Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction

Abstract

Most gene expression profiling studies of mesothelioma have been based on relatively small sample numbers, limiting their statistical power. We did Affymetrix U133A microarray analysis on 99 pleural mesotheliomas, in which multivariate analysis showed advanced-stage, sarcomatous histology and P16/CDKN2A homozygous deletion to be significant independent adverse prognostic factors. Comparison of the expression profiles of epithelioid versus sarcomatous mesotheliomas identified many genes significantly overexpressed among the former, including previously unrecognized ones, such as uroplakins and kallikrein 11, both confirmed by immunohistochemistry. Examination of the gene expression correlates of survival showed that more aggressive mesotheliomas expressed higher levels of Aurora kinases A and B and functionally related genes involved in mitosis and cell cycle control. Independent confirmation of the negative effect of Aurora kinase B was obtained by immunohistochemistry in a separate patient cohort. A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors. We then used our data to develop microarray-based predictors of 1 year survival; these achieved a maximal accuracy of 68% in cross-validation. However, this was inferior to prognostic prediction based on standard clinicopathologic variables and P16/CDNK2A status (accuracy, 73%), and adding the microarray model to the latter did not improve overall accuracy. Finally, we evaluated three recently published microarray-based outcome prediction models, but their accuracies ranged from 63% to 67%, consistently lower than reported. Gene expression profiling of mesotheliomas is an important discovery tool, but its power in clinical prognostication has been overestimated.

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

“…40,41 Despite the differences between peritoneal and pleural mesotheliomas, previous studies have demonstrated homozygous CDKN2A deletions in malignant mesothelioma are a poor prognostic indicator regardless of site. 22,25,32 Consistent with these reports, we found that patients with peritoneal mesothelioma harboring a homozygous CDKN2A deletion had decreased PFS and OS. In addition, patients with a hemizygous NF2 loss also exhibited poor PFS and OS.…”

“…[21][22][23] In addition, homozygous CDKN2A deletions are a poor prognostic indicator for patients with pleural mesothelioma. 22,24,25 NF2, located on chromosome 22q12, is mutated in 50% of pleural mesotheliomas with corresponding loss of the wild-type allele by deletion of either 22q or all of chromosome 22. 16,26 Hemizygous loss of NF2 is associated with increased mesothelioma proliferation, invasiveness, spreading, and migration.…”

Eighth International Mesothelioma Interest Group

“…These data are in contrast to those of M Ladanyi's laboratory (USA), who found that the accuracy of these microarrays is consistently lower than reported by Bueno and by others, and that their power in clinical prognostication has been overestimated (Lopez-Rios et al, 2006). JR Testa and colleagues (USA) exposed heterozygous Nf2 knockout mice to asbestos by intraperitoneal injection.…”

Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas

“…24 One of the most common genetic alterations in mesothelioma is the homozygous deletion of the 9p21 locus within a cluster of genes that includes CDKN2A, CDKN2B and MTAP. [25][26][27][28] Several cytogenetic and molecular studies have reported p16/ CDKN2A deletions in up to 72% of primary mesotheliomas. 29,30 Thus, detection of homozygous p16/ CDKN2A deletion by fluorescence in situ hybridization (FISH) seems to be feasible and helpful in confirming a diagnosis of mesothelioma in cytologic and surgical specimens.…”