Gene Expression Profiles Predict Survival and Progression of Pleural Mesothelioma

Purpose: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages. Experimental Design: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip. Using both dChip and SAM, neural networks constructed a common 27 gene classifier, which was associated with either the high-risk and low-risk group of patients. Data were validated using real-time PCR and immunohistochemical staining. The 27 gene classifier was also used for validation in a separate set of 17 MPM patients from another institution. Results: The groups predicted by the gene classifier recapitulated the actual time to progression and survival of the test set with 95.2% accuracy using 10-fold cross-validation. Clinical outcomes were independent of histology, and heterogeneity of progression and survival in early stage patients was defined by the classifier. The gene classifier had a 76% accuracy in the separate validation set of MPMs. Conclusions: These data suggest that pretherapy gene expression analysis of mesothelioma biopsies may predict which patients may benefit from a surgical approach.

[1]  R. K. Bright,et al.  VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours , 1999, British Journal of Cancer.

[2]  V. Rusch.  A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. , 1995, Chest.

[3]  P. Khatri,et al.  Global functional profiling of gene expression. , 2003, Genomics.

[4]  G. Pilkington,et al.  Nm23: an invasion suppressor gene in CNS tumours? , 1998, Anticancer research.

[5]  F. Tas,et al.  Prognostic Role of nm23 Gene Expression in Patients With Ovarian Cancer , 2002, American journal of clinical oncology.

[6]  S. Steinberg,et al.  Simian virus-40 large-T antigen binds p53 in human mesotheliomas , 1997, Nature Medicine.

[7]  H. Wada,et al.  Clinical significance of nm23 expression in resected pathologic-stage I, non-small cell lung cancer. , 2002, The Annals of thoracic surgery.

[8]  S. Ramaswamy,et al.  Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. , 2002, Cancer research.

[9]  D. Choi,et al.  Role of the nm23-H1 gene in the metastasis of gastric cancer. , 1997, Journal of Korean medical science.

[10]  C. Moran,et al.  Pleural amyloidosis mimicking mesothelioma: a clinicopathologic study of two cases. , 2001, Annals of diagnostic pathology.

[11]  Rogier Versteeg,et al.  The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2 , 2002, Oncogene.

[12]  D. Sugarbaker,et al.  Multimodality treatment of diffuse malignant pleural mesothelioma. , 2002, Seminars in oncology.

[13]  S. Jhanwar,et al.  SV40 infection induces telomerase activity in human mesothelial cells , 2002, Oncogene.

[14]  Martin Kk,et al.  Nm23: an invasion suppressor gene in CNS tumours? , 1998 .

[15]  P. Khatri,et al.  Profiling gene expression using onto-express. , 2002, Genomics.

[16]  D. Roymans,et al.  Nucleoside diphosphate kinase (NDPK/NM23) and the waltz with multiple partners: Possible consequences in tumor metastasis , 2004, Clinical & Experimental Metastasis.

[17]  K. McPherson,et al.  An age, period and cohort analysis of pleural cancer mortality in Europe. , 2000 .

[18]  K. Sletten,et al.  Amyloid A in systemic amyloidosis associated with cancer. , 1982, Cancer research.

[19]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[20]  A. Gazdar,et al.  SV40 and human tumours: myth, association or causality? , 2002, Nature Reviews Cancer.

[21]  I. Selikoff,et al.  High frequency of immune dysfunctions in asbestos workers and in patients with malignant mesothelioma , 1986, Journal of Clinical Immunology.

[22]  P. Hasleton,et al.  Immunoreactivity for cadherins, HGF/SF, met, and erbB‐2 in pleural malignant mesotheliomas , 2000, Histopathology.

[23]  P. Khatri,et al.  Global functional profiling of gene expression ? ? This work was funded in part by a Sun Microsystem , 2003 .

[24]  C. Rubio,et al.  Expression of nm23 gene in gastric cancer is associated with a poor 5-year survival. , 2001, Anticancer research.

[25]  F. Galateau-Sallé,et al.  Expression of Telomerase Reverse Transcriptase (TERT) in Malignant Mesotheliomas , 2002, The American journal of surgical pathology.

[26]  Z. Liu,et al.  Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors , 2003, Thorax.

[27]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[28]  C. la Vecchia,et al.  An age, period and cohort analysis of pleural cancer mortality in Europe. , 2000, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[29]  G. Kayser,et al.  Glycohistochemical properties of malignancies of lung and pleura. , 1998, International journal of oncology.

[30]  S. Matsuda,et al.  In search of a function for the TIS21/PC3/BTG1/TOB family , 2001, FEBS letters.

[31]  Rolf Larsson,et al.  A New Antibody Recognizing the vIII Mutation of Human Epidermal Growth Factor Receptor , 2002, Tumor Biology.

[32]  M. McNally,et al.  A Cellular Protein, hnRNP H, Binds to the Negative Regulator of Splicing Element from Rous Sarcoma Virus* , 2000, The Journal of Biological Chemistry.

[33]  B. Honoré,et al.  Calumenin interacts with serum amyloid P component , 2000, FEBS letters.

[34]  G. Soda,et al.  NM23 expression as prognostic factor in colorectal carcinoma. , 2002, Il Giornale di chirurgia.

[35]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  V. Vallyathan,et al.  Diseases caused by asbestos: mechanisms of injury and disease development. , 2002, International immunopharmacology.

[37]  C. Porta,et al.  SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Blumenstock,et al.  Using gene expression ratios to predict outcome among patients with mesothelioma. , 2003, Journal of the National Cancer Institute.

[39]  J. Wilusz,et al.  DSEF-1 is a member of the hnRNP H family of RNA-binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro. , 1998, Nucleic acids research.

[40]  M. McNally,et al.  Efficient polyadenylation of Rous sarcoma virus RNA requires the negative regulator of splicing element. , 2002, Nucleic acids research.

[41]  M. Cerrito,et al.  Retinoic acid inhibits fibronectin and laminin synthesis and cell migration of human pleural mesothelioma in vitro. , 2002, Oncology reports.

[42]  I. Screpanti,et al.  retSDR1, a short-chain retinol dehydrogenase/reductase, is retinoic acid-inducible and frequently deleted in human neuroblastoma cell lines. , 2002, Cancer research.

[43]  Xianglin Shi,et al.  Diseases caused by silica: mechanisms of injury and disease development. , 2002, International immunopharmacology.

[44]  B. Mossman,et al.  Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. , 2002, Cancer research.