Comprehensive Genomic Analysis Reveals Clinically Relevant Molecular Distinctions between Thymic Carcinomas and Thymomas

Clinical Cancer Research - Tập 15 Số 22 - Trang 6790-6799 - 2009
Nicolas Girard1,2,3,4, Ronglai Shen1,2,3,4, Tianhua Guo1,2,3,4, Maureen F. Zakowski1,2,3,4, Adriana Heguy1,2,3,4, Gregory J. Riely1,2,3,4, James Huang1,2,3,4, Carmen Lau1,2,3,4, Alex E. Lash1,2,3,4, Marc Ladanyi1,2,4, Agnès Viale1,2,3,4, Cristina R. Antonescu1,2,3,4, William D. Travis1,2,3,4, Valerie W. Rusch1,2,3,4, Mark G. Kris1,2,4, William Pao1,4
1Authors' Affiliations: 1Human Oncology and Pathogenesis Program (HOPP); Departments of 2Epidemiology and Biostatistics, and 3Pathology, 4Geoffrey Beene Translational Oncology Core Facility; 5Thoracic Oncology Service, 6Thoracic Surgery Service, 7Computational Biology Program, and 8Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center; and 9Weill Medical College of Cornell University, New York, New York
2Authors' Affiliations:Human Oncology and Pathogenesis Program (HOPP)
3Departments of Epidemiology and Biostatistics, and Pathology, Geoffrey Beene Translational Oncology Core Facility
4Weill Medical College of Cornell University, New York, New York

Tóm tắt

Abstract Purpose: Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown. Experimental Design: All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays. Results: We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge. Conclusions: Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies. (Clin Cancer Res 2009;15(22):67909)

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Tài liệu tham khảo

de Jong, 2008, Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy, Eur J Cancer, 44, 123, 10.1016/j.ejca.2007.11.004

Girard, 2008, Thymoma: a focus on current therapeutic management, J Thorac Oncol, 4, 119, 10.1097/JTO.0b013e31818e105c

Eng, 2004, Thymic carcinoma: state of the art review, Int J Radiat Oncol Biol Phys, 59, 654, 10.1016/j.ijrobp.2003.11.021

Travis, 2004, WHO histological classification of tumours of the thymus, World Health Organization classification of tumours. pathology and genetics of tumours of the lung, pleura, thymus and heart, 146

Masaoka, 1981, Follow-up study of thymomas with special reference to their clinical stages, Cancer, 48, 2485, 10.1002/1097-0142(19811201)48:11<2485::AID-CNCR2820481123>3.0.CO;2-R

Blumberg, 1995, Thymoma: a multivariate analysis of factors predicting survival, Ann Thorac Surg, 60, 908, 10.1016/0003-4975(95)00669-C

Yoh, 2008, Mutational status of EGFR and KIT in thymoma and thymic carcinoma, Lung Cancer, 62, 316, 10.1016/j.lungcan.2008.03.013

Tsuchida, 2008, Absence of gene mutations in KIT-positive thymic epithelial tumors, Lung Cancer, 62, 321, 10.1016/j.lungcan.2008.03.035

Meister, 2007, Mutational status of the epidermal growth factor receptor (EGFR) gene in thymomas and thymic carcinomas, Cancer Lett, 248, 186, 10.1016/j.canlet.2006.07.003

Suzuki, 2006, Expression and mutation statuses of epidermal growth factor receptor in thymic epithelial tumors, Jpn J Clin Oncol, 36, 351, 10.1093/jjco/hyl028

Pan, 2004, KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas, J Pathol, 202, 375, 10.1002/path.1514

Tateyama, 1995, p53 protein expression and p53 gene mutation in thymic epithelial tumors. An immunohistochemical and DNA sequencing study, Am J Clin Pathol, 104, 375, 10.1093/ajcp/104.4.375

Strbel, 2004, Thymic carcinoma with overexpression of mutated KIT and the response to imatinib, N Engl J Med, 350, 2625, 10.1056/NEJM200406173502523

Li, 2009, Response to sorafenib in cisplatin-resistant thymic carcinoma: a case report, Med Oncol, 26, 157, 10.1007/s12032-008-9100-0

Chuah, 2006, Dasatinib induces a response in malignant thymoma, J Clin Oncol, 24, e56, 10.1200/JCO.2006.08.8963

Christodoulou, 2008, Response of malignant thymoma to erlotinib, Ann Oncol, 19, 1361, 10.1093/annonc/mdn388

Farina, 2007, Response of thymoma to cetuximab, Lancet Oncol, 8, 449, 10.1016/S1470-2045(07)70141-9

Zettl, 2000, Recurrent genetic aberrations in thymoma and thymic carcinoma, Am J Pathol, 157, 257, 10.1016/S0002-9440(10)64536-1

Chitale, An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors, Oncogene

Ding, 2008, Somatic mutations affect key pathways in lung adenocarcinoma, Nature, 455, 1069, 10.1038/nature07423

Korn, 2002, Identifying pre-post chemotherapy differences in gene expression in breast tumours: a statistical method appropriate for this aim, Br J Cancer, 86, 1093, 10.1038/sj.bjc.6600216

Guo, 2007, Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor, Clin Cancer Res, 13, 4874, 10.1158/1078-0432.CCR-07-0484

Henley, 2004, Tyrosine kinase receptor expression in thymomas, J Cancer Res Clin Oncol, 130, 222, 10.1007/s00432-004-0545-z

Nakagawa, 2005, Immunohistochemical KIT (CD117) expression in thymic epithelial tumors, Chest, 128, 140, 10.1378/chest.128.1.140

Heinrich, 2003, Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor, J Clin Oncol, 21, 4342, 10.1200/JCO.2003.04.190

Mol, 2003, Structure of a c-kit product complex reveals the basis for kinase transactivation, J Biol Chem, 278, 31461, 10.1074/jbc.C300186200

Daley, 1988, Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein, Proc Natl Acad Sci U S A, 85, 9312, 10.1073/pnas.85.23.9312

Heinrich, 2008, Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor, J Clin Oncol, 26, 5352, 10.1200/JCO.2007.15.7461

Sasaki, 2002, Gene expression analysis of human thymoma correlates with tumor stage, Int J Cancer, 101, 342, 10.1002/ijc.10624

Penzel, 2003, Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka, Int J Cancer, 105, 494, 10.1002/ijc.11101

Lee, 2007, Genome-wide genetic aberrations of thymoma using cDNA microarray based comparative genomic hybridization, BMC Genomics, 8, 305, 10.1186/1471-2164-8-305

Suzuki, 2005, Aberrant methylation: common in thymic carcinomas, rare in thymomas, Oncol Rep, 14, 1621

Kurup, 2005, Phase II study of gefitinib treatment in advanced thymic malignancies, J Clin Oncol, 23, 7068, 10.1200/jco.2005.23.16_suppl.7068

Pao, 2005, KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib, PLoS Med, 2, e17, 10.1371/journal.pmed.0020017

Karapetis, 2008, K-ras mutations and benefit from cetuximab in advanced colorectal cancer, N Engl J Med, 359, 1757, 10.1056/NEJMoa0804385

Quinlan, 2009, Isoform-specific ras functions in development and cancer, Future Oncol, 5, 105, 10.2217/14796694.5.1.105

Fasano, 1984, Analysis of the transforming potential of the human H-ras gene by random mutagenesis, Proc Natl Acad Sci U S A, 81, 4008, 10.1073/pnas.81.13.4008

Qin, 2006, Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells, Cancer Chemother Pharmacol, 58, 577, 10.1007/s00280-006-0219-4

Inoue, 2006, Gefitinib-related gene signature in bladder cancer cells identified by a cDNA microarray, Anticancer Res, 26, 4195

Bedano, 2008, A phase II trial of erlotinib plus bevacizumab in patients with recurrent thymoma or thymic carcinoma, J Clin Oncol, 26, 19087, 10.1200/jco.2008.26.15_suppl.19087

Giaccone, 2008, Phase II study of imatinib in patients with WHO B3 and C thymomas, J Clin Oncol, 26, 14665, 10.1200/jco.2008.26.15_suppl.14665

Bisagni, 2009, Long lasting response to the multikinase inhibitor bay 43-9006 (Sorafenib) in a heavily pretreated metastatic thymic carcinoma, J Thorac Oncol, 4, 773, 10.1097/JTO.0b013e3181a52e25

Antonescu, 2005, Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation, Clin Cancer Res, 11, 4182, 10.1158/1078-0432.CCR-04-2245

Antonescu, 2007, L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition, Int J Cancer, 121, 257, 10.1002/ijc.22681

Salter, 2008, Imatinib for the treatment of thymic carcinoma, J Clin Oncol, 26, 8116, 10.1200/jco.2008.26.15_suppl.8116

Carvajal, 2009, A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT, J Clin Oncol, 27, 9001, 10.1200/jco.2009.27.15_suppl.9001

Sasaki, 2003, Glycosylphosphatidyl inositol-anchored protein (GPI-80) gene expression is correlated with human thymoma stage, Cancer Sci, 94, 809, 10.1111/j.1349-7006.2003.tb01523.x

Fujita, 1999, Comprehensive analysis of p53 gene mutation characteristics in lung carcinoma with special reference to histological subtypes, Int J Oncol, 15, 927

Suster, 1999, Thymoma, atypical thymoma, and thymic carcinoma. A novel conceptual approach to the classification of thymic epithelial neoplasms, Am J Clin Pathol, 111, 826, 10.1093/ajcp/111.6.826

Marchevsky, 2008, Evidence-based pathology and the pathologic evaluation of thymomas: the World Health Organization classification can be simplified into only 3 categories other than thymic carcinoma, Cancer, 112, 2780, 10.1002/cncr.23492

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Clinical Cancer Research

Tập 15 Số 22

6790-6799

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