyCaller
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